GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P24385	Q96PU4	ubiquitination	down-regulates quantity by destabilization	0.294	We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1.	SIGNOR-271885
Q9ULW0	P24941	phosphorylation	down-regulates activity	0.294	In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. \|Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle	SIGNOR-265099
O14733	O43379	relocalization	up-regulates activity	0.294	In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis	SIGNOR-271716
Q9Y6K1	Q03112	binding	up-regulates activity	0.293	The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA\|Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro.	SIGNOR-273432
O43318	P22607	phosphorylation	up-regulates activity	0.293	Indeed, we found that TAK1 was tyrosine phosphorylated in HEK293 cells transiently expressing constitutively active FGFR3 (K650E), but not the kinase-dead receptor (K508M), indicating that activated FGFR3 can either directly or indirectly tyrosine phosphorylate TAK1 (XREF_FIG).	SIGNOR-279176
P63096	P28335	binding	up-regulates activity	0.293	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256734
P04406	Q13131	phosphorylation	up-regulates activity	0.293	Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated.	SIGNOR-259857
O14983	P16157	binding	down-regulates activity	0.293	We recently reported that small ankyrin 1 (sAnk1) interacts with the sarco(endo)plasmic reticulum Ca2+-ATPase in skeletal muscle (SERCA1) to inhibit its activity.	SIGNOR-265927
P54762	Q969H4	binding	up-regulates activity	0.293	The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration.	SIGNOR-275921
P99999	P31751	phosphorylation	down-regulates activity	0.293	Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.	SIGNOR-277236
O60716	P27361	phosphorylation	down-regulates activity	0.293	Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation.	SIGNOR-277506
P22415	P78527	phosphorylation	up-regulates	0.293	Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation.	SIGNOR-184849
P04275	P29122	cleavage	up-regulates activity	0.293	Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine	SIGNOR-260367
P00533	Q32MZ4	transcriptional regulation	down-regulates quantity by repression	0.293	GC-binding factor 2 (GCF2) is a transcriptional repressor that decreases activity of the epidermal growth factor receptor (EGFR) and other genes. \|Deletion mutants of GCF2 revealed that amino acids 429–528 are required for both DNA binding and repression of the EGFR promoter.	SIGNOR-266057
P30622	P68400	phosphorylation	up-regulates	0.293	Herein, we have identified polo-like kinase 1 (plk1) and casein kinase 2 (ck2) as two kinases of clip-170 and mapped s195 and s1318 as their respective phosphorylation sites.Plk1- and ck2-associated phosphorylations of clip-170 are involved in the timely formation of kinetochore-microtubule attachments in mitosis	SIGNOR-167168
Q96MT3	Q8N4C8	phosphorylation	up-regulates activity	0.293	We show that Mink1 phosphorylates Prickle on a conserved threonine residue and regulates its Rab5-dependent endosomal trafficking, a process required for the localized plasma membrane accumulation and function of Prickle.	SIGNOR-263095
O00213	P49841	phosphorylation	up-regulates quantity	0.293	In this regards, GSK3beta may promote amyloidogenic processing of APP by regulating the cellular level of monomeric FE65 for the formation of LRP1, FE65, and APP complex.\|In this study, we showed that FE65 is phosphorylated at T579 by GSK3beta.	SIGNOR-278359
Q9HBW0	Q8WWY8	binding	up-regulates	0.293	When overexpressed in jurkat t cells, the edg4 protein mediated lpa-induced activation of a serum response element reporter gene with lpa concentration dependence (ec50 of 10 nm) and specificity.	SIGNOR-56093
Q5JVS0	P05129	phosphorylation	down-regulates activity	0.293	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249255
Q14524	P06241	phosphorylation	down-regulates	0.293	This study addresses the effects of the src family tyrosine kinase fyn on na(v)1.5 cardiac sodium channels. Sodium currents were acquired by whole cell recording on hek-293 cells transiently expressing na(v)1.5. Acute treatment of cells with insulin caused a depolarizing shift in steady-state inactivation, an effect eliminated by the src-specific tyrosine kinase inhibitor pp2 we provide evidence that this linker is a substrate for fyn in vitro, and that y1495 is a preferred phosphorylation site.	SIGNOR-135600
Q8IXJ6	Q13627	phosphorylation	up-regulates activity	0.293	This Minibrain/Dyrk1a kinase phosphorylates and activates the Silent information regulator 2/Sirtuin1 deacetylase, which in turn deacetylates and activates the FOXO transcription factor.	SIGNOR-279990
Q13887	P04150	transcriptional regulation	up-regulates quantity by expression	0.292	We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα	SIGNOR-256118
Q13131	P31749	phosphorylation	down-regulates activity	0.292	It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase.	SIGNOR-252739
P35226	P31751	phosphorylation	up-regulates activity	0.292	the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate	SIGNOR-249582
Q5JVS0	Q05513	phosphorylation	down-regulates activity	0.292	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249257
Q14332	Q9ULT6	ubiquitination	down-regulates	0.292	Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6.	SIGNOR-197417
P50549	P17612	phosphorylation	up-regulates activity	0.292	The camp-dependent protein kinase a (pka) phosphorylates er81 on ser(191)/ser(216)ser(191) and ser(216), were identified, whose mutation to alanine reduces er81 activity upon erk-mapk stimulation.	SIGNOR-92447
