GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
O43526	P17252	0	phosphorylation	up-regulates activity	0.324	Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. \| These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process.	SIGNOR-249209
P49768	Q9NZ42	0	cleavage	up-regulates	0.959	Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.	SIGNOR-97113
Q13761	P11802	0	phosphorylation	down-regulates	0.399	Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation.	SIGNOR-185120
P0C0L5	P48740	0	cleavage	up-regulates activity	0.676	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.\|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263426
Q8IXJ6	P06493	0	phosphorylation	down-regulates	0.412	Here, we demonstrate that sirt2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1. Overexpression of sirt2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation.	SIGNOR-154681
Q9UEW8	Q9UHW9	1	phosphorylation	down-regulates activity	0.569	We observed that in vitro activated STE20/SPS1-related proline/alanine-rich kinase (SPAK) complexed to its regulatory MO25 subunit phosphorylated KCC3 at Ser-96 and that in Xenopus laevis oocytes Ser-96 of human KCC3 is phosphorylated in isotonic conditions and becomes dephosphorylated during incubation in hypotonicity, leading to a dramatic increase in KCC3 function.	SIGNOR-276597
Q9Y4K3	O43474	1	ubiquitination	up-regulates quantity by stabilization	0.285	We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.	SIGNOR-277464
Q9UQL6	Q96GD4	0	phosphorylation	down-regulates	0.258	We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions	SIGNOR-198650
P15735	P06737	1	phosphorylation	up-regulates activity	0.656	It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267401
Q86YT6	Q9NR61	1	ubiquitination	up-regulates activity	0.553	Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.	SIGNOR-209626
Q9ULK5	P35790	0	phosphorylation	down-regulates activity	0.2	CKI\u03b5-dependent phosphorylation increases Stbm turnover at junctions, and thus promotes complex sorting, while phosphorylation of Dsh decreases its turnover.\|Interestingly, CKI\u03b5 has been implicated in phosphorylation of both Stbm and Dsh.	SIGNOR-278925
P63000	Q9P227	0	gtpase-activating protein	down-regulates activity	0.43	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-260480
P01100	O15391	0	transcriptional regulation	up-regulates quantity by expression	0.392	YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter.	SIGNOR-266212
O96004	Q99717	0	transcriptional regulation	up-regulates quantity	0.2	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-268941
Q16543	P53041	0	dephosphorylation	down-regulates activity	0.672	Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13\|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37.	SIGNOR-248539
Q05086	P78352	1	ubiquitination	down-regulates quantity by destabilization	0.349	E6-induced degradation of DLG4 depends on E6AP in vivo. Our findings as a whole indicate that E6AP is involved in E6-mediated ubiquitination and degradation of DLG4 both in vivo and in vitro.	SIGNOR-271397
Q13153	P10398	1	phosphorylation	up-regulates	0.267	Phosphorylation of endogenous a-raf, b-raf and raf-1 on the homologous pak phosphorylation sites (serine 299, serine 445, or serine 338 respectively)we found that the phosphorylation of a-raf on serine 299 was also stimulated by egf, although the duration of phosphorylation on this site was much shorter than for raf-1. Thus, by analogy with raf-1, phosphorylation of this site may play an important role in the a-raf activation mechanism.	SIGNOR-236342
O60936	P19784	0	phosphorylation	up-regulates activity	0.2	Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm.	SIGNOR-262836
P30304	Q15208	0	phosphorylation	down-regulates quantity	0.247	Here, we demonstrate that the depletion of serine-threonine kinase 38 (STK38) prevents the DNA-damage-induced degradation of CDC25A and subsequent G2 arrest, and that STK38 directly phosphorylates CDC25A at Ser-76, resulting in CDC25A's degradation.	SIGNOR-279488
P10071	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.537	We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog.	SIGNOR-219231
P62195	Q15751	0	ubiquitination	down-regulates quantity	0.2	HERC1 interacts with and ubiquitinates nascent PSMC5.\|PSMC5 produced in the absence of PAAF1 is presumably misfolded (consistent with its aggregation in the PURE system), triggering PSMC5 degradation by a HERC1-independent pathway.	SIGNOR-278812
P61020	Q5S007	0	phosphorylation	up-regulates activity	0.599	Using recombinant proteins, we show here that LRRK2 phosphorylates Rab5b at its Thr6 residue in in vitro kinase assays with mass spectrophotometry analysis. Phosphorylation of Rab5b by LRRK2 on the threonine residue was confirmed by western analysis using cells stably expressing LRRK2 G2019S. The phosphomimetic T6D mutant exhibited stronger GTPase activity than that of the wild-type Rab5b. In addition, phosphorylation of Rab5b by LRRK2 also exhibited GTPase activity stronger than that of the unphosphorylated Rab5b protein.	SIGNOR-276873
