GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P06213	P07550	1	phosphorylation	down-regulates activity	0.377	Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors.	SIGNOR-251302
Q96QT4	P16885	1	phosphorylation	up-regulates activity	0.263	We present data indicating that TRPM7 phosphorylates phospholipase C\u03b32 at position Ser1164 in the C2-domain, and at position Thr1045 in the linker between the catalytic region and the C2 domain.	SIGNOR-278460
P37231	P28482	0	relocalization	down-regulates	0.457	The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform	SIGNOR-179400
Q9NZJ5	P78352	1	phosphorylation	up-regulates activity	0.268	To elucidate the molecular mechanism, we found that activated PERK phosphorylates CAMP response element binding protein (CREB) and PSD95 directly at the S129 and T19 residues, respectively.	SIGNOR-280004
P17252	P35611	1	phosphorylation	up-regulates	0.2	These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc.	SIGNOR-43744
P36507	P10398	0	phosphorylation	up-regulates	0.754	Active raf phosphorylates mek.	SIGNOR-175142
P36888	Q14469	0	transcriptional regulation	down-regulates quantity by repression	0.2	We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity.	SIGNOR-261563
P58012	P63279	0	sumoylation	up-regulates	0.698	Foxl2 is sumoylated by ubc9, and this ubc9-mediated sumoylation is essential to the transcriptional activity of foxl2 on the star promoter. / the sumoylation site was identified at lysine 25 of foxl2	SIGNOR-187901
P49715	P49841	0	phosphorylation	up-regulates activity	0.379	Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes.	SIGNOR-251231
Q14571	Q96K19	0	polyubiquitination	down-regulates activity	0.331	In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound.	SIGNOR-271914
Q9C0C7	Q99496	0	ubiquitination	down-regulates quantity by destabilization	0.359	RNF2 ubiquitinates AMBRA1 at lysine 45.\|These data indicate that RNF2 directly accelerates the degradation of AMBRA1.	SIGNOR-278596
P24941	Q96T88	1	phosphorylation	down-regulates quantity by destabilization	0.303	UHRF1 is phosphorylated by CDK2/cyclin A. In vitro kinase assay was performed with CDK2/cyclin A using recombinant wild-type UHRF1 or UHRF1-S674A mutant	SIGNOR-277192
P17252	Q04637	1	phosphorylation	up-regulates activity	0.258	Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186.	SIGNOR-276327
P09769	Q9UHD2	1	phosphorylation	down-regulates activity	0.2	The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.	SIGNOR-276725
Q9Y6Y1	P01160	1	transcriptional regulation	up-regulates quantity by expression	0.429	CAMTA1 itself stimulates the expression of the anti-proliferative peptide NPPA.	SIGNOR-261570
O00429	Q9UM11	0	ubiquitination	down-regulates quantity	0.349	Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1 catalyzed by the APC/Ccdh1 (anaphase-promoting complex/cyclosome and its coactivator (Cdh1) E3 ubiquiting ligase complex	SIGNOR-274127
Q8NFG4	Q9HB90	1	gtpase-activating protein	up-regulates activity	0.695	The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur	SIGNOR-256503
P41229	Q16665	0	transcriptional regulation	up-regulates quantity by expression	0.259	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271564
P49841	Q14195	1	phosphorylation	up-regulates activity	0.475	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-146011
Q13418	O14974	1	phosphorylation	down-regulates activity	0.584	MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition	SIGNOR-262884
P06239	Q9H204	1	phosphorylation	up-regulates	0.439	Y64 of magicin is phosphorylated by lck creating a sh2-grb2 binding motif	SIGNOR-148704
Q13615	P42345	1	null	down-regulates activity	0.354	The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity.	SIGNOR-245105
P49137	P50549	1	phosphorylation	up-regulates	0.612	Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2	SIGNOR-166625
O75155	Q15386	0	ubiquitination	down-regulates quantity by destabilization	0.39	We show that KIAA10 indeed associates with 26 S proteasomes in mammalian cells but that this interaction is likely to depend on contacts with a subunit(s) besides S2/Rpn1. Most importantly, we provide strong evidence that TIP120B (TBP-interacting protein 120B (22)) is a specific substrate that is targeted for degradation in skeletal muscle through KIAA10-catalyzed polyubiquitination.	SIGNOR-271454
Q9BY41	P17612	0	phosphorylation	down-regulates	0.494	Negative regulation of histone deacetylase 8 activity by cyclic amp-dependent protein kinase athe pka phosphoacceptor site of hdac8 is ser(39)	SIGNOR-120643
P19525	P10636	1	phosphorylation	up-regulates quantity	0.2	Interestingly, PKR phosphorylated tau directly and no detectable labeling occurred when tau was incubated with 32 P\u2010ATP alone (Figure\u00a0 xref right).\|PKR kinase directly regulates tau expression and Alzheimer's disease-related tau phosphorylation.	SIGNOR-279735
Q16539	O75582	1	phosphorylation	up-regulates activity	0.611	In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1	SIGNOR-249199
Q99717	Q04771	0	phosphorylation	up-regulates	0.759	Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2	SIGNOR-60171
P17480	Q05195	0	transcriptional regulation	down-regulates quantity by repression	0.36	MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation\|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter.	SIGNOR-269646
