GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q9HD26	P13569	2	binding	down-regulates	0.721	Cal binds to cftr / cal affects insertion of cftr to the plasma membrane as well as its half-life in the plasma membrane.	SIGNOR-111671
Q9UNE7	P04626	1	ubiquitination	down-regulates quantity by destabilization	0.627	The ErbB2 kinase domain is required for GA-induced and CHIP-dependent ErbB2 ubiquitination and degradation .	SIGNOR-278645
O14939	P17252	0	phosphorylation	up-regulates	0.692	The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity	SIGNOR-138355
Q9H2C0	Q676U5	1	ubiquitination	down-regulates quantity	0.2	Here we identify Gigaxonin24, an E3 ligase mutated in a fatal neurodegenerative disease called giant axonal neuropathy (GAN)25, as the first regulator of ATG16L1. Gigaxonin poly-ubiquitinates and controls the degradation of ATG16L1, and is essential to activate autophagy.	SIGNOR-268948
O14974	O14757	0	phosphorylation	down-regulates quantity by destabilization	0.2	MYPT1 is phosphorylated by CDK1, thus recruiting protein phosphatase 1β (PP1cβ) to dephosphorylate and inactivate Plk1. Here we identified that Chk1 directly interacts with MYPT1 and preferentially phosphorylates MYPT1 at Ser20, which is essential for MYPT1-PP1cβ interaction and subsequent Plk1 dephosphorylation.	SIGNOR-277870
P10914	Q02556	2	binding	up-regulates activity	0.396	We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP.	SIGNOR-222841
Q9P0J1	O60674	0	phosphorylation	down-regulates activity	0.264	Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.	SIGNOR-276642
P51149	Q15904	2	binding	up-regulates activity	0.29	We found that Ac45 colocalized with Rab7 in resorbing osteoclasts cultured on bone slices (Fig. 6A). In addition, a co-immunoprecipitation assay revealed that Ac45 directly interacted with Rab7\| Therefore, Ac45’s role in extracellular acidification, lysosomal trafficking, and cathepsin K exocytosis may be through the Rab7 pathway.	SIGNOR-261484
O15530	Q16512	1	phosphorylation	up-regulates	0.567	It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)	SIGNOR-76640
P04150	Q53ET0	2	binding	up-regulates activity	0.294	We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR).	SIGNOR-256101
Q14814	P35580	1	transcriptional regulation	up-regulates quantity by expression	0.322	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238766
P42224	P45983	0	phosphorylation	up-regulates activity	0.445	SP600125 prevented phosphorylation of STAT1 at Tyr701 site [..] Western blot analysis confirmed that blocking p-JNK using SP600125 markedly reduced STAT3 localization in the nucleus and STAT1 phosphorylation	SIGNOR-251101
Q96F24	Q99570	2	binding	down-regulates activity	0.649	NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity.	SIGNOR-265878
P12931	Q92974	1	phosphorylation	up-regulates activity	0.415	Src activates GEF-H1.	SIGNOR-277478
Q7Z434	Q9BYX4	2	binding	up-regulates activity	0.814	Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ.	SIGNOR-260140
P68400	P08047	1	phosphorylation	down-regulates activity	0.34	Casein kinase II-mediated phosphorylation of the C terminus of Sp1 decreases its DNA binding activity. \| Mutation of a consensus CKII site at amino acid 579, within the second zinc finger, eliminates phosphorylation of this site and the CKII-mediated inhibition of Sp1 binding.	SIGNOR-250954
Q8WU17	O15503	1	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
Q16539	Q96L92	1	phosphorylation	down-regulates activity	0.2	Altogether, our study suggests that MAPK11 and MAPK14 mediate the phosphorylation of SNX27 at Ser51 in vitro and in vivo.	SIGNOR-279069
P31751	P99999	1	phosphorylation	down-regulates activity	0.293	Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.	SIGNOR-277236
Q04760	P00519	0	phosphorylation	up-regulates activity	0.2	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276187
A8MYZ6	Q12857	0	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-268875
P42229	Q15788	2	binding	up-regulates	0.405	Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain.	SIGNOR-100258
Q9H2X6	P12931	0	phosphorylation	up-regulates activity	0.307	Using mass spectrometry we identified 9 Src-mediated Tyr-phosphorylation sites within HIPK2, 5 of them positioned in the kinase domain.\|We demonstrate that ectopic expression of Src increases the half-life of HIPK2 by interfering with Siah-1-mediated HIPK2 degradation.	SIGNOR-278989
Q6P2M8	O43432	1	phosphorylation	up-regulates	0.2	Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii).	SIGNOR-197190
P50553	Q9HCK8	0	transcriptional regulation	down-regulates quantity	0.2	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268914
O60674	Q99683	1	phosphorylation	down-regulates quantity by destabilization	0.367	Furthermore, JAK2, but not JAK1, directly bound to and phosphorylated ASK1 at Tyr-718, leading to an enhanced association of ASK1 with SOCS1 and subsequent ASK1 degradation.	SIGNOR-276145
O75581	P17612	0	phosphorylation	up-regulates activity	0.2	These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit.	SIGNOR-181979