P05412	Q13177	0	phosphorylation	up-regulates	0.268	P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)	SIGNOR-170772
O15550	P41212	1	transcriptional regulation	down-regulates quantity by repression	0.3	Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase	SIGNOR-260032
Q9P107	P63000	1	gtpase-activating protein	down-regulates activity	0.445	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-260506
O75582	P07101	1	phosphorylation	up-regulates	0.337	Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax. studies on th from several species suggest that ser40 is the main site involved in direct activation of th	SIGNOR-95491
P05129	Q5JVS0	1	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
P18031	Q9UKV8	1	dephosphorylation	down-regulates activity	0.2	Taken together, our results indicate that Tyr 393 of AGO2 is hyperphosphorylated in response to PTP1B inactivation and may contribute to H-RAS V12 -induced development of senescence.\|We identified phospho-Tyr 393 of argonaute 2 (AGO2) as a direct substrate of PTP1B.	SIGNOR-277120
P68400	Q13698	1	phosphorylation	up-regulates activity	0.2	To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2.	SIGNOR-263114
Q8N752	P17612	0	phosphorylation	up-regulates	0.39	Mutation of either the three pka sites or pka-primed cki sites prevents phosphorylation of ci by cki in vitro and blocks ci cleavage in embryos	SIGNOR-144557
Q14493	P62805	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265376
P53350	Q6P2H3	1	phosphorylation	up-regulates activity	0.248	In summary, our results identify Cep85 as a platform to directly relay the activities of Plk1 and Mst2 to Nek2A activation at centrosomes through phospho-Nek2A-assistant Cep85 phosphorylation by Plk1 at the onset of mitosis.\|Plk1 Heavily Phosphorylates the Nek2A-Binding Domain in Cep85 at Centrosomes in Late G2.	SIGNOR-278367
P38398	O96028	1	ubiquitination	down-regulates quantity by destabilization	0.2	Proteomic data analysis revealed interaction between NSD2 and BRCA1 and further study revealed that BRCA1 ubiquitinates NSD2 at K292 residue.\|These results suggested that BRCA1 interacts with and promotes degradation of NSD2 via polyubiquitination .	SIGNOR-278745
P67775	Q12800	1	dephosphorylation	up-regulates	0.2	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a	SIGNOR-167385
Q9P1A6	Q9Y566	1	relocalization	up-regulates activity	0.756	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264589
O43426	Q00535	0	phosphorylation	down-regulates activity	0.505	Cdk5 phosphorylation inhibited the inositol 5-phosphatase activity of synaptojanin 1, whereas dephosphorylation by calcineurin stimulated such activity.\|The activity of synaptojanin 1 was also stimulated by its interaction with endophilin 1, its major binding partner at the synapse. Notably, Cdk5 phosphorylated serine 1144, which is adjacent to the endophilin binding site.	SIGNOR-279685
O43463	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.4	A recent report showed that the p53 inducible E3 ligase MDM2 causes SUV39H1 degradation.\|Furthermore, it was reported that MDM2 can ubiquitinate and degrade SUV39H1.	SIGNOR-278631
Q14938	P29322	1	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268910
O95628	P41229	1	ubiquitination	down-regulates quantity by destabilization	0.545	In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome. Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression.	SIGNOR-271468
O43665	P17612	0	phosphorylation	down-regulates activity	0.334	We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel.	SIGNOR-109173
Q13315	P54274	1	phosphorylation	up-regulates activity	0.571	Telomeric protein pin2/trf1 as an important atm target in response to double strand dna breaks. activated atm directly phosphorylated pin2/trf1 preferentially on the conserved ser(219)-gln site in vitro and in vivo.	SIGNOR-108419
P18031	Q13480	1	dephosphorylation	down-regulates activity	0.38	Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well.\|The results indicate that PTP1B completely dephosphorylated Gab1 and the mutant protein failed to dephosphorylate Gab1 (Figure\u00a0 xref C).	SIGNOR-276965
Q14247	Q14689	0	acetylation	up-regulates activity	0.2	DIP2A binds to cortactin and modulates cortactin acetylation. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin.	SIGNOR-266589
P06730	O14965	0	phosphorylation	up-regulates activity	0.278	In this study, we demonstrated for the first time that AURKA can phosphorylate and activate EIF4E.	SIGNOR-279495
P51812	P05204	1	phosphorylation	down-regulates activity	0.29	We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets.	SIGNOR-249102
Q9H0K1	P27986	1	phosphorylation	up-regulates activity	0.322	The Regulatory Subunit of PI3K Is a Direct Catalytic Target of SIK2. These data confirm that p85α is a direct catalytic substrate of SIK2 and that SIK2 S154 phosphorylation significantly increases the activity of the PI3K/AKT pathway in ovarian cancer cells.	SIGNOR-277269