P51795	Q96PU5	ubiquitination	down-regulates quantity by destabilization	0.292	The presence of albumin triggers the formation of an endocytic complex that includes ClC-5. (iii) Nedd4-2 is recruited to this complex and ubiquitinates ClC-5. This ubiquitination by Nedd4-2 shunts ClC-5 into the albumin uptake/degradative pathway.	SIGNOR-272665
Q13164	P15056	phosphorylation	up-regulates quantity	0.292	Our data indicate that oncogenic BRAF increases ERK5 protein level, phosphorylation at several residues and kinase activity.\|Overexpression of oncogenic BRAF induced ERK5 phosphorylation at Thr218 and Tyr220, although to a lower level than that induced by MEK5DD.	SIGNOR-278353
Q9P0J1	P11362	phosphorylation	down-regulates activity	0.292	Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.	SIGNOR-276640
Q9UMX1	Q9UKB1	binding	up-regulates	0.292	We found that in vitro-translated 35s- labeled slimb indeed specifically bound to su(fu) in the gst pull-down assay. In our functional gli reporter assay, slimb alone did not alter gli-induced reporter expression;however, when cotransfected with hsu(fu), slimb significantly potentiated the inhibitory effect of su(fu) on gli activity.	SIGNOR-72240
P63096	P29275	binding	up-regulates activity	0.292	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257039
P38405	P33032	binding	up-regulates activity	0.292	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256941
P35498	Q96PU5	ubiquitination	down-regulates quantity by destabilization	0.292	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253457
P04629	P12931	phosphorylation	up-regulates activity	0.292	Direct phosphorylation of TrkA by Src family kinases has been demonstrated in vitro, and our studies suggest that Src may lead to selective activation of TrkA.	SIGNOR-279291
P63092	P24530	binding	up-regulates activity	0.292	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256781
P60709	P12277	relocalization	up-regulates quantity	0.292	In summary, data presented here strongly suggest that locally generated ATP is an important regulator for actin-based cytoskeletal dynamics involved in cell extension and motility and that CK-B is a controlling enzyme in the compartmentalization of ATP availability. CK-B co-localizes with cortical actin and facilitates spreading of astrocytes	SIGNOR-265791
P31277	P09429	binding	up-regulates activity	0.292	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-240559
P25815	Q9UNE7	polyubiquitination	down-regulates quantity by destabilization	0.292	S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.	SIGNOR-272919
P28358	P09429	binding	up-regulates activity	0.292	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-240556
P36888	P06241	phosphorylation	up-regulates activity	0.292	FYN phosphorylates FLT3 on tyrosine residues (A\u2013B) COS1 cells were transfected with plasmids expressing FLT3 wild-type and FYN wild-type or mutants.\|It was not completely unexpected that FYN associates wild-type FLT3 in the absence of ligand stimulation in COS-1 cells, as overexpression of wild-type FLT3 results in ligand independent activation of FLT3 (data not shown).	SIGNOR-279715
Q01094	P27361	phosphorylation	up-regulates	0.292	Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1	SIGNOR-121991
P63000	Q38SD2	phosphorylation	up-regulates activity	0.292	In vitro kinase assays confirmed that recombinant Lrrk1 phosphorylated RAC1-GST protein, and immunoprecipitation showed that the interaction of Lrrk1 with RAC1 occurred within 10 min after RANKL treatment.\|Lrrk1 phosphorylates and activates RAC1 and Cdc42 small GTPase proteins in osteoclasts.	SIGNOR-279626
P24941	P35813	dephosphorylation	down-regulates activity	0.292	Moreover, purified recombinant PP2C alpha and PP2C beta 2 proteins efficiently dephosphorylated monomeric Cdk2/Cdk6 in vitro.	SIGNOR-277107
P29317	Q15418	phosphorylation	up-regulates activity	0.292	These comprehensive analyses indicate that high matrix stiffness activates ERK/RSK1-mediated EPHA2 non-canonical signalling to induce LYN activation, TWIST1 nuclear localization, and cell invasion (Fig. 6M).\|We next knocked down the most abundant RSK family members and found that loss of RSK1, but not RSK2 or RSK3, drastically inhibited EPHA2 S897 phosphorylation, prevented ECM stiffness-induced LYN activation and recruitment to EPHA2, and inhibited cell EMT and invasion induced by increasing rigidities (Fig. 6F\u2013I and S6H\u2013L).	SIGNOR-280113
P49715	P35712	transcriptional regulation	up-regulates quantity by expression	0.292	We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST	SIGNOR-255824
O75364	Q9H334	transcriptional regulation	up-regulates quantity by expression	0.292	We identified FoxP1 as a novel marker for midbrain dopamine neurons. Enforced expression of FoxP1 in embryonic stem cells actuates the expression of Pitx3, a homeobox protein that is exclusively expressed in midbrain dopaminergic neurons and is required for their differentiation and survival during development and from embryonic stem cells in vitro. We show that FoxP1 can be recruited to the Pitx3 locus in embryonic stem cells and regulate Pitx3 promoter activity in a dual-luciferase assay.	SIGNOR-269049
P15172	P26651	post transcriptional regulation	down-regulates quantity by destabilization	0.292	The TTP binding site in the 3â€² UTR of MyoD would permit TTP-mediated mRNA decay	SIGNOR-253597
O00141	P51608	transcriptional regulation	down-regulates quantity by repression	0.292	These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress.	SIGNOR-264543
Q8IXJ6	P12931	phosphorylation	down-regulates quantity by destabilization	0.291	In this study, we investigated the potential regulation of SIRT2 function by c-Src. We found that the protein levels of SIRT2 were decreased by c-Src, and subsequently rescued by the addition of a Src specific inhibitor, SU6656, or by siRNA-mediated knockdown of c-Src. The c-Src interacts with and phosphorylates SIRT2 at Tyr104.	SIGNOR-263104