P24941	P49916	1	phosphorylation	down-regulates	0.418	Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm.	SIGNOR-150121
Q05513	O95863	1	phosphorylation	down-regulates quantity by destabilization	0.2	APKC kinases phosphorylate S249 of SNAI1, which leads to protein degradation.	SIGNOR-277437
P29350	P04629	1	dephosphorylation	down-regulates activity	0.476	Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675.	SIGNOR-248468
Q13315	Q99638	1	phosphorylation	up-regulates activity	0.767	Hyperphosphorylation of hrad9 induced by ir is dependent on atm. Ser(272) of hrad9 is phosphorylated directly by atm in vitro. / our results suggest that the atm-mediated phosphorylation of hrad9 is required for ir-induced checkpoint activation.	SIGNOR-105243
Q8TCQ1	P06213	1	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation.	SIGNOR-278819
Q16820	P17252	0	phosphorylation	down-regulates quantity	0.2	These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.	SIGNOR-263172
P29350	Q12809	1	dephosphorylation	down-regulates	0.2	Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1.	SIGNOR-94007
P49418	P68400	0	phosphorylation	down-regulates	0.2	Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin.	SIGNOR-149314
Q12899	P78549	1	ubiquitination	down-regulates quantity by destabilization	0.263	We also demonstrated that TRIM26 directly polyubiquitylates NTH1 in cells and that TRIM26 targets newly synthesized NTH1 protein for ubiquitylation dependent degradation.	SIGNOR-278733
Q8IYU2	Q96CV9	1	ubiquitination	down-regulates quantity by destabilization	0.401	Here we report that tumor suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62 and SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux.\|Ubiquitylation of Autophagy Receptor Optineurin by HACE1 Activates Selective Autophagy for Tumor Suppression.\|HACE1 mediated K48 linked poly-Ub chains targets OPTN for autophagic degradation.	SIGNOR-278748
Q9H853	Q5SQI0	0	acetylation	up-regulates quantity by stabilization	0.2	Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.\|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules	SIGNOR-272252
P28482	P13056	1	phosphorylation	down-regulates activity	0.2	We also reported that ERK2-phosphorylated TR2 is recruited to PML nuclear bodies (PML NBs) for its subsequent small ubiquitin-like modification (SUMOylation) and function as a potent transcriptional repressor xref , xref .	SIGNOR-278957
P25098	P16671	1	phosphorylation	down-regulates quantity by destabilization	0.2	We, therefore, propose a pathway by which inhibition of GRK2 in the failing heart prevents CD36 phosphorylation, ubiquitination, and, in turn, induces its proteasomal degradation.\|Our data reveal direct phosphorylation of CD36 by GRK2.	SIGNOR-279524
P05771	Q96D31	1	phosphorylation	down-regulates	0.2	We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30.	SIGNOR-166040
O95477	Q8TBB1	0	ubiquitination	down-regulates quantity by destabilization	0.242	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272902
P01130	Q8WY64	0	ubiquitination	down-regulates quantity by destabilization	0.723	The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells.	SIGNOR-271485
O15503	Q8WU17	0	ubiquitination	down-regulates quantity	0.477	TRC8/RNF139 encodes an endoplasmic reticulum-resident E3 ubiquitin ligase that inhibits growth in a RING- and ubiquitylation-dependent manner. TRC8 also contains a predicted sterol-sensing domain. Here, we report that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG. Thus, we conclude that INSIG-1 and 2 physically interact with TRC8, and that TRC8 enhances ubiquitylation of INSIG-1 in a RING-dependent manner	SIGNOR-271955
P31749	P63000	1	phosphorylation	down-regulates activity	0.725	Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1	SIGNOR-252576
P42338	P49841	1	phosphorylation	down-regulates activity	0.48	In our cultures, both p110alpha and p110beta phosphorylated GSK-3beta at Ser9 confirming previous data.\|Whereas p110alpha reduced the protein levels of the CDK2-inhibitor p27 Kip1, p110beta phosphorylated and inactivated GSK-3beta.	SIGNOR-279089
Q53ET0	P35558	1	transcriptional regulation	up-regulates quantity	0.386	These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK.	SIGNOR-256106
Q08J23	Q96GD4	0	phosphorylation	down-regulates	0.72	Aurora-b phosphorylated nsun2 at ser139. Aurora-b-phosphorylation and the phosphorylation-mimic mutation (s139e) suppressed methyltransferase activities of nsun2.	SIGNOR-152001
Q96KR7	Q00535	0	phosphorylation	down-regulates quantity	0.2	We show that scapinin is phosphorylated at a highly conserved site in the central region of the protein (Ser-277) by Cdk5 in vitro. Expression of a scapinin phospho-mimetic mutant (S277D) restored normal axon elongation without affecting actin binding. Instead, phosphorylated scapinin was sequestered in the cytoplasm of neurons and away from the axon.	SIGNOR-273607
P05412	P01137	1	transcriptional regulation	up-regulates quantity by expression	0.542	MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production	SIGNOR-251713