Q6MZQ0	Q8WZ73	0	polyubiquitination	down-regulates quantity by destabilization	0.261	RFFL is an E3 ligase for PRR5L.	SIGNOR-271495
Q02156	P18507	1	phosphorylation	down-regulates activity	0.233	Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol.	SIGNOR-263174
P31268	O15550	0	transcriptional regulation	up-regulates quantity by expression	0.275	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260024
Q16512	Q92974	1	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
P07288	P19838	0	transcriptional regulation	up-regulates quantity by expression	0.2	NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer.	SIGNOR-253668
Q16539	Q16690	0	dephosphorylation	down-regulates	0.537	The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues.	SIGNOR-166574
P42336	Q13043	0	phosphorylation	down-regulates activity	0.2	MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061	SIGNOR-277920
Q96EB6	O15105	1	deacetylation	down-regulates	0.441	Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells.	SIGNOR-150595
P28482	P19793	1	phosphorylation	down-regulates activity	0.534	In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma\|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE	SIGNOR-262958
P17844	Q9P286	0	phosphorylation	up-regulates quantity by stabilization	0.2	PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer\|The increased expression levels of PAK5 and phospho-DDX5 threonine 69 are associated with metastasis and poor clinical outcomes of patients. PAK5 facilitates the phosphorylation-dependent sumoylation of DDX5 to stabilize DDX5. Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing.	SIGNOR-275658
Q5XUX0	P31749	0	phosphorylation	down-regulates quantity by destabilization	0.2	Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT.	SIGNOR-277376
P28482	Q9NYA1	1	phosphorylation	up-regulates	0.561	Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.	SIGNOR-118546
P36888	P43405	0	phosphorylation	up-regulates activity	0.407	Only two mutants, FLT3-KD (V5) Y768A and Y955A, were resistant to SYK-mediated FLT3 phosphorylation, suggesting that SYK directly phosphorylates FLT3 at sites Y768 and Y955 ( ).\|SYK Enhances FLT3 WT and Mutant Activation by Phosphorylation of Residues Y768 and Y955.	SIGNOR-278431
Q13422	P36873	0	dephosphorylation	up-regulates	0.329	Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-174865
Q96SW2	Q9H3D4	1	polyubiquitination	down-regulates quantity by destabilization	0.2	CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs.When thalidomide binds to CRBN, substrate specificity of CRL4CRBN is altered and CRBN neomorphically binds to ∆Np63, TAp63 and other neosubstrates and ubiquitinates them for proteasomal degradation.	SIGNOR-272214
Q13315	Q15911	1	phosphorylation	up-regulates activity	0.346	Indeed, ATM phosphorylates ATBF1 at Ser1180 in HEK293T cells exposed to 10-Gy radiation [ xref ].\|We also found in this study that ATBF1 mediated neuronal death is dependent on ATM signals because the blockage of ATM by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 functions in neuronal death.	SIGNOR-279138
Q9H204	P06239	0	phosphorylation	up-regulates	0.439	Y64 of magicin is phosphorylated by lck creating a sh2-grb2 binding motif	SIGNOR-148704
O14757	P31749	0	phosphorylation	down-regulates	0.43	The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1.	SIGNOR-124365
Q9Y243	Q01860	1	phosphorylation	up-regulates quantity by stabilization	0.257	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-242107
P36897	P36873	0	dephosphorylation	down-regulates	0.469	We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI.	SIGNOR-121277
Q05655	O15350	1	phosphorylation	up-regulates	0.307	The results show that pkcdeltacf phosphorylates the p73beta transactivation and dna-binding domains. pkcdeltacf-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation.	SIGNOR-90279
Q05655	Q16206	1	phosphorylation	up-regulates	0.2	Tnox is phosphorylated by protein kinase c_ (pkc_) both in vitro and in vivo. Replacement of serine-504 with alanine significantly reduces phosphorylation by pkc_. C. overexpression of the s504a tnox mutant leads to diminished cell proliferation and migration, reflecting reduced stability of the unphosphorylatable tnox mutant protein.	SIGNOR-197706
Q99558	P41279	0	phosphorylation	up-regulates activity	0.559	In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha	SIGNOR-249387
Q15672	Q9UGI0	0	deubiquitination	down-regulates activity	0.331	Trabid inhibits Twist1 activity by cleaving RNF8-mediated Twist1 K63-linked ubiquitination	SIGNOR-273502
Q92973	P09651	1	relocalization	up-regulates activity	0.572	TNPO1 only mediates the nuclear import of a subset of proteins.\|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import	SIGNOR-262099
Q12778	P53350	0	phosphorylation	down-regulates activity	0.316	In conclusion, we provide evidence that PLK1-dependent phosphorylation of FOXO1 induces its nuclear exclusion and negatively regulates FOXO1 transcriptional activity in PCa.\|We previously demonstrated that PLK1 inhibits the transcriptional activity of FOXO1 by promoting its nuclear exclusion in U2OS cells .	SIGNOR-278269