P10244	P10909	1	transcriptional regulation	up-regulates quantity by expression	0.274	Here we show that the human ApoJ/Clusterin gene contains a Myb binding site in its 5' flanking region, which interacts with bacterially synthesized B-MYB protein and mediates B-MYB-dependent transactivation of the ApoJ/Clusterin promoter in transient transfection assays. Endogenous ApoJ/Clusterin expression is induced in mammalian cell lines following transient transfection of a B-MYB cDNA.	SIGNOR-269800
Q14790	Q7Z434	0	relocalization	up-regulates	0.587	Another protein suggested to play a role in caspase-8 translocation to mitochondria is the mitochondrial membrane protein cardif	SIGNOR-143572
Q96S38	Q9NYA1	2	binding	up-regulates activity	0.384	The PSK2 domain of RPK118 is required for binding to SPHK1 as demonstrated by the results from immunoprecipitation analyses (Fig. 6) as well as yeast two-hybrid screening (Fig. 1A). The overexpression of RPK118 in COS7 cells did not cause any change in the intracellular content of SPP with repeated experiments, and RPK118 binding to SPHK1 did not alter the enzymatic activity of SPHK1 in vitro (data not shown), suggesting that RPK118 may function only as an adaptor molecule for SPHK1	SIGNOR-273744
O00401	Q05397	0	phosphorylation	up-regulates activity	0.69	In addition, FAK can phosphorylate N-WASP and promote actin polymerization, and inhibition of FAK kinase activity suppresses N-WASP activity.	SIGNOR-278977
Q9UPX8	O95886	0	relocalization	up-regulates activity	0.788	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-264593
P06241	P05067	1	phosphorylation	up-regulates quantity	0.451	Fyn induced phosphorylation of APP at Tyr-757 of the (757)YENPTY(762) motif and increased cell surface expression of APP.	SIGNOR-278378
Q8IXJ6	P24941	0	phosphorylation	down-regulates	0.395	We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2.	SIGNOR-177972
P37173	P27986	2	binding	up-regulates	0.448	These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.	SIGNOR-227521
O14920	Q99704	1	phosphorylation	up-regulates	0.253	Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility.	SIGNOR-131447
P46934	P43405	1	polyubiquitination	down-regulates quantity by destabilization	0.291	The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is implicated in the maintenance of viral latency and appears to function in part by inhibiting B-cell receptor (BCR) signaling. LMP2A enhances Lyn and Syk ubiquitination in vivo in a fashion that depends on the activity of Nedd4 family members and correlates with destabilization of the Lyn tyrosine kinase. These results suggest that LMP2A serves as a molecular scaffold to recruit both B-cell tyrosine kinases and C2/WW/Hect domain E3 protein-ubiquitin ligases.	SIGNOR-272581
P17752	P17612	0	phosphorylation	up-regulates activity	0.35	The activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme.	SIGNOR-250062
Q00987	P35790	0	phosphorylation	down-regulates quantity by destabilization	0.274	The data presented here provides evidence for a molecular mechanism by which CKI-dependent phosphorylation of Mdm2 at multiple sites triggers SCF \u03b2-TRCP -mediated Mdm2 destruction ( xref ).	SIGNOR-279606
O14965	Q96CX2	1	phosphorylation	up-regulates activity	0.272	In addition, Aurora A phosphorylated KCTD12 at serine 243, thereby initiating a positive feedback loop necessary for KCTD12 to exert its cancer-promoting effects.	SIGNOR-273544
Q8N726	P06748	2	binding	down-regulates quantity by destabilization	0.552	The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division	SIGNOR-245077
P29350	P08922	1	dephosphorylation	down-regulates	0.368	Overexpression of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation. We propose that shp-1 is an important downstream regulator of ros signaling.	SIGNOR-105922
P52306	P60953	2	binding	up-regulates	0.288	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171412
P10619	P19484	0	transcriptional regulation	up-regulates quantity by expression	0.298	Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy\|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1\|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants	SIGNOR-276549
P10415	Q14457	2	binding	down-regulates	0.739	In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function.	SIGNOR-156941
Q15942	P06493	0	phosphorylation	up-regulates activity	0.309	As predicted by our hypothesis, the Cdc2 dependent phosphorylation has been shown to allow the full-length zyxin to interact with h-warts and LATS1 (XREF_FIG A).\|Phosphorylation of Zyxin by Cdc2 Regulates Binding to h-warts and LATS1.	SIGNOR-279498
P48730	P02810	1	phosphorylation	up-regulates	0.2	Ser22 may be phosphorylated by a g-ck that recognizes an atypical substrate sequence or by a novel kinase. While prp1 secreted from salivary glands is fully phosphorylated at ser8 and 22	SIGNOR-75272
P67775	Q92769	1	dephosphorylation	down-regulates activity	0.281	In contrast, in the present work, PPP2CA reduced HDAC2 S394 phosphorylation.\|We postulated that PPP2CA would negatively regulate phospho dependent HDAC2 activity.	SIGNOR-277049