Q8WYL5	Q9BZL6	phosphorylation	down-regulates	0.291	Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1.	SIGNOR-173441
Q05397	Q13164	phosphorylation	up-regulates activity	0.291	Remarkably, the reduction in ERK5 expression correlated with decreased p-FAK(Tyr397) staining, consistent with the requirement of ERK5 for mediating FAK activation in vivo (Fig. 6C).\|We confirmed that JWG-045, a novel pharmacological inhibitor of ERK5 exhibiting significantly reduced affinity for BRD4 compared with XMD8-92 (25, 26), did not suppress FAK phosphorylation at Tyr397 in MDA-MB-231 cells (Supplementary Fig. S3B and C).	SIGNOR-279304
Q9NZH5	P06493	phosphorylation	up-regulates activity	0.291	HPTTG is phosphorylated by Cdc2 at Ser165. we show that hPTTG is phosphorylated during mitosis. The direct phosphorylation of hPTTG by Cdc2 is interesting in itself since the substrates of this master mitotic kinase are supposed to play important roles in the initiation and progression of mitosis.	SIGNOR-262700
P04150	P24941	phosphorylation	up-regulates activity	0.291	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.\|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-249427
P36894	O95476	binding	up-regulates	0.291	We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors (bmprs). Dullard preferentially complexes with the bmp type ii receptor (bmprii) and partially colocalizes with the caveolin-1-positive compartment, suggesting that dullard promotes bmpr degradation via the lipid raft-caveolar pathway	SIGNOR-150998
P63092	P25100	binding	up-regulates activity	0.291	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256808
P34897	P01106	transcriptional regulation	up-regulates quantity by expression	0.291	Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis	SIGNOR-267380
Q08999	O43524	transcriptional regulation	up-regulates quantity	0.291	Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression.	SIGNOR-238606
Q969H0	O00141	phosphorylation	up-regulates	0.291	Here, we report that the serum- and glucocorticoid-inducible protein kinase sgk1 remarkably reduced the protein stability of the active form of notch1 through fbw7activated sgk1 phosphorylated fbw7 at serine 227	SIGNOR-170404
P43405	P46934	polyubiquitination	down-regulates quantity by destabilization	0.291	The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is implicated in the maintenance of viral latency and appears to function in part by inhibiting B-cell receptor (BCR) signaling. LMP2A enhances Lyn and Syk ubiquitination in vivo in a fashion that depends on the activity of Nedd4 family members and correlates with destabilization of the Lyn tyrosine kinase. These results suggest that LMP2A serves as a molecular scaffold to recruit both B-cell tyrosine kinases and C2/WW/Hect domain E3 protein-ubiquitin ligases.	SIGNOR-272581
Q9UGP8	P68400	phosphorylation	up-regulates activity	0.291	Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.	SIGNOR-265267
P62380	O96017	phosphorylation	down-regulates activity	0.291	In vitro, TRF2 was phosphorylated by recombinant Chk2 ( Figure\u00a04 C) on residues located in the first 350 aa ( Figure\u00a0S11 ).\|To evaluate whether Chk2 activity affected the binding of TRF2 for telomeric TTAGGG repeats in duplex DNA, electrophoretic mobility shift assays (EMSA) were performed in the presence of ATP to allow phosphorylation and found that in contrast to Chk2 KD, Chk2 WT decreased the binding of TRF2 to DNA.	SIGNOR-280227
P56962	Q9UHD2	phosphorylation	up-regulates activity	0.291	Stx17 is phosphorylated by TBK1 whereby phospho-Stx17 controls the formation of the ATG13+FIP200+ mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202.	SIGNOR-273812
P13726	Q16539	phosphorylation	down-regulates	0.291	We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. Our current study has identified p38_ as a major kinase, responsible for the phosphorylation of ser258 within the cytoplasmic domain of tf	SIGNOR-199868
P41594	Q04759	phosphorylation	up-regulates activity	0.291	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249290
Q14524	Q13555	phosphorylation	up-regulates activity	0.291	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).\|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. \| Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275779
P12931	P31943	post transcriptional regulation	up-regulates quantity by expression	0.291	HnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells.	SIGNOR-261273
P63092	P35348	binding	up-regulates activity	0.291	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256812
Q01543	Q09472	binding	up-regulates	0.291	P300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380	SIGNOR-202682
Q13188	Q9H2K8	phosphorylation	up-regulates	0.291	In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2	SIGNOR-201333
P04150	P62136	dephosphorylation	up-regulates activity	0.291	The current study assessed whether PP1\u03b1 can stimulate GR function and tested two different hypotheses: First, that PP1\u03b1 regulates GR activity through suppression of MDM2 activity by dephosphorylating it at Ser166, thereby reducing the MDM2-mediated ubiquitination of GR and the subsequent proteasomal degradation of the receptor, as shown for the MR and AR ( xref ; xref ); and second, that PP1\u03b1 directly dephosphorylates the GR at a particular site to relieve functional repression as demonstrated for PP2A and PP5 ( xref ; xref ; xref ).\|The involvement of GR-Ser211 phosphorylation supports the assumption that altered subcellular trafficking is a mechanism less likely contributing to the PP1\u03b1-dependent GR activation.	SIGNOR-277161
P03372	O00170	transcriptional regulation	down-regulates activity	0.291	The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α.	SIGNOR-253644