P49736	P50613	0	phosphorylation	up-regulates activity	0.299	Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. \| Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2.	SIGNOR-259849
P04908	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265397
P27361	O95644	1	phosphorylation	down-regulates	0.532	We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.	SIGNOR-74564
P22694	Q14896	1	phosphorylation	up-regulates	0.274	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163772
Q9P1W9	P42229	0	transcriptional regulation	up-regulates quantity by expression	0.41	The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells.	SIGNOR-249622
Q96RU2	P01106	1	deubiquitination	up-regulates	0.703	Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc.	SIGNOR-155590
O43318	Q13555	0	phosphorylation	up-regulates	0.2	Camkii interacts with and phosphorylates tak1.	SIGNOR-96422
P10398	P36507	1	phosphorylation	up-regulates	0.754	Active raf phosphorylates mek.	SIGNOR-175142
P68871	O95600	0	transcriptional regulation	down-regulates quantity by repression	0.2	These results establish KLF8 as a CACCC-box binding protein that associates with CtBP and represses transcription.	SIGNOR-266052
Q92574	P28482	0	phosphorylation	down-regulates	0.49	Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin.	SIGNOR-157162
P28482	P06239	1	phosphorylation	up-regulates activity	0.583	Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.\|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.	SIGNOR-249412
P62330	Q5JU85	0	guanine nucleotide exchange factor	up-regulates activity	0.457	Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6.	SIGNOR-264906
Q96FA3	O15151	1	ubiquitination	up-regulates activity	0.434	We found that Peli1 induces Mdmx ubiquitination without promoting its degradation, which leads to the cytoplasmic localization of Mdmx and subsequent activation of p53 function.	SIGNOR-278773
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
P63000	Q15311	0	gtpase-activating protein	down-regulates activity	0.582	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-260513
Q8IUR6	Q15011	1	transcriptional regulation	up-regulates quantity by expression	0.2	Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element.	SIGNOR-261575
Q9H4E7	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.392	Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner.	SIGNOR-253369
P04637	Q2Q1W2	0	ubiquitination	down-regulates quantity	0.272	LIN41 promotes ubiquitination of p53 in response to RA.\|Loss of LIN41 elevates p53 steady-state levels and reduces p53 ubiquitination.	SIGNOR-278679
P09874	P08581	0	phosphorylation	up-regulates activity	0.388	Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907).\|To address whether c-Met activates PARP1, we exposed MDA-MB-231 cells expressing control shRNA or c-Met shRNA to H 2 O 2 and subjected them to a comet assay to evaluate the extent of DNA damage.	SIGNOR-279470
O14543	P40763	0	transcriptional regulation	up-regulates quantity by expression	0.709	We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells	SIGNOR-253583
P40337	P48200	1	ubiquitination	down-regulates quantity by destabilization	0.359	We show here that IRP2 can interact with pVHL in co-transfection/co-immunoprecipitation assays. Furthermore, pVHL is able to promote the ubiquitination and the decay of transfected IRP2.	SIGNOR-271421
Q9H3Y6	Q13451	1	phosphorylation	down-regulates quantity by destabilization	0.267	SRMS binds FKBP51 and phosphorylates tyrosine 54. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway.	SIGNOR-277564
P17612	P41240	1	phosphorylation	up-regulates activity	0.338	Activation of the cooh-terminal src kinase (csk) by camp-dependent protein kinase inhibits signaling through the t cell receptor.Pka phosphorylates csk at s364 in vitro and in vivo leading to a two- to fourfold increase in csk activity that is necessary for camp-mediated inhibition of tcr-induced interleukin 2 secretion.	SIGNOR-105229
Q13501	P00533	0	phosphorylation	down-regulates activity	0.33	Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturbs the sequestration function of SQSTM1 and causes autophagic flux blocking.	SIGNOR-277500
P51817	P98161	1	phosphorylation	up-regulates	0.257	The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd.	SIGNOR-158852
P17612	Q13185	1	phosphorylation	up-regulates	0.2	We demonstrate that p-ser 83-hp1gamma has an exclusively euchromatic localization, interacts with ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation.	SIGNOR-145109
P35568	P45983	0	phosphorylation	down-regulates activity	0.771	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-96948
O60674	Q9UGK3	1	phosphorylation	up-regulates activity	0.343	To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase \|On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 8060% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2.	SIGNOR-249372