P84243	P17612	0	phosphorylation	up-regulates activity	0.2	Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation.	SIGNOR-70424
Q92900	P31751	0	phosphorylation	up-regulates activity	0.2	AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity	SIGNOR-277595
P27361	Q15796	1	phosphorylation	down-regulates	0.748	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3	SIGNOR-66778
Q16539	Q16512	0	phosphorylation	up-regulates	0.378	At the same time, rho signals to c-jun n-terminal kinase (jnk) and p38 through rock and protein kinase n (pkn), leading to the transcriptional regulation of jun	SIGNOR-152765
P14210	P08047	0	transcriptional regulation	up-regulates quantity by expression	0.2	Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.	SIGNOR-251739
P38435	P00742	1	carboxylation	up-regulates activity	0.615	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. \|We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.\|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; \| 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263667
Q8NG06	Q13409	1	polyubiquitination	down-regulates quantity by destabilization	0.298	Trim58 ubiquitinates dynein and promotes its proteasomal degradation. Trim58 binds DIC directly, polyubiquitinates it in vitro, and induces proteasomal degradation of the dynein holocomplex in vivo.	SIGNOR-272841
Q15025	Q9UHD2	0	phosphorylation	down-regulates quantity by destabilization	0.375	TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1	SIGNOR-275733
Q9NZQ3	P27361	0	phosphorylation	up-regulates	0.422	Spin90 was phosphorylated by erk1, which was, itself, activated by cell adhesion and platelet-derived growth factor. Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck	SIGNOR-118747
Q96BF3	O14920	0	phosphorylation	up-regulates activity	0.2	Manipulating the IκB kinase β activity coupled with in vivo and in vitro kinase assays demonstrated that IκB kinase β is a key serine/threonine kinase activated by autophagy stimuli and that it catalyzes phosphorylation of IGPR-1 at Ser220 The subsequent activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase, which leads to phosphorylation of the major pro-autophagy proteins ULK1 and Beclin-1 (BECN1), increased LC3-II levels, and accumulation of LC3 punctum.	SIGNOR-273642
Q92934	P16298	0	dephosphorylation	up-regulates activity	0.364	Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD\|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.	SIGNOR-248384
O43791	Q9NZQ7	1	ubiquitination	down-regulates quantity	0.325	Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens.	SIGNOR-274978
Q9BYX4	P62136	0	dephosphorylation	up-regulates activity	0.2	Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5\|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.	SIGNOR-264577
P53396	P07948	0	phosphorylation	up-regulates activity	0.2	We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.	SIGNOR-274105
P22681	P00519	1	ubiquitination	down-regulates quantity by destabilization	0.614	We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins	SIGNOR-167194
Q8N726	Q13207	0	transcriptional regulation	down-regulates quantity by repression	0.522	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249594
Q9UQM7	P07101	1	phosphorylation	up-regulates	0.256	This increase in ser19 phosphorylation was associated with enhanced th activity and was due, in part, to glutamate-receptor-mediated calcium influx and possibly calcium/calmodulin-dependent protein kinase ii (camkii) activation.	SIGNOR-20912
P55010	O60841	1	relocalization	up-regulates activity	0.75	eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC.	SIGNOR-269122
P06241	P29350	1	phosphorylation	up-regulates activity	0.551	By contrast, receptor multivalent aggregation induced a Fyn-dependent SHP-1 S591 phosphorylation (Fig.\u00a0 xref ).\|Fyn simultaneously activates the PI3K-PKC\u03b1 pathway, leading to SHP-1 phosphorylation on serine 591.	SIGNOR-279716
P35222	P49674	0	phosphorylation	down-regulates activity	0.657	Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45).	SIGNOR-244102
Q9UPZ9	P67775	0	dephosphorylation	down-regulates	0.2	In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif.	SIGNOR-138432
P49910	Q969W9	1	transcriptional regulation	down-regulates quantity by repression	0.271	ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1.	SIGNOR-266094
P52333	P40763	1	phosphorylation	up-regulates	0.792	Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256254
O95644	P49841	0	phosphorylation	down-regulates activity	0.588	In T-cells, calcineurin de-phosphorylates NFATc1, leading to its nuclear import, while glycogen synthase kinase 3 beta (GSK3beta) phosphorylates NFATc1 and promotes its nuclear export.\|We conclude that GSK3beta negatively regulates NFATc1 in vSMCs, and GSK3beta must be inactivated to allow NFAT activation during wound repair.Male Sprague-Dawley rats were obtained from Charles River (Montreal, PQ, Canada).	SIGNOR-279185
P06276	Q9H2X6	0	phosphorylation	down-regulates quantity	0.2	As shown in XREF_FIG, HIPK2 overexpression strongly reduced Myc-Che-1 levels, whereas it produced little effect on Che-1 T144A expression.\|Notably, we found that HIPK2 phosphorylates a specific residue of Che-1, which is required for its interaction with Pin1 and for its degradation through the proteasome pathway.	SIGNOR-279190