Q9UPN4	P49137	phosphorylation	down-regulates quantity	0.291	We identify CEP131 as a major Centriolar satellites-associated substrate of p38-dependent, MK2-mediated phosphorylation on two defined residues and show that these modifications promote binding to 14-3-3 proteins, in turn leading to cytoplasmic sequestration of CEP131 and associated Centriolar satellites factors.\|We therefore conclude that MK2 dependent phosphorylation of CEP131 at S47 and S78 and the ensuing binding of 14-3-3 proteins play an essential role in triggering stress induced remodelling of CS.	SIGNOR-278181
Q8N1W1	P50148	binding	up-regulates activity	0.291	Taken together, the results suggest that active G13 and Gq form a complex with Rgnef and that G13 and Gq are upstream activators of Rgnef.	SIGNOR-278065
P23771	Q15797	transcriptional regulation	up-regulates quantity	0.291	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268938
P40763	Q13233	phosphorylation	up-regulates activity	0.291	Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna.	SIGNOR-236346
Q13131	Q8IWQ3	phosphorylation	up-regulates	0.291	Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.	SIGNOR-176594
P56178	Q16539	phosphorylation	up-regulates activity	0.291	We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38	SIGNOR-255792
Q92974	Q16512	phosphorylation	down-regulates	0.291	Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules.	SIGNOR-122191
Q15375	P31271	transcriptional regulation	up-regulates quantity by expression	0.291	Analysis of normalized luciferase expression confirmed that wt HOXA13 regulates gene expression through the EphA7 cis-regulatory DNA element	SIGNOR-261631
P49840	Q13554	phosphorylation	down-regulates	0.291	Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival.	SIGNOR-167962
Q6IE81	Q8IUQ4	polyubiquitination	down-regulates quantity by destabilization	0.291	Siah-1 decreases Jade-1 abundance and enhances Jade-1 ubiquitination	SIGNOR-272915
Q70YC5	P04637	transcriptional regulation	up-regulates quantity by expression	0.29	Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability\| Our study identified ZNF365 as a necessary target whose activation by p53 in the presence of critically short telomeres contributes to genomic stability. We provide evidence that loss of ZNF365 leads to increased expression of CFS and dysfunctional telomeres, aberrant sister telomere recombination, and increased aneuploidy	SIGNOR-272476
Q5JVS0	P17252	phosphorylation	down-regulates activity	0.29	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249246
P43699	P84022	binding	down-regulates activity	0.29	TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function.	SIGNOR-254169
P46531	Q6UY11	binding	down-regulates activity	0.29	Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts.	SIGNOR-219377
O75116	P55040	binding	down-regulates activity	0.29	Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively.	SIGNOR-261711
O95630	O00238	phosphorylation	up-regulates activity	0.29	BMP type I receptor activation stimulates AMSH phosphorylation \| The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. \| Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads.	SIGNOR-250600
Q96AQ6	Q9UHD2	phosphorylation	down-regulates quantity by destabilization	0.29	Phosphorylation of HPIP on serine 147 by TBK1 promotes E2-mediated GREB1 expression. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.	SIGNOR-273643
Q96AQ6	Q00987	polyubiquitination	down-regulates quantity by destabilization	0.29	. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.	SIGNOR-272850
Q86UR1	P17252	phosphorylation	down-regulates	0.29	Phosphorylation of nadph oxidase activator 1 (noxa1) on serine 282 by map kinases and on serine 172 by protein kinase c and protein kinase a prevents nox1 hyperactivation.	SIGNOR-163667
P14618	P36956	transcriptional regulation	up-regulates quantity by expression	0.29	Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk)	SIGNOR-166381
Q5JVS0	Q05655	phosphorylation	down-regulates activity	0.29	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249254
Q13422	P68400	phosphorylation	down-regulates	0.29	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo	SIGNOR-174832
P51168	P28482	phosphorylation	down-regulates quantity by destabilization	0.29	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-249446
Q16875	O14920	phosphorylation	down-regulates activity	0.29	IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3.We demonstrate that IKKβ directly interacts with and phosphorylates 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase isoform 3 (PFKFB3), a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low.	SIGNOR-277278
P51149	Q15904	binding	up-regulates activity	0.29	We found that Ac45 colocalized with Rab7 in resorbing osteoclasts cultured on bone slices (Fig. 6A). In addition, a co-immunoprecipitation assay revealed that Ac45 directly interacted with Rab7\| Therefore, Ac45’s role in extracellular acidification, lysosomal trafficking, and cathepsin K exocytosis may be through the Rab7 pathway.	SIGNOR-261484
O00401	P17706	dephosphorylation	down-regulates	0.29	Similarly, the t cell phosphatase has a 30-fold lower kcat/km toward autoinhibited p-n-wasp than toward the isolated p-gbd, and again this effect is largely reversed by that cdc42	SIGNOR-141652
P53350	P00519	phosphorylation	up-regulates activity	0.29	C-ABL can directly phosphorylate PLK1 and activate PLK1. \| The above results indicate that c-ABL–mediated PLK1 Y425 phosphorylation regulates PLK1 ubiquitination and stability.	SIGNOR-260935
P04114	Q9UKV5	ubiquitination	down-regulates quantity by destabilization	0.29	In physiological condition, the unnecessary apoB is usually ubiquitinated by E3 ligase AMFR, and subsequently degraded by ubiquitination proteasomes.	SIGNOR-278685