O43526

P17252

0

phosphorylation

up-regulates activity

0.324

Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process.

SIGNOR-249209

P49768

Q9NZ42

0

cleavage

up-regulates

0.959

Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.

SIGNOR-97113

Q13761

P11802

0

phosphorylation

down-regulates

0.399

Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation.

SIGNOR-185120

P0C0L5

P48740

0

cleavage

up-regulates activity

0.676

The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.

SIGNOR-263426

Q8IXJ6

P06493

0

phosphorylation

down-regulates

0.412

Here, we demonstrate that sirt2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1. Overexpression of sirt2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation.

SIGNOR-154681

Q9UEW8

Q9UHW9

1

phosphorylation

down-regulates activity

0.569

We observed that in vitro activated STE20/SPS1-related proline/alanine-rich kinase (SPAK) complexed to its regulatory MO25 subunit phosphorylated KCC3 at Ser-96 and that in Xenopus laevis oocytes Ser-96 of human KCC3 is phosphorylated in isotonic conditions and becomes dephosphorylated during incubation in hypotonicity, leading to a dramatic increase in KCC3 function.

SIGNOR-276597

Q9Y4K3

O43474

1

ubiquitination

up-regulates quantity by stabilization

0.285

We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.

SIGNOR-277464

Q9UQL6

Q96GD4

0

phosphorylation

down-regulates

0.258

We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions

SIGNOR-198650

P15735

P06737

1

phosphorylation

up-regulates activity

0.656

It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15

SIGNOR-267401

Q86YT6

Q9NR61

1

ubiquitination

up-regulates activity

0.553

Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.

SIGNOR-209626

Q9ULK5

P35790

0

phosphorylation

down-regulates activity

0.2

CKI\u03b5-dependent phosphorylation increases Stbm turnover at junctions, and thus promotes complex sorting, while phosphorylation of Dsh decreases its turnover.|Interestingly, CKI\u03b5 has been implicated in phosphorylation of both Stbm and Dsh.

SIGNOR-278925

P63000

Q9P227

0

gtpase-activating protein

down-regulates activity

0.43

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-260480

P01100

O15391

0

transcriptional regulation

up-regulates quantity by expression

0.392

YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter.

SIGNOR-266212

O96004

Q99717

0

transcriptional regulation

up-regulates quantity

0.2

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-268941

Q16543

P53041

0

dephosphorylation

down-regulates activity

0.672

Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37.

SIGNOR-248539

Q05086

P78352

1

ubiquitination

down-regulates quantity by destabilization

0.349

E6-induced degradation of DLG4 depends on E6AP in vivo. Our findings as a whole indicate that E6AP is involved in E6-mediated ubiquitination and degradation of DLG4 both in vivo and in vitro.

SIGNOR-271397

Q13153

P10398

1

phosphorylation

up-regulates

0.267

Phosphorylation of endogenous a-raf, b-raf and raf-1 on the homologous pak phosphorylation sites (serine 299, serine 445, or serine 338 respectively)we found that the phosphorylation of a-raf on serine 299 was also stimulated by egf, although the duration of phosphorylation on this site was much shorter than for raf-1. Thus, by analogy with raf-1, phosphorylation of this site may play an important role in the a-raf activation mechanism.

SIGNOR-236342

O60936

P19784

0

phosphorylation

up-regulates activity

0.2

Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm.

SIGNOR-262836

P30304

Q15208

0

phosphorylation

down-regulates quantity

0.247

Here, we demonstrate that the depletion of serine-threonine kinase 38 (STK38) prevents the DNA-damage-induced degradation of CDC25A and subsequent G2 arrest, and that STK38 directly phosphorylates CDC25A at Ser-76, resulting in CDC25A's degradation.

SIGNOR-279488

P10071

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.537

We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog.

SIGNOR-219231

P62195

Q15751

0

ubiquitination

down-regulates quantity

0.2

HERC1 interacts with and ubiquitinates nascent PSMC5.|PSMC5 produced in the absence of PAAF1 is presumably misfolded (consistent with its aggregation in the PURE system), triggering PSMC5 degradation by a HERC1-independent pathway.

SIGNOR-278812

P61020

Q5S007

0

phosphorylation

up-regulates activity

0.599

Using recombinant proteins, we show here that LRRK2 phosphorylates Rab5b at its Thr6 residue in in vitro kinase assays with mass spectrophotometry analysis. Phosphorylation of Rab5b by LRRK2 on the threonine residue was confirmed by western analysis using cells stably expressing LRRK2 G2019S. The phosphomimetic T6D mutant exhibited stronger GTPase activity than that of the wild-type Rab5b. In addition, phosphorylation of Rab5b by LRRK2 also exhibited GTPase activity stronger than that of the unphosphorylated Rab5b protein.