P09038	P09629	0	transcriptional regulation	up-regulates quantity by expression	0.396	Band shift and cotransfection experiments showed that HOXB7 directly transactivates the hFGF gene through one out of five putative homeodomain binding sites present in its promoter.	SIGNOR-261639
P54646	Q13393	1	phosphorylation	up-regulates	0.2	Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp.	SIGNOR-164293
O00165	Q05655	0	phosphorylation	down-regulates quantity by destabilization	0.2	FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.\|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells,	SIGNOR-275562
P17612	Q9Y2K6	1	phosphorylation	down-regulates quantity by destabilization	0.311	Upon β2AR activation, a specific isoform of the second messenger cAMP-dependent protein kinase A (PKAα) rapidly phosphorylates USP20 on serine 333 located in its unique insertion domain. This phosphorylation of USP20 correlates with a characteristic SDS-PAGE mobility shift of the protein, blocks its deubiquitinase activity, promotes its dissociation from the activated β2AR complex, and facilitates trafficking of the ubiquitinated β2AR to autophagosomes, which fuse with lysosomes to form autolysosomes where receptors are degraded.	SIGNOR-273795
Q969U6	Q6UVJ0	1	ubiquitination	down-regulates quantity by destabilization	0.536	We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. \|expression of the wild-type form of FBXW5 accelerated the degradation of HsSAS-6 to a half-life of less than two hours	SIGNOR-275478
P49716	P04150	0	transcriptional regulation	up-regulates quantity	0.315	We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPδ; C/EBPδ then binds to PPARγ2 promoter and transactivates PPARγ2 gene expression.	SIGNOR-253061
Q92974	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.806	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260529
P49841	Q9NP62	1	phosphorylation	down-regulates quantity by destabilization	0.2	We demonstrated that GSK-3beta mediates phosphorylation of GCM1 on Ser322, which is recognized by the F-box protein, FBW2, to promote GCM1 ubiquitination and degradation.	SIGNOR-278940
Q15717	Q16539	0	phosphorylation	up-regulates	0.523	P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna.	SIGNOR-186135
Q9P253	Q9NYY3	1	ubiquitination	down-regulates quantity by destabilization	0.2	VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4.	SIGNOR-271550
Q96GD4	Q3KR16	1	phosphorylation	up-regulates	0.254	In this study we report that aurora b-mediated phosphorylation of myogef at thr-544 creates a docking site for plk1, leading to the localization and activation of myogef at the central spindle.	SIGNOR-204534
P67775	Q9Y570	0	demethylation	down-regulates activity	0.905	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits \|Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans.	SIGNOR-265748
P12931	Q9Y4D1	1	phosphorylation	up-regulates activity	0.325	Our findings reveal a novel mechanism by which reversible tyrosine phosphorylation of DAAM1 by Src and PTPN3 regulates actin dynamics and lung cancer invasiveness.\|PTPN3 suppresses lung cancer cell invasiveness by counteracting Src mediated DAAM1 activation and actin polymerization.	SIGNOR-280128
Q13535	Q9UBU7	1	phosphorylation	down-regulates	0.657	Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.	SIGNOR-177809
O15294	Q8NFU7	1	glycosylation	up-regulates activity	0.44	The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt.	SIGNOR-259184
O00311	O14757	0	phosphorylation	up-regulates	0.734	Chk1 directly phosphorylates essential s-phase kinases cdc7.	SIGNOR-163161
O75385	Q8N122	1	phosphorylation	down-regulates activity	0.704	ULK1 phosphorylates RPTOR at S792, S855, and S859.\|When active, ULK1 inhibits MTOR complex 1 through phosphorylation of RPTOR, which has the effect of limiting RPTOR-mediated recruitment of MTOR substrates to MTOR complex 1 [ ].	SIGNOR-278461
P24941	P04183	1	phosphorylation	down-regulates	0.296	Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.	SIGNOR-95578
P06241	Q99490	1	phosphorylation	up-regulates	0.467	We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival.	SIGNOR-147936
Q12857	P41161	1	transcriptional regulation	down-regulates quantity	0.2	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268874
Q8N726	Q9UHC7	0	polyubiquitination	down-regulates quantity by destabilization	0.366	Biochemical analyses confirmed that MKRN1 targets p14ARF for ubiquitination and subsequent proteasome-dependent degradation.The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro.	SIGNOR-272036
P84022	Q9UNE7	0	ubiquitination	down-regulates quantity by destabilization	0.57	These results suggest that Smad3 could be easily ubiquitinated and degraded by CHIP when Hsp90 activity was inhibited.To demonstrate the role of Hsp70 and Hsp90 on the regulation of Smad3 by CHIP, we over-expressed Hsp70 and Hsp90 in mammalian cells.	SIGNOR-278785
Q9UGU0	P08254	1	transcriptional regulation	up-regulates quantity by expression	0.416	This result indicates that expression of SPBP is sufficient to transactivate a minimal promoter containing a single copy of the SPRE, as well as the full-length stromelysin promoter.	SIGNOR-266223