P24385

Q96PU4

0

ubiquitination

down-regulates quantity by destabilization

0.294

We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1.

SIGNOR-271885

Q9ULW0

P24941

0

phosphorylation

down-regulates activity

0.294

In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle

SIGNOR-265099

O14733

O43379

0

relocalization

up-regulates activity

0.294

In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis

SIGNOR-271716

Q9Y6K1

Q03112

0

binding

up-regulates activity

0.293

The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA|Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro.

SIGNOR-273432

O43318

P22607

0

phosphorylation

up-regulates activity

0.293

Indeed, we found that TAK1 was tyrosine phosphorylated in HEK293 cells transiently expressing constitutively active FGFR3 (K650E), but not the kinase-dead receptor (K508M), indicating that activated FGFR3 can either directly or indirectly tyrosine phosphorylate TAK1 (XREF_FIG).

SIGNOR-279176

P63096

P28335

0

binding

up-regulates activity

0.293

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256734

P04406

Q13131

0

phosphorylation

up-regulates activity

0.293

Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated.

SIGNOR-259857

O14983

P16157

0

binding

down-regulates activity

0.293

We recently reported that small ankyrin 1 (sAnk1) interacts with the sarco(endo)plasmic reticulum Ca2+-ATPase in skeletal muscle (SERCA1) to inhibit its activity.

SIGNOR-265927

P54762

Q969H4

0

binding

up-regulates activity

0.293

The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration.

SIGNOR-275921

P99999

P31751

0

phosphorylation

down-regulates activity

0.293

Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.

SIGNOR-277236

O60716

P27361

0

phosphorylation

down-regulates activity

0.293

Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation.

SIGNOR-277506

P22415

P78527

0

phosphorylation

up-regulates

0.293

Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation.

SIGNOR-184849

P04275

P29122

0

cleavage

up-regulates activity

0.293

Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine

SIGNOR-260367

P00533

Q32MZ4

0

transcriptional regulation

down-regulates quantity by repression

0.293

GC-binding factor 2 (GCF2) is a transcriptional repressor that decreases activity of the epidermal growth factor receptor (EGFR) and other genes. |Deletion mutants of GCF2 revealed that amino acids 429–528 are required for both DNA binding and repression of the EGFR promoter.

SIGNOR-266057

P30622

P68400

0

phosphorylation

up-regulates

0.293

Herein, we have identified polo-like kinase 1 (plk1) and casein kinase 2 (ck2) as two kinases of clip-170 and mapped s195 and s1318 as their respective phosphorylation sites.Plk1- and ck2-associated phosphorylations of clip-170 are involved in the timely formation of kinetochore-microtubule attachments in mitosis

SIGNOR-167168

Q96MT3

Q8N4C8

0

phosphorylation

up-regulates activity

0.293

We show that Mink1 phosphorylates Prickle on a conserved threonine residue and regulates its Rab5-dependent endosomal trafficking, a process required for the localized plasma membrane accumulation and function of Prickle.

SIGNOR-263095

O00213

P49841

0

phosphorylation

up-regulates quantity

0.293

In this regards, GSK3beta may promote amyloidogenic processing of APP by regulating the cellular level of monomeric FE65 for the formation of LRP1, FE65, and APP complex.|In this study, we showed that FE65 is phosphorylated at T579 by GSK3beta.

SIGNOR-278359

Q9HBW0

Q8WWY8

0

binding

up-regulates

0.293

When overexpressed in jurkat t cells, the edg4 protein mediated lpa-induced activation of a serum response element reporter gene with lpa concentration dependence (ec50 of 10 nm) and specificity.

SIGNOR-56093

Q5JVS0

P05129

0

phosphorylation

down-regulates activity

0.293

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249255

Q14524

P06241

0

phosphorylation

down-regulates

0.293

This study addresses the effects of the src family tyrosine kinase fyn on na(v)1.5 cardiac sodium channels. Sodium currents were acquired by whole cell recording on hek-293 cells transiently expressing na(v)1.5. Acute treatment of cells with insulin caused a depolarizing shift in steady-state inactivation, an effect eliminated by the src-specific tyrosine kinase inhibitor pp2 we provide evidence that this linker is a substrate for fyn in vitro, and that y1495 is a preferred phosphorylation site.

SIGNOR-135600

Q8IXJ6

Q13627

0

phosphorylation

up-regulates activity

0.293

This Minibrain/Dyrk1a kinase phosphorylates and activates the Silent information regulator 2/Sirtuin1 deacetylase, which in turn deacetylates and activates the FOXO transcription factor.

SIGNOR-279990

Q13887

P04150

0

transcriptional regulation

up-regulates quantity by expression

0.292

We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα

SIGNOR-256118

Q13131

P31749

0

phosphorylation

down-regulates activity

0.292

It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase.

SIGNOR-252739

P35226

P31751

0

phosphorylation

up-regulates activity

0.292

the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate

SIGNOR-249582

Q5JVS0

Q05513

0

phosphorylation

down-regulates activity

0.292

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249257

Q14332

Q9ULT6

0

ubiquitination

down-regulates

0.292

Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6.

SIGNOR-197417

P50549

P17612

0

phosphorylation

up-regulates activity

0.292

The camp-dependent protein kinase a (pka) phosphorylates er81 on ser(191)/ser(216)ser(191) and ser(216), were identified, whose mutation to alanine reduces er81 activity upon erk-mapk stimulation.

SIGNOR-92447

P51795

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.292

The presence of albumin triggers the formation of an endocytic complex that includes ClC-5. (iii) Nedd4-2 is recruited to this complex and ubiquitinates ClC-5. This ubiquitination by Nedd4-2 shunts ClC-5 into the albumin uptake/degradative pathway.