Q9UQ26	Q9UFD9	2	binding	down-regulates activity	0.358	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264365
P00519	O43586	1	phosphorylation	up-regulates activity	0.597	PSTPIP1 was phosphorylated by c-Abl. Tyr-344 is a major c-Abl phosphorylation site.PSTPIP1 was able to bridge c-Abl to the PEST-type PTPs.	SIGNOR-251431
Q13418	Q9HBI1	1	phosphorylation	up-regulates activity	0.965	These results indicate that affixin directly associates with \u03b1-actinin only when its CH2 domain is phosphorylated by ILK.\|This may indicate that phosphorylation of the CH2 domain by ILK induces a conformational change of the CH2 domain of affixin, which enables affixin to interact with alpha-actinin to evoke the subsequent maturation of the FA complex.	SIGNOR-278259
Q03112	P68400	0	phosphorylation	up-regulates activity	0.2	We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation.	SIGNOR-273427
P53350	Q99708	1	phosphorylation	up-regulates activity	0.347	PLK1 targets CtIP to promote microhomology mediated end joining.\|We further showed that the DSB repair factor CtIP is jointly phosphorylated by CDK1 and Aurora A and PLK1.	SIGNOR-279253
P50570	P29033	2	binding	down-regulates	0.328	This study identifies dynamin 2 (dyn2) as a cx26 interactor in yeast and mammalian cells / we demonstrate that dyn2 regulates cx26 endocytosis and ubiquitination	SIGNOR-205372
O14647	P09874	2	binding	up-regulates quantity	0.2	Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage.	SIGNOR-264526
Q96NI6	Q13332	2	binding	up-regulates activity	0.368	SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1).	SIGNOR-264088
Q9Y6F9	Q9NPG1	2	binding	up-regulates	0.628	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131891
P15941	P78536	0	cleavage	down-regulates	0.308	These characteristics along with studies conducted with cell lines genetically deficient in various adams (for a disintegrin and metalloprotease) identified tumor necrosis factor-alpha converting enzyme (tace)/adam 17 as a muc1 sheddase.	SIGNOR-95630
Q9Y3L3	P63000	1	gtpase-activating protein	down-regulates activity	0.38	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-260514
Q12913	P35222	1	dephosphorylation	up-regulates activity	0.519	Our data demonstrate that CD148 promotes E-cadherin cell adhesion by regulating Rac1 activity, concomitant with modulation of p120, \u03b2-catenin, and Src tyrosine phosphorylation, and that this effect requires E-cadherin and p120 association.\|Taken together, it is likely that CD148 dephosphorylation of \u03b2-catenin enhances the cadherin cell adhesion independent of Rho family GTPases.	SIGNOR-276992
P48200	Q9UKA1	2	binding	down-regulates quantity by destabilization	0.746	We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus.	SIGNOR-271882
P08047	P08581	1	transcriptional regulation	up-regulates quantity by expression	0.319	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-241490
P03372	P50613	0	phosphorylation	up-regulates	0.413	Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7.	SIGNOR-81170
P54578	P31749	0	phosphorylation	up-regulates activity	0.424	Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system\|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt.	SIGNOR-265056
Q16539	P15336	1	phosphorylation	up-regulates	0.793	On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.	SIGNOR-65597
P42261	Q5JU85	0	relocalization	up-regulates quantity	0.2	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264912
P49841	Q7Z2W4	1	phosphorylation	up-regulates activity	0.2	GSK3beta sequentially phosphorylated Ser 270, Ser 266, Ser 262, and Ser 257 of rat ZAP.\|Inhibition of GSK3\u03b2 by inhibitor SB216763 or down-regulation of GSK3\u03b2 by RNAi reduced the antiviral activity of Zinc-finger antiviral protein.	SIGNOR-278401
Q5H8C1	Q6UXI9	1	transcriptional regulation	up-regulates quantity by expression	0.366	The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome.	SIGNOR-253308
P42679	P07948	1	phosphorylation	down-regulates activity	0.333	In vitro phosphorylation assays showed that Chk suppressed Lyn activity by phosphorylating its C-terminal negative regulatory tyrosine.	SIGNOR-250177
O94761	P24941	0	phosphorylation	up-regulates activity	0.329	During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs.	SIGNOR-277374
Q99801	Q9Y463	0	phosphorylation	down-regulates quantity by destabilization	0.332	In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover.	SIGNOR-279610
Q14344	P17612	0	phosphorylation	down-regulates activity	0.366	PKA directly phosphorylates Galpha(13). Galpha(13)-T203A mutant (in COS-7 cells) could not be phosphorylated by PKA. PKA blocks Rho activation by phosphorylation of Galpha(13) Thr(203).	SIGNOR-249985
P17252	P11387	1	phosphorylation	up-regulates activity	0.2	In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells.	SIGNOR-276154
Q9GZX6	Q08334	2	binding	up-regulates	0.696	See table 2	SIGNOR-151880
Q13882	P31749	1	phosphorylation	up-regulates	0.476	Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6.	SIGNOR-252622
P36508	P17987	1	transcriptional regulation	up-regulates quantity by expression	0.347	The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription.	SIGNOR-266221