P06213

P07550

1

phosphorylation

down-regulates activity

0.377

Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors.

SIGNOR-251302

Q96QT4

P16885

1

phosphorylation

up-regulates activity

0.263

We present data indicating that TRPM7 phosphorylates phospholipase C\u03b32 at position Ser1164 in the C2-domain, and at position Thr1045 in the linker between the catalytic region and the C2 domain.

SIGNOR-278460

P37231

P28482

0

relocalization

down-regulates

0.457

The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform

SIGNOR-179400

Q9NZJ5

P78352

1

phosphorylation

up-regulates activity

0.268

To elucidate the molecular mechanism, we found that activated PERK phosphorylates CAMP response element binding protein (CREB) and PSD95 directly at the S129 and T19 residues, respectively.

SIGNOR-280004

P17252

P35611

1

phosphorylation

up-regulates

0.2

These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc.

SIGNOR-43744

P36507

P10398

0

phosphorylation

up-regulates

0.754

Active raf phosphorylates mek.

SIGNOR-175142

P36888

Q14469

0

transcriptional regulation

down-regulates quantity by repression

0.2

We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity.

SIGNOR-261563

P58012

P63279

0

sumoylation

up-regulates

0.698

Foxl2 is sumoylated by ubc9, and this ubc9-mediated sumoylation is essential to the transcriptional activity of foxl2 on the star promoter. / the sumoylation site was identified at lysine 25 of foxl2

SIGNOR-187901

P49715

P49841

0

phosphorylation

up-regulates activity

0.379

Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes.

SIGNOR-251231

Q14571

Q96K19

0

polyubiquitination

down-regulates activity

0.331

In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound.

SIGNOR-271914

Q9C0C7

Q99496

0

ubiquitination

down-regulates quantity by destabilization

0.359

RNF2 ubiquitinates AMBRA1 at lysine 45.|These data indicate that RNF2 directly accelerates the degradation of AMBRA1.

SIGNOR-278596

P24941

Q96T88

1

phosphorylation

down-regulates quantity by destabilization

0.303

UHRF1 is phosphorylated by CDK2/cyclin A. In vitro kinase assay was performed with CDK2/cyclin A using recombinant wild-type UHRF1 or UHRF1-S674A mutant

SIGNOR-277192

P17252

Q04637

1

phosphorylation

up-regulates activity

0.258

Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186.

SIGNOR-276327

P09769

Q9UHD2

1

phosphorylation

down-regulates activity

0.2

The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.

SIGNOR-276725

Q9Y6Y1

P01160

1

transcriptional regulation

up-regulates quantity by expression

0.429

CAMTA1 itself stimulates the expression of the anti-proliferative peptide NPPA.

SIGNOR-261570

O00429

Q9UM11

0

ubiquitination

down-regulates quantity

0.349

Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1 catalyzed by the APC/Ccdh1 (anaphase-promoting complex/cyclosome and its coactivator (Cdh1) E3 ubiquiting ligase complex

SIGNOR-274127

Q8NFG4

Q9HB90

1

gtpase-activating protein

up-regulates activity

0.695

The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur

SIGNOR-256503

P41229

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.259

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271564

P49841

Q14195

1

phosphorylation

up-regulates activity

0.475

Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro

SIGNOR-146011

Q13418

O14974

1

phosphorylation

down-regulates activity

0.584

MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition

SIGNOR-262884

P06239

Q9H204

1

phosphorylation

up-regulates

0.439

Y64 of magicin is phosphorylated by lck creating a sh2-grb2 binding motif

SIGNOR-148704

Q13615

P42345

1

null

down-regulates activity

0.354

The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity.

SIGNOR-245105

P49137

P50549

1

phosphorylation

up-regulates

0.612

Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2

SIGNOR-166625

O75155

Q15386

0

ubiquitination

down-regulates quantity by destabilization

0.39

We show that KIAA10 indeed associates with 26 S proteasomes in mammalian cells but that this interaction is likely to depend on contacts with a subunit(s) besides S2/Rpn1. Most importantly, we provide strong evidence that TIP120B (TBP-interacting protein 120B (22)) is a specific substrate that is targeted for degradation in skeletal muscle through KIAA10-catalyzed polyubiquitination.

SIGNOR-271454

Q9BY41

P17612

0

phosphorylation

down-regulates

0.494

Negative regulation of histone deacetylase 8 activity by cyclic amp-dependent protein kinase athe pka phosphoacceptor site of hdac8 is ser(39)

SIGNOR-120643

P19525

P10636

1

phosphorylation

up-regulates quantity

0.2

Interestingly, PKR phosphorylated tau directly and no detectable labeling occurred when tau was incubated with 32 P\u2010ATP alone (Figure\u00a0 xref right).|PKR kinase directly regulates tau expression and Alzheimer's disease-related tau phosphorylation.