SIGNOR-272665

Q13164

P15056

0

phosphorylation

up-regulates quantity

0.292

Our data indicate that oncogenic BRAF increases ERK5 protein level, phosphorylation at several residues and kinase activity.|Overexpression of oncogenic BRAF induced ERK5 phosphorylation at Thr218 and Tyr220, although to a lower level than that induced by MEK5DD.

SIGNOR-278353

Q9P0J1

P11362

0

phosphorylation

down-regulates activity

0.292

Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.

SIGNOR-276640

Q9UMX1

Q9UKB1

0

binding

up-regulates

0.292

We found that in vitro-translated 35s- labeled slimb indeed specifically bound to su(fu) in the gst pull-down assay. In our functional gli reporter assay, slimb alone did not alter gli-induced reporter expression;however, when cotransfected with hsu(fu), slimb significantly potentiated the inhibitory effect of su(fu) on gli activity.

SIGNOR-72240

P63096

P29275

0

binding

up-regulates activity

0.292

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257039

P38405

P33032

0

binding

up-regulates activity

0.292

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256941

P35498

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.292

The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).

SIGNOR-253457

P04629

P12931

0

phosphorylation

up-regulates activity

0.292

Direct phosphorylation of TrkA by Src family kinases has been demonstrated in vitro, and our studies suggest that Src may lead to selective activation of TrkA.

SIGNOR-279291

P63092

P24530

0

binding

up-regulates activity

0.292

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256781

P60709

P12277

0

relocalization

up-regulates quantity

0.292

In summary, data presented here strongly suggest that locally generated ATP is an important regulator for actin-based cytoskeletal dynamics involved in cell extension and motility and that CK-B is a controlling enzyme in the compartmentalization of ATP availability. CK-B co-localizes with cortical actin and facilitates spreading of astrocytes

SIGNOR-265791

P31277

P09429

0

binding

up-regulates activity

0.292

We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.

SIGNOR-240559

P25815

Q9UNE7

0

polyubiquitination

down-regulates quantity by destabilization

0.292

S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.

SIGNOR-272919

P28358

P09429

0

binding

up-regulates activity

0.292

We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.

SIGNOR-240556

P36888

P06241

0

phosphorylation

up-regulates activity

0.292

FYN phosphorylates FLT3 on tyrosine residues (A\u2013B) COS1 cells were transfected with plasmids expressing FLT3 wild-type and FYN wild-type or mutants.|It was not completely unexpected that FYN associates wild-type FLT3 in the absence of ligand stimulation in COS-1 cells, as overexpression of wild-type FLT3 results in ligand independent activation of FLT3 (data not shown).

SIGNOR-279715

Q01094

P27361

0

phosphorylation

up-regulates

0.292

Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1

SIGNOR-121991

P63000

Q38SD2

0

phosphorylation

up-regulates activity

0.292

In vitro kinase assays confirmed that recombinant Lrrk1 phosphorylated RAC1-GST protein, and immunoprecipitation showed that the interaction of Lrrk1 with RAC1 occurred within 10 min after RANKL treatment.|Lrrk1 phosphorylates and activates RAC1 and Cdc42 small GTPase proteins in osteoclasts.

SIGNOR-279626

P24941

P35813

0

dephosphorylation

down-regulates activity

0.292

Moreover, purified recombinant PP2C alpha and PP2C beta 2 proteins efficiently dephosphorylated monomeric Cdk2/Cdk6 in vitro.

SIGNOR-277107

P29317

Q15418

0

phosphorylation

up-regulates activity

0.292

These comprehensive analyses indicate that high matrix stiffness activates ERK/RSK1-mediated EPHA2 non-canonical signalling to induce LYN activation, TWIST1 nuclear localization, and cell invasion (Fig. 6M).|We next knocked down the most abundant RSK family members and found that loss of RSK1, but not RSK2 or RSK3, drastically inhibited EPHA2 S897 phosphorylation, prevented ECM stiffness-induced LYN activation and recruitment to EPHA2, and inhibited cell EMT and invasion induced by increasing rigidities (Fig. 6F\u2013I and S6H\u2013L).

SIGNOR-280113

P49715

P35712

0

transcriptional regulation

up-regulates quantity by expression

0.292

We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST

SIGNOR-255824

O75364

Q9H334

0

transcriptional regulation

up-regulates quantity by expression

0.292

We identified FoxP1 as a novel marker for midbrain dopamine neurons. Enforced expression of FoxP1 in embryonic stem cells actuates the expression of Pitx3, a homeobox protein that is exclusively expressed in midbrain dopaminergic neurons and is required for their differentiation and survival during development and from embryonic stem cells in vitro. We show that FoxP1 can be recruited to the Pitx3 locus in embryonic stem cells and regulate Pitx3 promoter activity in a dual-luciferase assay.

SIGNOR-269049

P15172

P26651

0

post transcriptional regulation

down-regulates quantity by destabilization

0.292

The TTP binding site in the 3â€² UTR of MyoD would permit TTP-mediated mRNA decay

SIGNOR-253597

O00141

P51608

0

transcriptional regulation

down-regulates quantity by repression

0.292

These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress.

SIGNOR-264543

Q8IXJ6

P12931

0

phosphorylation

down-regulates quantity by destabilization

0.291

In this study, we investigated the potential regulation of SIRT2 function by c-Src. We found that the protein levels of SIRT2 were decreased by c-Src, and subsequently rescued by the addition of a Src specific inhibitor, SU6656, or by siRNA-mediated knockdown of c-Src. The c-Src interacts with and phosphorylates SIRT2 at Tyr104.