SIGNOR-276873

P05412

Q13177

0

phosphorylation

up-regulates

0.268

P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)

SIGNOR-170772

O15550

P41212

1

transcriptional regulation

down-regulates quantity by repression

0.3

Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase

SIGNOR-260032

Q9P107

P63000

1

gtpase-activating protein

down-regulates activity

0.445

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-260506

O75582

P07101

1

phosphorylation

up-regulates

0.337

Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax. studies on th from several species suggest that ser40 is the main site involved in direct activation of th

SIGNOR-95491

P05129

Q5JVS0

1

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

P18031

Q9UKV8

1

dephosphorylation

down-regulates activity

0.2

Taken together, our results indicate that Tyr 393 of AGO2 is hyperphosphorylated in response to PTP1B inactivation and may contribute to H-RAS V12 -induced development of senescence.|We identified phospho-Tyr 393 of argonaute 2 (AGO2) as a direct substrate of PTP1B.

SIGNOR-277120

P68400

Q13698

1

phosphorylation

up-regulates activity

0.2

To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2.

SIGNOR-263114

Q8N752

P17612

0

phosphorylation

up-regulates

0.39

Mutation of either the three pka sites or pka-primed cki sites prevents phosphorylation of ci by cki in vitro and blocks ci cleavage in embryos

SIGNOR-144557

Q14493

P62805

1

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265376

P53350

Q6P2H3

1

phosphorylation

up-regulates activity

0.248

In summary, our results identify Cep85 as a platform to directly relay the activities of Plk1 and Mst2 to Nek2A activation at centrosomes through phospho-Nek2A-assistant Cep85 phosphorylation by Plk1 at the onset of mitosis.|Plk1 Heavily Phosphorylates the Nek2A-Binding Domain in Cep85 at Centrosomes in Late G2.

SIGNOR-278367

P38398

O96028

1

ubiquitination

down-regulates quantity by destabilization

0.2

Proteomic data analysis revealed interaction between NSD2 and BRCA1 and further study revealed that BRCA1 ubiquitinates NSD2 at K292 residue.|These results suggested that BRCA1 interacts with and promotes degradation of NSD2 via polyubiquitination .

SIGNOR-278745

P67775

Q12800

1

dephosphorylation

up-regulates

0.2

We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a

SIGNOR-167385

Q9P1A6

Q9Y566

1

relocalization

up-regulates activity

0.756

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264589

O43426

Q00535

0

phosphorylation

down-regulates activity

0.505

Cdk5 phosphorylation inhibited the inositol 5-phosphatase activity of synaptojanin 1, whereas dephosphorylation by calcineurin stimulated such activity.|The activity of synaptojanin 1 was also stimulated by its interaction with endophilin 1, its major binding partner at the synapse. Notably, Cdk5 phosphorylated serine 1144, which is adjacent to the endophilin binding site.

SIGNOR-279685

O43463

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.4

A recent report showed that the p53 inducible E3 ligase MDM2 causes SUV39H1 degradation.|Furthermore, it was reported that MDM2 can ubiquitinate and degrade SUV39H1.

SIGNOR-278631

Q14938

P29322

1

transcriptional regulation

up-regulates quantity

0.2

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268910

O95628

P41229

1

ubiquitination

down-regulates quantity by destabilization

0.545

In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome. Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression.

SIGNOR-271468

O43665

P17612

0

phosphorylation

down-regulates activity

0.334

We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel.

SIGNOR-109173

Q13315

P54274

1

phosphorylation

up-regulates activity

0.571

Telomeric protein pin2/trf1 as an important atm target in response to double strand dna breaks. activated atm directly phosphorylated pin2/trf1 preferentially on the conserved ser(219)-gln site in vitro and in vivo.

SIGNOR-108419

P18031

Q13480

1

dephosphorylation

down-regulates activity

0.38

Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well.|The results indicate that PTP1B completely dephosphorylated Gab1 and the mutant protein failed to dephosphorylate Gab1 (Figure\u00a0 xref C).

SIGNOR-276965

Q14247

Q14689

0

acetylation

up-regulates activity

0.2

DIP2A binds to cortactin and modulates cortactin acetylation. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin.

SIGNOR-266589

P06730

O14965

0

phosphorylation

up-regulates activity

0.278

In this study, we demonstrated for the first time that AURKA can phosphorylate and activate EIF4E.

SIGNOR-279495

P51812

P05204

1

phosphorylation

down-regulates activity

0.29

We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets.