SIGNOR-279735

Q16539

O75582

1

phosphorylation

up-regulates activity

0.611

In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1

SIGNOR-249199

Q99717

Q04771

0

phosphorylation

up-regulates

0.759

Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2

SIGNOR-60171

P17480

Q05195

0

transcriptional regulation

down-regulates quantity by repression

0.36

MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter.

SIGNOR-269646

P24941

P49916

1

phosphorylation

down-regulates

0.418

Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm.

SIGNOR-150121

Q05513

O95863

1

phosphorylation

down-regulates quantity by destabilization

0.2

APKC kinases phosphorylate S249 of SNAI1, which leads to protein degradation.

SIGNOR-277437

P29350

P04629

1

dephosphorylation

down-regulates activity

0.476

Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675.

SIGNOR-248468

Q13315

Q99638

1

phosphorylation

up-regulates activity

0.767

Hyperphosphorylation of hrad9 induced by ir is dependent on atm. Ser(272) of hrad9 is phosphorylated directly by atm in vitro. / our results suggest that the atm-mediated phosphorylation of hrad9 is required for ir-induced checkpoint activation.

SIGNOR-105243

Q8TCQ1

P06213

1

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation.

SIGNOR-278819

Q16820

P17252

0

phosphorylation

down-regulates quantity

0.2

These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.

SIGNOR-263172

P29350

Q12809

1

dephosphorylation

down-regulates

0.2

Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1.

SIGNOR-94007

P49418

P68400

0

phosphorylation

down-regulates

0.2

Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin.

SIGNOR-149314

Q12899

P78549

1

ubiquitination

down-regulates quantity by destabilization

0.263

We also demonstrated that TRIM26 directly polyubiquitylates NTH1 in cells and that TRIM26 targets newly synthesized NTH1 protein for ubiquitylation dependent degradation.

SIGNOR-278733

Q8IYU2

Q96CV9

1

ubiquitination

down-regulates quantity by destabilization

0.401

Here we report that tumor suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62 and SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux.|Ubiquitylation of Autophagy Receptor Optineurin by HACE1 Activates Selective Autophagy for Tumor Suppression.|HACE1 mediated K48 linked poly-Ub chains targets OPTN for autophagic degradation.

SIGNOR-278748

Q9H853

Q5SQI0

0

acetylation

up-regulates quantity by stabilization

0.2

Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules

SIGNOR-272252

P28482

P13056

1

phosphorylation

down-regulates activity

0.2

We also reported that ERK2-phosphorylated TR2 is recruited to PML nuclear bodies (PML NBs) for its subsequent small ubiquitin-like modification (SUMOylation) and function as a potent transcriptional repressor xref , xref .

SIGNOR-278957

P25098

P16671

1

phosphorylation

down-regulates quantity by destabilization

0.2

We, therefore, propose a pathway by which inhibition of GRK2 in the failing heart prevents CD36 phosphorylation, ubiquitination, and, in turn, induces its proteasomal degradation.|Our data reveal direct phosphorylation of CD36 by GRK2.

SIGNOR-279524

P05771

Q96D31

1

phosphorylation

down-regulates

0.2

We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30.

SIGNOR-166040

O95477

Q8TBB1

0

ubiquitination

down-regulates quantity by destabilization

0.242

We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.

SIGNOR-272902

P01130

Q8WY64

0

ubiquitination

down-regulates quantity by destabilization

0.723

The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells.

SIGNOR-271485

O15503

Q8WU17

0

ubiquitination

down-regulates quantity

0.477

TRC8/RNF139 encodes an endoplasmic reticulum-resident E3 ubiquitin ligase that inhibits growth in a RING- and ubiquitylation-dependent manner. TRC8 also contains a predicted sterol-sensing domain. Here, we report that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG. Thus, we conclude that INSIG-1 and 2 physically interact with TRC8, and that TRC8 enhances ubiquitylation of INSIG-1 in a RING-dependent manner

SIGNOR-271955

P31749

P63000

1

phosphorylation

down-regulates activity

0.725

Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1

SIGNOR-252576

P42338

P49841

1

phosphorylation

down-regulates activity

0.48

In our cultures, both p110alpha and p110beta phosphorylated GSK-3beta at Ser9 confirming previous data.|Whereas p110alpha reduced the protein levels of the CDK2-inhibitor p27 Kip1, p110beta phosphorylated and inactivated GSK-3beta.

SIGNOR-279089

Q53ET0

P35558

1

transcriptional regulation

up-regulates quantity

0.386

These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK.

SIGNOR-256106

Q08J23

Q96GD4

0

phosphorylation

down-regulates

0.72

Aurora-b phosphorylated nsun2 at ser139. Aurora-b-phosphorylation and the phosphorylation-mimic mutation (s139e) suppressed methyltransferase activities of nsun2.

SIGNOR-152001

Q96KR7

Q00535

0

phosphorylation

down-regulates quantity

0.2

We show that scapinin is phosphorylated at a highly conserved site in the central region of the protein (Ser-277) by Cdk5 in vitro. Expression of a scapinin phospho-mimetic mutant (S277D) restored normal axon elongation without affecting actin binding. Instead, phosphorylated scapinin was sequestered in the cytoplasm of neurons and away from the axon.