Q7Z434	Q9UHD2	2	binding	up-regulates activity	0.913	After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively.	SIGNOR-260145
Q04759	P29474	1	phosphorylation	down-regulates activity	0.2	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251636
Q08881	Q06187	2	phosphorylation	down-regulates activity	0.497	Btk-SH3 mutant Y223A was not phosphorylated by Itk. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.\|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role	SIGNOR-251333
P12931	Q9H2X6	1	phosphorylation	up-regulates activity	0.307	Using mass spectrometry we identified 9 Src-mediated Tyr-phosphorylation sites within HIPK2, 5 of them positioned in the kinase domain.\|We demonstrate that ectopic expression of Src increases the half-life of HIPK2 by interfering with Siah-1-mediated HIPK2 degradation.	SIGNOR-278989
O15550	P31276	1	transcriptional regulation	up-regulates quantity by expression	0.267	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-260027
P61328	Q15858	2	binding	down-regulates activity	0.2	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253424
P05412	Q14164	0	phosphorylation	up-regulates activity	0.316	Indeed, using an in vitro kinase assay, we demonstrated that both JNK and IKKepsilon phosphorylated c-Jun (XREF_FIG and XREF_SUPPLEMENTARY).	SIGNOR-279621
P00533	P19174	1	phosphorylation	up-regulates	0.841	We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation.	SIGNOR-20984
Q9UEW8	P55011	1	phosphorylation	up-regulates activity	0.6	This phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1	SIGNOR-264642
O00273	P42574	0	cleavage	up-regulates activity	0.755	DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3.	SIGNOR-47416
Q9ULW0	P06493	0	phosphorylation	down-regulates activity	0.637	In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. \|Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle	SIGNOR-265096
Q12986	P11940	2	binding	up-regulates activity	0.344	NFX1-123 augments the activation of hTERT expression through interactions with PABPCs	SIGNOR-226011
O15344	P18031	1	ubiquitination	down-regulates quantity	0.2	Proteasome inhibitor treatment diminished the decrease of PTP1B (Figure 5F) caused by TRIM18 overexpression.\|TRIM18 Interacts With PTP1B and Promotes PTP1B Ubiquitination.	SIGNOR-278703
P10636	Q15759	0	phosphorylation	down-regulates activity	0.341	Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in its ability to promote microtubule assembly.\|Tau phosphorylated by SAPK2b and SAPK2a also reacted with AT8, whereas AT8 failed to recognise tau phosphorylated by SAPK1gamma.	SIGNOR-279637
P53420	Q92626	0	catalytic activity	up-regulates quantity by stabilization	0.256	Peroxidasin (PXDN), an ECM protein with peroxidase activity, is integral to basement membrane consolidation through catalysis of sulfilimine bonds in collagen IV. PXDN has been shown to form dityrosine crosslinks and also catalyses sulfilimine bonds, in the presence of hypohalous acids, to connect collagen IV protomers, which are an integral component of the basement membrane	SIGNOR-265250
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
Q8IYL9	P63096	2	binding	up-regulates activity	0.271	GPR65 is playing a critical role in phagocytic cells that require high levels of V-ATPase activity to maintain phagosomal and lysosomal pH, and this activity aids in the direct clearance of enteric pathogens.	SIGNOR-272502
P38405	P35368	2	binding	up-regulates activity	0.278	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256950
Q15910	Q8NG27	0	ubiquitination	down-regulates quantity by destabilization	0.488	Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2	SIGNOR-255664
Q01094	O96017	0	phosphorylation	up-regulates quantity by stabilization	0.487	We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage	SIGNOR-100898
P53667	P49137	0	phosphorylation	up-regulates	0.36	Mk2 activated limk1 by phosphorylation at ser-323.	SIGNOR-144333
Q02078	Q86X55	0	methylation	up-regulates	0.387	The first evidence alluding to a role of PRMTs in mediating skeletal muscle plasticity, specifically myogenesis, arose from the identification of CARM1 as a glucocorticoid receptor-interacting protein 1 (GRIP1) binding protein. (Chen et al., 2000). Here, GRIP1 and MEF2 were co-expressed in the nucleus during skeletal muscle differentiation. These initial findings led to an investigation that revealed that this methyltransferase was responsible for coactivating the transcription of myocyte enhancer factor-2C (MEF2C) via GRIP1	SIGNOR-255964
Q9Y3I1	O43379	1	ubiquitination	down-regulates quantity by destabilization	0.2	WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. \|JNK1 can induce the phosphorylation of WDR62 T1053	SIGNOR-271711
P02671	P45452	0	cleavage	down-regulates quantity by destabilization	0.2	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII\| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.\|MMP-13 27YVATRDN g-chain\| 20ADSGEGD a-chain\| 124RNSVDXLNXN b-chain\| 442LRTGKEKV a-chain	SIGNOR-263613