SIGNOR-263104

Q8WYL5

Q9BZL6

0

phosphorylation

down-regulates

0.291

Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1.

SIGNOR-173441

Q05397

Q13164

0

phosphorylation

up-regulates activity

0.291

Remarkably, the reduction in ERK5 expression correlated with decreased p-FAK(Tyr397) staining, consistent with the requirement of ERK5 for mediating FAK activation in vivo (Fig. 6C).|We confirmed that JWG-045, a novel pharmacological inhibitor of ERK5 exhibiting significantly reduced affinity for BRD4 compared with XMD8-92 (25, 26), did not suppress FAK phosphorylation at Tyr397 in MDA-MB-231 cells (Supplementary Fig. S3B and C).

SIGNOR-279304

Q9NZH5

P06493

0

phosphorylation

up-regulates activity

0.291

HPTTG is phosphorylated by Cdc2 at Ser165. we show that hPTTG is phosphorylated during mitosis. The direct phosphorylation of hPTTG by Cdc2 is interesting in itself since the substrates of this master mitotic kinase are supposed to play important roles in the initiation and progression of mitosis.

SIGNOR-262700

P04150

P24941

0

phosphorylation

up-regulates activity

0.291

Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.

SIGNOR-249427

P36894

O95476

0

binding

up-regulates

0.291

We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors (bmprs). Dullard preferentially complexes with the bmp type ii receptor (bmprii) and partially colocalizes with the caveolin-1-positive compartment, suggesting that dullard promotes bmpr degradation via the lipid raft-caveolar pathway

SIGNOR-150998

P63092

P25100

0

binding

up-regulates activity

0.291

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256808

P34897

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.291

Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis

SIGNOR-267380

Q08999

O43524

0

transcriptional regulation

up-regulates quantity

0.291

Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression.

SIGNOR-238606

Q969H0

O00141

0

phosphorylation

up-regulates

0.291

Here, we report that the serum- and glucocorticoid-inducible protein kinase sgk1 remarkably reduced the protein stability of the active form of notch1 through fbw7activated sgk1 phosphorylated fbw7 at serine 227

SIGNOR-170404

P43405

P46934

0

polyubiquitination

down-regulates quantity by destabilization

0.291

The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is implicated in the maintenance of viral latency and appears to function in part by inhibiting B-cell receptor (BCR) signaling. LMP2A enhances Lyn and Syk ubiquitination in vivo in a fashion that depends on the activity of Nedd4 family members and correlates with destabilization of the Lyn tyrosine kinase. These results suggest that LMP2A serves as a molecular scaffold to recruit both B-cell tyrosine kinases and C2/WW/Hect domain E3 protein-ubiquitin ligases.

SIGNOR-272581

Q9UGP8

P68400

0

phosphorylation

up-regulates activity

0.291

Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.

SIGNOR-265267

P62380

O96017

0

phosphorylation

down-regulates activity

0.291

In vitro, TRF2 was phosphorylated by recombinant Chk2 ( Figure\u00a04 C) on residues located in the first 350 aa ( Figure\u00a0S11 ).|To evaluate whether Chk2 activity affected the binding of TRF2 for telomeric TTAGGG repeats in duplex DNA, electrophoretic mobility shift assays (EMSA) were performed in the presence of ATP to allow phosphorylation and found that in contrast to Chk2 KD, Chk2 WT decreased the binding of TRF2 to DNA.

SIGNOR-280227

P56962

Q9UHD2

0

phosphorylation

up-regulates activity

0.291

Stx17 is phosphorylated by TBK1 whereby phospho-Stx17 controls the formation of the ATG13+FIP200+ mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202.

SIGNOR-273812

P13726

Q16539

0

phosphorylation

down-regulates

0.291

We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. Our current study has identified p38_ as a major kinase, responsible for the phosphorylation of ser258 within the cytoplasmic domain of tf

SIGNOR-199868

P41594

Q04759

0

phosphorylation

up-regulates activity

0.291

Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.

SIGNOR-249290

Q14524

Q13555

0

phosphorylation

up-regulates activity

0.291

Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5

SIGNOR-275779

P12931

P31943

0

post transcriptional regulation

up-regulates quantity by expression

0.291

HnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells.

SIGNOR-261273

P63092

P35348

0

binding

up-regulates activity

0.291

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256812

Q01543

Q09472

0

binding

up-regulates

0.291

P300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380

SIGNOR-202682

Q13188

Q9H2K8

0

phosphorylation

up-regulates

0.291

In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2

SIGNOR-201333

P04150

P62136

0

dephosphorylation

up-regulates activity

0.291

The current study assessed whether PP1\u03b1 can stimulate GR function and tested two different hypotheses: First, that PP1\u03b1 regulates GR activity through suppression of MDM2 activity by dephosphorylating it at Ser166, thereby reducing the MDM2-mediated ubiquitination of GR and the subsequent proteasomal degradation of the receptor, as shown for the MR and AR ( xref ; xref ); and second, that PP1\u03b1 directly dephosphorylates the GR at a particular site to relieve functional repression as demonstrated for PP2A and PP5 ( xref ; xref ; xref ).|The involvement of GR-Ser211 phosphorylation supports the assumption that altered subcellular trafficking is a mechanism less likely contributing to the PP1\u03b1-dependent GR activation.

SIGNOR-277161

P03372

O00170

0

transcriptional regulation

down-regulates activity

0.291

The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α.