SIGNOR-273607

P05412

P01137

1

transcriptional regulation

up-regulates quantity by expression

0.542

MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production

SIGNOR-251713

P84243

P17612

0

phosphorylation

up-regulates activity

0.2

Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation.

SIGNOR-70424

Q92900

P31751

0

phosphorylation

up-regulates activity

0.2

AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity

SIGNOR-277595

P27361

Q15796

1

phosphorylation

down-regulates

0.748

These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3

SIGNOR-66778

Q16539

Q16512

0

phosphorylation

up-regulates

0.378

At the same time, rho signals to c-jun n-terminal kinase (jnk) and p38 through rock and protein kinase n (pkn), leading to the transcriptional regulation of jun

SIGNOR-152765

P14210

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.2

Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.

SIGNOR-251739

P38435

P00742

1

carboxylation

up-regulates activity

0.615

This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).

SIGNOR-263667

Q8NG06

Q13409

1

polyubiquitination

down-regulates quantity by destabilization

0.298

Trim58 ubiquitinates dynein and promotes its proteasomal degradation. Trim58 binds DIC directly, polyubiquitinates it in vitro, and induces proteasomal degradation of the dynein holocomplex in vivo.

SIGNOR-272841

Q15025

Q9UHD2

0

phosphorylation

down-regulates quantity by destabilization

0.375

TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1

SIGNOR-275733

Q9NZQ3

P27361

0

phosphorylation

up-regulates

0.422

Spin90 was phosphorylated by erk1, which was, itself, activated by cell adhesion and platelet-derived growth factor. Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck

SIGNOR-118747

Q96BF3

O14920

0

phosphorylation

up-regulates activity

0.2

Manipulating the IκB kinase β activity coupled with in vivo and in vitro kinase assays demonstrated that IκB kinase β is a key serine/threonine kinase activated by autophagy stimuli and that it catalyzes phosphorylation of IGPR-1 at Ser220 The subsequent activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase, which leads to phosphorylation of the major pro-autophagy proteins ULK1 and Beclin-1 (BECN1), increased LC3-II levels, and accumulation of LC3 punctum.

SIGNOR-273642

Q92934

P16298

0

dephosphorylation

up-regulates activity

0.364

Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.

SIGNOR-248384

O43791

Q9NZQ7

1

ubiquitination

down-regulates quantity

0.325

Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens.

SIGNOR-274978

Q9BYX4

P62136

0

dephosphorylation

up-regulates activity

0.2

Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.

SIGNOR-264577

P53396

P07948

0

phosphorylation

up-regulates activity

0.2

We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.

SIGNOR-274105

P22681

P00519

1

ubiquitination

down-regulates quantity by destabilization

0.614

We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins

SIGNOR-167194

Q8N726

Q13207

0

transcriptional regulation

down-regulates quantity by repression

0.522

TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS

SIGNOR-249594

Q9UQM7

P07101

1

phosphorylation

up-regulates

0.256

This increase in ser19 phosphorylation was associated with enhanced th activity and was due, in part, to glutamate-receptor-mediated calcium influx and possibly calcium/calmodulin-dependent protein kinase ii (camkii) activation.

SIGNOR-20912

P55010

O60841

1

relocalization

up-regulates activity

0.75

eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC.

SIGNOR-269122

P06241

P29350

1

phosphorylation

up-regulates activity

0.551

By contrast, receptor multivalent aggregation induced a Fyn-dependent SHP-1 S591 phosphorylation (Fig.\u00a0 xref ).|Fyn simultaneously activates the PI3K-PKC\u03b1 pathway, leading to SHP-1 phosphorylation on serine 591.

SIGNOR-279716

P35222

P49674

0

phosphorylation

down-regulates activity

0.657

Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45).

SIGNOR-244102

Q9UPZ9

P67775

0

dephosphorylation

down-regulates

0.2

In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif.

SIGNOR-138432

P49910

Q969W9

1

transcriptional regulation

down-regulates quantity by repression

0.271

ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1.

SIGNOR-266094

P52333

P40763

1

phosphorylation

up-regulates

0.792

Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated

SIGNOR-256254

O95644

P49841

0

phosphorylation

down-regulates activity

0.588

In T-cells, calcineurin de-phosphorylates NFATc1, leading to its nuclear import, while glycogen synthase kinase 3 beta (GSK3beta) phosphorylates NFATc1 and promotes its nuclear export.|We conclude that GSK3beta negatively regulates NFATc1 in vSMCs, and GSK3beta must be inactivated to allow NFAT activation during wound repair.Male Sprague-Dawley rats were obtained from Charles River (Montreal, PQ, Canada).

SIGNOR-279185

P06276

Q9H2X6

0

phosphorylation

down-regulates quantity

0.2

As shown in XREF_FIG, HIPK2 overexpression strongly reduced Myc-Che-1 levels, whereas it produced little effect on Che-1 T144A expression.|Notably, we found that HIPK2 phosphorylates a specific residue of Che-1, which is required for its interaction with Pin1 and for its degradation through the proteasome pathway.