Q9HD26

P13569

2

binding

down-regulates

0.721

Cal binds to cftr / cal affects insertion of cftr to the plasma membrane as well as its half-life in the plasma membrane.

SIGNOR-111671

Q9UNE7

P04626

1

ubiquitination

down-regulates quantity by destabilization

0.627

The ErbB2 kinase domain is required for GA-induced and CHIP-dependent ErbB2 ubiquitination and degradation .

SIGNOR-278645

O14939

P17252

0

phosphorylation

up-regulates

0.692

The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity

SIGNOR-138355

Q9H2C0

Q676U5

1

ubiquitination

down-regulates quantity

0.2

Here we identify Gigaxonin24, an E3 ligase mutated in a fatal neurodegenerative disease called giant axonal neuropathy (GAN)25, as the first regulator of ATG16L1. Gigaxonin poly-ubiquitinates and controls the degradation of ATG16L1, and is essential to activate autophagy.

SIGNOR-268948

O14974

O14757

0

phosphorylation

down-regulates quantity by destabilization

0.2

MYPT1 is phosphorylated by CDK1, thus recruiting protein phosphatase 1β (PP1cβ) to dephosphorylate and inactivate Plk1. Here we identified that Chk1 directly interacts with MYPT1 and preferentially phosphorylates MYPT1 at Ser20, which is essential for MYPT1-PP1cβ interaction and subsequent Plk1 dephosphorylation.

SIGNOR-277870

P10914

Q02556

2

binding

up-regulates activity

0.396

We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP.

SIGNOR-222841

Q9P0J1

O60674

0

phosphorylation

down-regulates activity

0.264

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

SIGNOR-276642

P51149

Q15904

2

binding

up-regulates activity

0.29

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

SIGNOR-261484

O15530

Q16512

1

phosphorylation

up-regulates

0.567

It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)

SIGNOR-76640

P04150

Q53ET0

2

binding

up-regulates activity

0.294

We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR).

SIGNOR-256101

Q14814

P35580

1

transcriptional regulation

up-regulates quantity by expression

0.322

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238766

P42224

P45983

0

phosphorylation

up-regulates activity

0.445

SP600125 prevented phosphorylation of STAT1 at Tyr701 site [..] Western blot analysis confirmed that blocking p-JNK using SP600125 markedly reduced STAT3 localization in the nucleus and STAT1 phosphorylation

SIGNOR-251101

Q96F24

Q99570

2

binding

down-regulates activity

0.649

NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity.

SIGNOR-265878

P12931

Q92974

1

phosphorylation

up-regulates activity

0.415

Src activates GEF-H1.

SIGNOR-277478

Q7Z434

Q9BYX4

2

binding

up-regulates activity

0.814

Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ.

SIGNOR-260140

P68400

P08047

1

phosphorylation

down-regulates activity

0.34

Casein kinase II-mediated phosphorylation of the C terminus of Sp1 decreases its DNA binding activity. | Mutation of a consensus CKII site at amino acid 579, within the second zinc finger, eliminates phosphorylation of this site and the CKII-mediated inhibition of Sp1 binding.

SIGNOR-250954

Q8WU17

O15503

1

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

Q16539

Q96L92

1

phosphorylation

down-regulates activity

0.2

Altogether, our study suggests that MAPK11 and MAPK14 mediate the phosphorylation of SNX27 at Ser51 in vitro and in vivo.

SIGNOR-279069

P31751

P99999

1

phosphorylation

down-regulates activity

0.293

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

SIGNOR-277236

Q04760

P00519

0

phosphorylation

up-regulates activity

0.2

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).

SIGNOR-276187

A8MYZ6

Q12857

0

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-268875

P42229

Q15788

2

binding

up-regulates

0.405

Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain.

SIGNOR-100258

Q9H2X6

P12931

0

phosphorylation

up-regulates activity

0.307

Using mass spectrometry we identified 9 Src-mediated Tyr-phosphorylation sites within HIPK2, 5 of them positioned in the kinase domain.|We demonstrate that ectopic expression of Src increases the half-life of HIPK2 by interfering with Siah-1-mediated HIPK2 degradation.

SIGNOR-278989

Q6P2M8

O43432

1

phosphorylation

up-regulates

0.2

Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii).