SIGNOR-253644

Q9UPN4

P49137

0

phosphorylation

down-regulates quantity

0.291

We identify CEP131 as a major Centriolar satellites-associated substrate of p38-dependent, MK2-mediated phosphorylation on two defined residues and show that these modifications promote binding to 14-3-3 proteins, in turn leading to cytoplasmic sequestration of CEP131 and associated Centriolar satellites factors.|We therefore conclude that MK2 dependent phosphorylation of CEP131 at S47 and S78 and the ensuing binding of 14-3-3 proteins play an essential role in triggering stress induced remodelling of CS.

SIGNOR-278181

Q8N1W1

P50148

0

binding

up-regulates activity

0.291

Taken together, the results suggest that active G13 and Gq form a complex with Rgnef and that G13 and Gq are upstream activators of Rgnef.

SIGNOR-278065

P23771

Q15797

0

transcriptional regulation

up-regulates quantity

0.291

Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation

SIGNOR-268938

P40763

Q13233

0

phosphorylation

up-regulates activity

0.291

Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna.

SIGNOR-236346

Q13131

Q8IWQ3

0

phosphorylation

up-regulates

0.291

Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.

SIGNOR-176594

P56178

Q16539

0

phosphorylation

up-regulates activity

0.291

We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38

SIGNOR-255792

Q92974

Q16512

0

phosphorylation

down-regulates

0.291

Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules.

SIGNOR-122191

Q15375

P31271

0

transcriptional regulation

up-regulates quantity by expression

0.291

Analysis of normalized luciferase expression confirmed that wt HOXA13 regulates gene expression through the EphA7 cis-regulatory DNA element

SIGNOR-261631

P49840

Q13554

0

phosphorylation

down-regulates

0.291

Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival.

SIGNOR-167962

Q6IE81

Q8IUQ4

0

polyubiquitination

down-regulates quantity by destabilization

0.291

Siah-1 decreases Jade-1 abundance and enhances Jade-1 ubiquitination

SIGNOR-272915

Q70YC5

P04637

0

transcriptional regulation

up-regulates quantity by expression

0.29

Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability| Our study identified ZNF365 as a necessary target whose activation by p53 in the presence of critically short telomeres contributes to genomic stability. We provide evidence that loss of ZNF365 leads to increased expression of CFS and dysfunctional telomeres, aberrant sister telomere recombination, and increased aneuploidy

SIGNOR-272476

Q5JVS0

P17252

0

phosphorylation

down-regulates activity

0.29

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249246

P43699

P84022

0

binding

down-regulates activity

0.29

TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function.

SIGNOR-254169

P46531

Q6UY11

0

binding

down-regulates activity

0.29

Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts.

SIGNOR-219377

O75116

P55040

0

binding

down-regulates activity

0.29

Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively.

SIGNOR-261711

O95630

O00238

0

phosphorylation

up-regulates activity

0.29

BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads.

SIGNOR-250600

Q96AQ6

Q9UHD2

0

phosphorylation

down-regulates quantity by destabilization

0.29

Phosphorylation of HPIP on serine 147 by TBK1 promotes E2-mediated GREB1 expression. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.

SIGNOR-273643

Q96AQ6

Q00987

0

polyubiquitination

down-regulates quantity by destabilization

0.29

. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.

SIGNOR-272850

Q86UR1

P17252

0

phosphorylation

down-regulates

0.29

Phosphorylation of nadph oxidase activator 1 (noxa1) on serine 282 by map kinases and on serine 172 by protein kinase c and protein kinase a prevents nox1 hyperactivation.

SIGNOR-163667

P14618

P36956

0

transcriptional regulation

up-regulates quantity by expression

0.29

Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk)

SIGNOR-166381

Q5JVS0

Q05655

0

phosphorylation

down-regulates activity

0.29

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249254

Q13422

P68400

0

phosphorylation

down-regulates

0.29

We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo

SIGNOR-174832

P51168

P28482

0

phosphorylation

down-regulates quantity by destabilization

0.29

Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.

SIGNOR-249446

Q16875

O14920

0

phosphorylation

down-regulates activity

0.29

IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3.We demonstrate that IKKβ directly interacts with and phosphorylates 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase isoform 3 (PFKFB3), a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low.

SIGNOR-277278

P51149

Q15904

0

binding

up-regulates activity

0.29

We found that Ac45 colocalized with Rab7 in resorbing osteoclasts cultured on bone slices (Fig. 6A). In addition, a co-immunoprecipitation assay revealed that Ac45 directly interacted with Rab7| Therefore, Ac45’s role in extracellular acidification, lysosomal trafficking, and cathepsin K exocytosis may be through the Rab7 pathway.

SIGNOR-261484

O00401

P17706

0

dephosphorylation

down-regulates

0.29

Similarly, the t cell phosphatase has a 30-fold lower kcat/km toward autoinhibited p-n-wasp than toward the isolated p-gbd, and again this effect is largely reversed by that cdc42

SIGNOR-141652

P53350

P00519

0

phosphorylation

up-regulates activity

0.29

C-ABL can directly phosphorylate PLK1 and activate PLK1. | The above results indicate that c-ABL–mediated PLK1 Y425 phosphorylation regulates PLK1 ubiquitination and stability.

SIGNOR-260935

P04114

Q9UKV5

0

ubiquitination

down-regulates quantity by destabilization

0.29

In physiological condition, the unnecessary apoB is usually ubiquitinated by E3 ligase AMFR, and subsequently degraded by ubiquitination proteasomes.

SIGNOR-278685