SIGNOR-279190

P09038

P09629

0

transcriptional regulation

up-regulates quantity by expression

0.396

Band shift and cotransfection experiments showed that HOXB7 directly transactivates the hFGF gene through one out of five putative homeodomain binding sites present in its promoter.

SIGNOR-261639

P54646

Q13393

1

phosphorylation

up-regulates

0.2

Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp.

SIGNOR-164293

O00165

Q05655

0

phosphorylation

down-regulates quantity by destabilization

0.2

FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells,

SIGNOR-275562

P17612

Q9Y2K6

1

phosphorylation

down-regulates quantity by destabilization

0.311

Upon β2AR activation, a specific isoform of the second messenger cAMP-dependent protein kinase A (PKAα) rapidly phosphorylates USP20 on serine 333 located in its unique insertion domain. This phosphorylation of USP20 correlates with a characteristic SDS-PAGE mobility shift of the protein, blocks its deubiquitinase activity, promotes its dissociation from the activated β2AR complex, and facilitates trafficking of the ubiquitinated β2AR to autophagosomes, which fuse with lysosomes to form autolysosomes where receptors are degraded.

SIGNOR-273795

Q969U6

Q6UVJ0

1

ubiquitination

down-regulates quantity by destabilization

0.536

We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. |expression of the wild-type form of FBXW5 accelerated the degradation of HsSAS-6 to a half-life of less than two hours

SIGNOR-275478

P49716

P04150

0

transcriptional regulation

up-regulates quantity

0.315

We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPδ; C/EBPδ then binds to PPARγ2 promoter and transactivates PPARγ2 gene expression.

SIGNOR-253061

Q92974

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.806

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260529

P49841

Q9NP62

1

phosphorylation

down-regulates quantity by destabilization

0.2

We demonstrated that GSK-3beta mediates phosphorylation of GCM1 on Ser322, which is recognized by the F-box protein, FBW2, to promote GCM1 ubiquitination and degradation.

SIGNOR-278940

Q15717

Q16539

0

phosphorylation

up-regulates

0.523

P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna.

SIGNOR-186135

Q9P253

Q9NYY3

1

ubiquitination

down-regulates quantity by destabilization

0.2

VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4.

SIGNOR-271550

Q96GD4

Q3KR16

1

phosphorylation

up-regulates

0.254

In this study we report that aurora b-mediated phosphorylation of myogef at thr-544 creates a docking site for plk1, leading to the localization and activation of myogef at the central spindle.

SIGNOR-204534

P67775

Q9Y570

0

demethylation

down-regulates activity

0.905

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans.

SIGNOR-265748

P12931

Q9Y4D1

1

phosphorylation

up-regulates activity

0.325

Our findings reveal a novel mechanism by which reversible tyrosine phosphorylation of DAAM1 by Src and PTPN3 regulates actin dynamics and lung cancer invasiveness.|PTPN3 suppresses lung cancer cell invasiveness by counteracting Src mediated DAAM1 activation and actin polymerization.

SIGNOR-280128

Q13535

Q9UBU7

1

phosphorylation

down-regulates

0.657

Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.

SIGNOR-177809

O15294

Q8NFU7

1

glycosylation

up-regulates activity

0.44

The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt.

SIGNOR-259184

O00311

O14757

0

phosphorylation

up-regulates

0.734

Chk1 directly phosphorylates essential s-phase kinases cdc7.

SIGNOR-163161

O75385

Q8N122

1

phosphorylation

down-regulates activity

0.704

ULK1 phosphorylates RPTOR at S792, S855, and S859.|When active, ULK1 inhibits MTOR complex 1 through phosphorylation of RPTOR, which has the effect of limiting RPTOR-mediated recruitment of MTOR substrates to MTOR complex 1 [ ].

SIGNOR-278461

P24941

P04183

1

phosphorylation

down-regulates

0.296

Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.

SIGNOR-95578

P06241

Q99490

1

phosphorylation

up-regulates

0.467

We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival.

SIGNOR-147936

Q12857

P41161

1

transcriptional regulation

down-regulates quantity

0.2

By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development

SIGNOR-268874

Q8N726

Q9UHC7

0

polyubiquitination

down-regulates quantity by destabilization

0.366

Biochemical analyses confirmed that MKRN1 targets p14ARF for ubiquitination and subsequent proteasome-dependent degradation.The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro.

SIGNOR-272036

P84022

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.57

These results suggest that Smad3 could be easily ubiquitinated and degraded by CHIP when Hsp90 activity was inhibited.To demonstrate the role of Hsp70 and Hsp90 on the regulation of Smad3 by CHIP, we over-expressed Hsp70 and Hsp90 in mammalian cells.

SIGNOR-278785

Q9UGU0

P08254

1

transcriptional regulation

up-regulates quantity by expression

0.416

This result indicates that expression of SPBP is sufficient to transactivate a minimal promoter containing a single copy of the SPRE, as well as the full-length stromelysin promoter.

SIGNOR-266223