SIGNOR-197190

P50553

Q9HCK8

0

transcriptional regulation

down-regulates quantity

0.2

Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells

SIGNOR-268914

O60674

Q99683

1

phosphorylation

down-regulates quantity by destabilization

0.367

Furthermore, JAK2, but not JAK1, directly bound to and phosphorylated ASK1 at Tyr-718, leading to an enhanced association of ASK1 with SOCS1 and subsequent ASK1 degradation.

SIGNOR-276145

O75581

P17612

0

phosphorylation

up-regulates activity

0.2

These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit.

SIGNOR-181979

P10244

P10909

1

transcriptional regulation

up-regulates quantity by expression

0.274

Here we show that the human ApoJ/Clusterin gene contains a Myb binding site in its 5' flanking region, which interacts with bacterially synthesized B-MYB protein and mediates B-MYB-dependent transactivation of the ApoJ/Clusterin promoter in transient transfection assays. Endogenous ApoJ/Clusterin expression is induced in mammalian cell lines following transient transfection of a B-MYB cDNA.

SIGNOR-269800

Q14790

Q7Z434

0

relocalization

up-regulates

0.587

Another protein suggested to play a role in caspase-8 translocation to mitochondria is the mitochondrial membrane protein cardif

SIGNOR-143572

Q96S38

Q9NYA1

2

binding

up-regulates activity

0.384

The PSK2 domain of RPK118 is required for binding to SPHK1 as demonstrated by the results from immunoprecipitation analyses (Fig. 6) as well as yeast two-hybrid screening (Fig. 1A). The overexpression of RPK118 in COS7 cells did not cause any change in the intracellular content of SPP with repeated experiments, and RPK118 binding to SPHK1 did not alter the enzymatic activity of SPHK1 in vitro (data not shown), suggesting that RPK118 may function only as an adaptor molecule for SPHK1

SIGNOR-273744

O00401

Q05397

0

phosphorylation

up-regulates activity

0.69

In addition, FAK can phosphorylate N-WASP and promote actin polymerization, and inhibition of FAK kinase activity suppresses N-WASP activity.

SIGNOR-278977

Q9UPX8

O95886

0

relocalization

up-regulates activity

0.788

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-264593

P06241

P05067

1

phosphorylation

up-regulates quantity

0.451

Fyn induced phosphorylation of APP at Tyr-757 of the (757)YENPTY(762) motif and increased cell surface expression of APP.

SIGNOR-278378

Q8IXJ6

P24941

0

phosphorylation

down-regulates

0.395

We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2.

SIGNOR-177972

P37173

P27986

2

binding

up-regulates

0.448

These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.

SIGNOR-227521

O14920

Q99704

1

phosphorylation

up-regulates

0.253

Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility.

SIGNOR-131447

P46934

P43405

1

polyubiquitination

down-regulates quantity by destabilization

0.291

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

SIGNOR-272581

P17752

P17612

0

phosphorylation

up-regulates activity

0.35

The activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme.

SIGNOR-250062

Q00987

P35790

0

phosphorylation

down-regulates quantity by destabilization

0.274

The data presented here provides evidence for a molecular mechanism by which CKI-dependent phosphorylation of Mdm2 at multiple sites triggers SCF \u03b2-TRCP -mediated Mdm2 destruction ( xref ).

SIGNOR-279606

O14965

Q96CX2

1

phosphorylation

up-regulates activity

0.272

In addition, Aurora A phosphorylated KCTD12 at serine 243, thereby initiating a positive feedback loop necessary for KCTD12 to exert its cancer-promoting effects.

SIGNOR-273544

Q8N726

P06748

2

binding

down-regulates quantity by destabilization

0.552

The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division

SIGNOR-245077

P29350

P08922

1

dephosphorylation

down-regulates

0.368

Overexpression of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation. We propose that shp-1 is an important downstream regulator of ros signaling.

SIGNOR-105922

P52306

P60953

2

binding

up-regulates

0.288

Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob

SIGNOR-171412

P10619

P19484

0

transcriptional regulation

up-regulates quantity by expression

0.298

Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants

SIGNOR-276549

P10415

Q14457

2

binding

down-regulates

0.739

In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function.

SIGNOR-156941

Q15942

P06493

0

phosphorylation

up-regulates activity

0.309

As predicted by our hypothesis, the Cdc2 dependent phosphorylation has been shown to allow the full-length zyxin to interact with h-warts and LATS1 (XREF_FIG A).|Phosphorylation of Zyxin by Cdc2 Regulates Binding to h-warts and LATS1.

SIGNOR-279498

P48730

P02810

1

phosphorylation

up-regulates

0.2

Ser22 may be phosphorylated by a g-ck that recognizes an atypical substrate sequence or by a novel kinase. While prp1 secreted from salivary glands is fully phosphorylated at ser8 and 22

SIGNOR-75272

P67775

Q92769

1

dephosphorylation

down-regulates activity

0.281

In contrast, in the present work, PPP2CA reduced HDAC2 S394 phosphorylation.|We postulated that PPP2CA would negatively regulate phospho dependent HDAC2 activity.