SIGNOR-249102

Q9H0K1

P27986

1

phosphorylation

up-regulates activity

0.322

The Regulatory Subunit of PI3K Is a Direct Catalytic Target of SIK2. These data confirm that p85α is a direct catalytic substrate of SIK2 and that SIK2 S154 phosphorylation significantly increases the activity of the PI3K/AKT pathway in ovarian cancer cells.

SIGNOR-277269

Q6MZQ0

Q8WZ73

0

polyubiquitination

down-regulates quantity by destabilization

0.261

RFFL is an E3 ligase for PRR5L.

SIGNOR-271495

Q02156

P18507

1

phosphorylation

down-regulates activity

0.233

Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol.

SIGNOR-263174

P31268

O15550

0

transcriptional regulation

up-regulates quantity by expression

0.275

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260024

Q16512

Q92974

1

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

P07288

P19838

0

transcriptional regulation

up-regulates quantity by expression

0.2

NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer.

SIGNOR-253668

Q16539

Q16690

0

dephosphorylation

down-regulates

0.537

The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues.

SIGNOR-166574

P42336

Q13043

0

phosphorylation

down-regulates activity

0.2

MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061

SIGNOR-277920

Q96EB6

O15105

1

deacetylation

down-regulates

0.441

Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells.

SIGNOR-150595

P28482

P19793

1

phosphorylation

down-regulates activity

0.534

In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE

SIGNOR-262958

P17844

Q9P286

0

phosphorylation

up-regulates quantity by stabilization

0.2

PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer|The increased expression levels of PAK5 and phospho-DDX5 threonine 69 are associated with metastasis and poor clinical outcomes of patients. PAK5 facilitates the phosphorylation-dependent sumoylation of DDX5 to stabilize DDX5. Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing.

SIGNOR-275658

Q5XUX0

P31749

0

phosphorylation

down-regulates quantity by destabilization

0.2

Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT.

SIGNOR-277376

P28482

Q9NYA1

1

phosphorylation

up-regulates

0.561

Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.

SIGNOR-118546

P36888

P43405

0

phosphorylation

up-regulates activity

0.407

Only two mutants, FLT3-KD (V5) Y768A and Y955A, were resistant to SYK-mediated FLT3 phosphorylation, suggesting that SYK directly phosphorylates FLT3 at sites Y768 and Y955 ( ).|SYK Enhances FLT3 WT and Mutant Activation by Phosphorylation of Residues Y768 and Y955.

SIGNOR-278431

Q13422

P36873

0

dephosphorylation

up-regulates

0.329

Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway

SIGNOR-174865

Q96SW2

Q9H3D4

1

polyubiquitination

down-regulates quantity by destabilization

0.2

CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs.When thalidomide binds to CRBN, substrate specificity of CRL4CRBN is altered and CRBN neomorphically binds to ∆Np63, TAp63 and other neosubstrates and ubiquitinates them for proteasomal degradation.

SIGNOR-272214

Q13315

Q15911

1

phosphorylation

up-regulates activity

0.346

Indeed, ATM phosphorylates ATBF1 at Ser1180 in HEK293T cells exposed to 10-Gy radiation [ xref ].|We also found in this study that ATBF1 mediated neuronal death is dependent on ATM signals because the blockage of ATM by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 functions in neuronal death.

SIGNOR-279138

Q9H204

P06239

0

phosphorylation

up-regulates

0.439

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

SIGNOR-148704

O14757

P31749

0

phosphorylation

down-regulates

0.43

The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1.

SIGNOR-124365

Q9Y243

Q01860

1

phosphorylation

up-regulates quantity by stabilization

0.257

Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.

SIGNOR-242107

P36897

P36873

0

dephosphorylation

down-regulates

0.469

We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI.

SIGNOR-121277

Q05655

O15350

1

phosphorylation

up-regulates

0.307

The results show that pkcdeltacf phosphorylates the p73beta transactivation and dna-binding domains. pkcdeltacf-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation.

SIGNOR-90279

Q05655

Q16206

1

phosphorylation

up-regulates

0.2

Tnox is phosphorylated by protein kinase c_ (pkc_) both in vitro and in vivo. Replacement of serine-504 with alanine significantly reduces phosphorylation by pkc_. C. overexpression of the s504a tnox mutant leads to diminished cell proliferation and migration, reflecting reduced stability of the unphosphorylatable tnox mutant protein.

SIGNOR-197706

Q99558

P41279

0

phosphorylation

up-regulates activity

0.559

In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha

SIGNOR-249387

Q15672

Q9UGI0

0

deubiquitination

down-regulates activity

0.331

Trabid inhibits Twist1 activity by cleaving RNF8-mediated Twist1 K63-linked ubiquitination

SIGNOR-273502

Q92973

P09651

1

relocalization

up-regulates activity

0.572

TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import

SIGNOR-262099

Q12778

P53350

0

phosphorylation

down-regulates activity

0.316

In conclusion, we provide evidence that PLK1-dependent phosphorylation of FOXO1 induces its nuclear exclusion and negatively regulates FOXO1 transcriptional activity in PCa.|We previously demonstrated that PLK1 inhibits the transcriptional activity of FOXO1 by promoting its nuclear exclusion in U2OS cells .