SIGNOR-277049

Q9UQ26

Q9UFD9

2

binding

down-regulates activity

0.358

SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.

SIGNOR-264365

P00519

O43586

1

phosphorylation

up-regulates activity

0.597

PSTPIP1 was phosphorylated by c-Abl. Tyr-344 is a major c-Abl phosphorylation site.PSTPIP1 was able to bridge c-Abl to the PEST-type PTPs.

SIGNOR-251431

Q13418

Q9HBI1

1

phosphorylation

up-regulates activity

0.965

These results indicate that affixin directly associates with \u03b1-actinin only when its CH2 domain is phosphorylated by ILK.|This may indicate that phosphorylation of the CH2 domain by ILK induces a conformational change of the CH2 domain of affixin, which enables affixin to interact with alpha-actinin to evoke the subsequent maturation of the FA complex.

SIGNOR-278259

Q03112

P68400

0

phosphorylation

up-regulates activity

0.2

We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation.

SIGNOR-273427

P53350

Q99708

1

phosphorylation

up-regulates activity

0.347

PLK1 targets CtIP to promote microhomology mediated end joining.|We further showed that the DSB repair factor CtIP is jointly phosphorylated by CDK1 and Aurora A and PLK1.

SIGNOR-279253

P50570

P29033

2

binding

down-regulates

0.328

This study identifies dynamin 2 (dyn2) as a cx26 interactor in yeast and mammalian cells / we demonstrate that dyn2 regulates cx26 endocytosis and ubiquitination

SIGNOR-205372

O14647

P09874

2

binding

up-regulates quantity

0.2

Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage.

SIGNOR-264526

Q96NI6

Q13332

2

binding

up-regulates activity

0.368

SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1).

SIGNOR-264088

Q9Y6F9

Q9NPG1

2

binding

up-regulates

0.628

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131891

P15941

P78536

0

cleavage

down-regulates

0.308

These characteristics along with studies conducted with cell lines genetically deficient in various adams (for a disintegrin and metalloprotease) identified tumor necrosis factor-alpha converting enzyme (tace)/adam 17 as a muc1 sheddase.

SIGNOR-95630

Q9Y3L3

P63000

1

gtpase-activating protein

down-regulates activity

0.38

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-260514

Q12913

P35222

1

dephosphorylation

up-regulates activity

0.519

Our data demonstrate that CD148 promotes E-cadherin cell adhesion by regulating Rac1 activity, concomitant with modulation of p120, \u03b2-catenin, and Src tyrosine phosphorylation, and that this effect requires E-cadherin and p120 association.|Taken together, it is likely that CD148 dephosphorylation of \u03b2-catenin enhances the cadherin cell adhesion independent of Rho family GTPases.

SIGNOR-276992

P48200

Q9UKA1

2

binding

down-regulates quantity by destabilization

0.746

We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus.

SIGNOR-271882

P08047

P08581

1

transcriptional regulation

up-regulates quantity by expression

0.319

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-241490

P03372

P50613

0

phosphorylation

up-regulates

0.413

Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7.

SIGNOR-81170

P54578

P31749

0

phosphorylation

up-regulates activity

0.424

Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt.

SIGNOR-265056

Q16539

P15336

1

phosphorylation

up-regulates

0.793

On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.

SIGNOR-65597

P42261

Q5JU85

0

relocalization

up-regulates quantity

0.2

BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.

SIGNOR-264912

P49841

Q7Z2W4

1

phosphorylation

up-regulates activity

0.2

GSK3beta sequentially phosphorylated Ser 270, Ser 266, Ser 262, and Ser 257 of rat ZAP.|Inhibition of GSK3\u03b2 by inhibitor SB216763 or down-regulation of GSK3\u03b2 by RNAi reduced the antiviral activity of Zinc-finger antiviral protein.

SIGNOR-278401

Q5H8C1

Q6UXI9

1

transcriptional regulation

up-regulates quantity by expression

0.366

The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome.

SIGNOR-253308

P42679

P07948

1

phosphorylation

down-regulates activity

0.333

In vitro phosphorylation assays showed that Chk suppressed Lyn activity by phosphorylating its C-terminal negative regulatory tyrosine.

SIGNOR-250177

O94761

P24941

0

phosphorylation

up-regulates activity

0.329

During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs.

SIGNOR-277374

Q99801

Q9Y463

0

phosphorylation

down-regulates quantity by destabilization

0.332

In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover.

SIGNOR-279610

Q14344

P17612

0

phosphorylation

down-regulates activity

0.366

PKA directly phosphorylates Galpha(13). Galpha(13)-T203A mutant (in COS-7 cells) could not be phosphorylated by PKA. PKA blocks Rho activation by phosphorylation of Galpha(13) Thr(203).

SIGNOR-249985

P17252

P11387

1

phosphorylation

up-regulates activity

0.2

In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells.

SIGNOR-276154

Q9GZX6

Q08334

2

binding

up-regulates

0.696

See table 2

SIGNOR-151880

Q13882

P31749

1

phosphorylation

up-regulates

0.476

Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6.

SIGNOR-252622

P36508

P17987

1

transcriptional regulation

up-regulates quantity by expression

0.347

The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription.

SIGNOR-266221

Q7Z434

Q9UHD2

2

binding

up-regulates activity

0.913

After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively.

SIGNOR-260145

Q04759

P29474

1

phosphorylation

down-regulates activity

0.2

The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites

SIGNOR-251636

Q08881

Q06187

2

phosphorylation

down-regulates activity

0.497

Btk-SH3 mutant Y223A was not phosphorylated by Itk. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role

SIGNOR-251333

P12931

Q9H2X6

1

phosphorylation

up-regulates activity

0.307

Using mass spectrometry we identified 9 Src-mediated Tyr-phosphorylation sites within HIPK2, 5 of them positioned in the kinase domain.|We demonstrate that ectopic expression of Src increases the half-life of HIPK2 by interfering with Siah-1-mediated HIPK2 degradation.

SIGNOR-278989

O15550

P31276

1

transcriptional regulation

up-regulates quantity by expression

0.267

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-260027

P61328

Q15858

2

binding

down-regulates activity

0.2

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253424

P05412

Q14164

0

phosphorylation

up-regulates activity

0.316

Indeed, using an in vitro kinase assay, we demonstrated that both JNK and IKKepsilon phosphorylated c-Jun (XREF_FIG and XREF_SUPPLEMENTARY).

SIGNOR-279621

P00533

P19174

1

phosphorylation

up-regulates

0.841

We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation.

SIGNOR-20984

Q9UEW8

P55011

1

phosphorylation

up-regulates activity

0.6

This phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1

SIGNOR-264642

O00273

P42574

0

cleavage

up-regulates activity

0.755

DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3.

SIGNOR-47416

Q9ULW0

P06493

0

phosphorylation

down-regulates activity

0.637

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

SIGNOR-265096

Q12986

P11940

2

binding

up-regulates activity

0.344

NFX1-123 augments the activation of hTERT expression through interactions with PABPCs

SIGNOR-226011

O15344

P18031

1

ubiquitination

down-regulates quantity

0.2

Proteasome inhibitor treatment diminished the decrease of PTP1B (Figure 5F) caused by TRIM18 overexpression.|TRIM18 Interacts With PTP1B and Promotes PTP1B Ubiquitination.

SIGNOR-278703

P10636

Q15759

0

phosphorylation

down-regulates activity

0.341

Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in its ability to promote microtubule assembly.|Tau phosphorylated by SAPK2b and SAPK2a also reacted with AT8, whereas AT8 failed to recognise tau phosphorylated by SAPK1gamma.

SIGNOR-279637

P53420

Q92626

0

catalytic activity

up-regulates quantity by stabilization

0.256

Peroxidasin (PXDN), an ECM protein with peroxidase activity, is integral to basement membrane consolidation through catalysis of sulfilimine bonds in collagen IV. PXDN has been shown to form dityrosine crosslinks and also catalyses sulfilimine bonds, in the presence of hypohalous acids, to connect collagen IV protomers, which are an integral component of the basement membrane

SIGNOR-265250

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

Q8IYL9

P63096

2

binding

up-regulates activity

0.271

GPR65 is playing a critical role in phagocytic cells that require high levels of V-ATPase activity to maintain phagosomal and lysosomal pH, and this activity aids in the direct clearance of enteric pathogens.

SIGNOR-272502

P38405

P35368

2

binding

up-regulates activity

0.278

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

SIGNOR-256950

Q15910

Q8NG27

0

ubiquitination

down-regulates quantity by destabilization

0.488

Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2

SIGNOR-255664

Q01094

O96017

0

phosphorylation

up-regulates quantity by stabilization

0.487

We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage

SIGNOR-100898

P53667

P49137

0

phosphorylation

up-regulates

0.36

Mk2 activated limk1 by phosphorylation at ser-323.

SIGNOR-144333

Q02078

Q86X55

0

methylation

up-regulates

0.387

The first evidence alluding to a role of PRMTs in mediating skeletal muscle plasticity, specifically myogenesis, arose from the identification of CARM1 as a glucocorticoid receptor-interacting protein 1 (GRIP1) binding protein. (Chen et al., 2000). Here, GRIP1 and MEF2 were co-expressed in the nucleus during skeletal muscle differentiation. These initial findings led to an investigation that revealed that this methyltransferase was responsible for coactivating the transcription of myocyte enhancer factor-2C (MEF2C) via GRIP1

SIGNOR-255964

Q9Y3I1

O43379

1

ubiquitination

down-regulates quantity by destabilization

0.2

WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053

SIGNOR-271711

P02671

P45452

0

cleavage

down-regulates quantity by destabilization

0.2

Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain

SIGNOR-263613