SIGNOR-278269

P49736

P50613

0

phosphorylation

up-regulates activity

0.299

Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2.

SIGNOR-259849

P04908

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265397

P27361

O95644

1

phosphorylation

down-regulates

0.532

We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.

SIGNOR-74564

P22694

Q14896

1

phosphorylation

up-regulates

0.274

Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).

SIGNOR-163772

Q9P1W9

P42229

0

transcriptional regulation

up-regulates quantity by expression

0.41

The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells.

SIGNOR-249622

Q96RU2

P01106

1

deubiquitination

up-regulates

0.703

Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc.

SIGNOR-155590

O43318

Q13555

0

phosphorylation

up-regulates

0.2

Camkii interacts with and phosphorylates tak1.

SIGNOR-96422

P10398

P36507

1

phosphorylation

up-regulates

0.754

Active raf phosphorylates mek.

SIGNOR-175142

P68871

O95600

0

transcriptional regulation

down-regulates quantity by repression

0.2

These results establish KLF8 as a CACCC-box binding protein that associates with CtBP and represses transcription.

SIGNOR-266052

Q92574

P28482

0

phosphorylation

down-regulates

0.49

Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin.

SIGNOR-157162

P28482

P06239

1

phosphorylation

up-regulates activity

0.583

Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.

SIGNOR-249412

P62330

Q5JU85

0

guanine nucleotide exchange factor

up-regulates activity

0.457

Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6.

SIGNOR-264906

Q96FA3

O15151

1

ubiquitination

up-regulates activity

0.434

We found that Peli1 induces Mdmx ubiquitination without promoting its degradation, which leads to the cytoplasmic localization of Mdmx and subsequent activation of p53 function.

SIGNOR-278773

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

P63000

Q15311

0

gtpase-activating protein

down-regulates activity

0.582

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-260513

Q8IUR6

Q15011

1

transcriptional regulation

up-regulates quantity by expression

0.2

Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element.

SIGNOR-261575

Q9H4E7

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.392

Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner.

SIGNOR-253369

P04637

Q2Q1W2

0

ubiquitination

down-regulates quantity

0.272

LIN41 promotes ubiquitination of p53 in response to RA.|Loss of LIN41 elevates p53 steady-state levels and reduces p53 ubiquitination.

SIGNOR-278679

P09874

P08581

0

phosphorylation

up-regulates activity

0.388

Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907).|To address whether c-Met activates PARP1, we exposed MDA-MB-231 cells expressing control shRNA or c-Met shRNA to H 2 O 2 and subjected them to a comet assay to evaluate the extent of DNA damage.

SIGNOR-279470

O14543

P40763

0

transcriptional regulation

up-regulates quantity by expression

0.709

We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells

SIGNOR-253583

P40337

P48200

1

ubiquitination

down-regulates quantity by destabilization

0.359

We show here that IRP2 can interact with pVHL in co-transfection/co-immunoprecipitation assays. Furthermore, pVHL is able to promote the ubiquitination and the decay of transfected IRP2.

SIGNOR-271421

Q9H3Y6

Q13451

1

phosphorylation

down-regulates quantity by destabilization

0.267

SRMS binds FKBP51 and phosphorylates tyrosine 54. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway.

SIGNOR-277564

P17612

P41240

1

phosphorylation

up-regulates activity

0.338

Activation of the cooh-terminal src kinase (csk) by camp-dependent protein kinase inhibits signaling through the t cell receptor.Pka phosphorylates csk at s364 in vitro and in vivo leading to a two- to fourfold increase in csk activity that is necessary for camp-mediated inhibition of tcr-induced interleukin 2 secretion.

SIGNOR-105229

Q13501

P00533

0

phosphorylation

down-regulates activity

0.33

Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturbs the sequestration function of SQSTM1 and causes autophagic flux blocking.

SIGNOR-277500

P51817

P98161

1

phosphorylation

up-regulates

0.257

The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd.

SIGNOR-158852

P17612

Q13185

1

phosphorylation

up-regulates

0.2

We demonstrate that p-ser 83-hp1gamma has an exclusively euchromatic localization, interacts with ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation.

SIGNOR-145109

P35568

P45983

0

phosphorylation

down-regulates activity

0.771

Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.

SIGNOR-96948

O60674

Q9UGK3

1

phosphorylation

up-regulates activity

0.343

To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 8060% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2.

SIGNOR-249372