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
Q969V4	Q92949	0	transcriptional regulation	up-regulates quantity by expression	0.364	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266936
Q01668	Q86UR5	2	binding	up-regulates activity	0.365	Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells.	SIGNOR-264358
Q96PM5	P50750	0	phosphorylation	down-regulates	0.46	We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr.	SIGNOR-201923
Q13263	O14757	0	phosphorylation	up-regulates activity	0.282	These data suggested that KAP1 Ser473 phosphorylation by Chk1 and Chk2 does not take place predominantly at sites of DNA damage, and are consistent with previous work indicating that, following their DNA-damage-localized phosphorylation and activation by ATR and ATM, Chk1 and Chk2 dissociate from chromatin to phosphorylate their substrates , ].\|These results therefore indicated that both Chk1 and Chk2 can target KAP1 Ser473, and are in agreement with IR triggering both the ATM and Chk2 and ATR and Chk1 pathways .	SIGNOR-280226
Q6YBV0	Q6IQ22	0	relocalization	down-regulates quantity by destabilization	0.445	We also found that Rab12 promotes constitutive degradation of PAT4 (proton‐coupled amino‐acid transporter 4\|Rab12 regulates lysosomal localization or degradation of amino‐acid transporters.	SIGNOR-264763
Q00532	P42772	1	phosphorylation	up-regulates activity	0.2	We demonstrated that depletion of CDKL1 notably upregulated the protein expression of P15. P15 is shown to be a target of CDKL1 in CRC, either direct or indirect.	SIGNOR-273862
Q92934	P16298	0	dephosphorylation	up-regulates activity	0.364	Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD\|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.	SIGNOR-248384
Q676U5	Q9H082	2	binding	up-regulates	0.751	Olgi-resident small gtpase rab33b interacts with atg16l and modulates autophagosome formation.	SIGNOR-178542
P63096	P41145	2	binding	up-regulates activity	0.475	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-256710
P20042	Q13144	0	guanine nucleotide exchange factor	up-regulates activity	0.877	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269128
Q92585	O60563	1	relocalization	up-regulates	0.2	Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.	SIGNOR-130712
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
P49815	Q05655	0	phosphorylation	down-regulates activity	0.2	In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC.	SIGNOR-277427
Q06413	P51608	0	transcriptional regulation	down-regulates quantity by repression	0.346	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264680
P29372	P51965	2	binding	up-regulates activity	0.2	Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E)	SIGNOR-271929
Q16539	Q13541	1	phosphorylation	down-regulates activity	0.433	4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E.	SIGNOR-250097
P07954	P78527	0	phosphorylation	up-regulates activity	0.2	We show that exposure to ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions.	SIGNOR-266349
P23677	P17252	0	null	down-regulates activity	0.37	In contrast, phosphorylation of the A isoform with PKC caused a significant decrease in activity whether assayed in the presence or absence of calcium/calmodulin (to _25% of the unphosphorylated enzyme activity).	SIGNOR-248991
Q9Y4K3	O43561	1	ubiquitination	up-regulates activity	0.345	Interestingly, this study has demonstrated that the membrane-proximal region of linker for activation of T cells preceding tyrosine-132 mediates its association with TRAF6, which promotes the ubiquitination of linker for activation of T cells and, in turn, the phosphorylation of tyrosine residues on linker for activation of T cells.\|Moreover, LAT was ubiquitinated at Lysine 88 by TRAF6 via K63 linked chain.	SIGNOR-278675
P40933	P31785	2	binding	up-regulates	0.853	The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex.	SIGNOR-108815
Q96PY6	P48163	1	phosphorylation	down-regulates activity	0.2	PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation.	SIGNOR-275570
O43464	P31749	0	phosphorylation	down-regulates	0.322	Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212	SIGNOR-252500
P78318	P29372	0	monoubiquitination	down-regulates quantity by destabilization	0.2	We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. MID1 serves as the E3 ligase for α4 (2B), leading to a conformational change in α4 whereby the UIM of α4 binds in cis to the covalently attached ubiquitin (Ub; 3). This structural rearrangement then leads to calpain-mediated cleavage of the C terminus of α4 (4), allowing for polyubiquitination of PP2Ac by a currently unknown E3 ligase (5) and subsequent degradation by the proteasome.	SIGNOR-272040
Q8TDV5	P50148	2	binding	up-regulates activity	0.25	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-257366
P68400	P35226	1	phosphorylation	down-regulates quantity by destabilization	0.269	Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. e-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function.	SIGNOR-277345
P20701	P05362	2	binding	up-regulates	0.922	This leads to further neutrophil-endothelial cell interactions through the binding of LFA-1 to its endothelial counterreceptor ICAM-1 during the slow rolling phase	SIGNOR-255040
Q9NZN5	Q03113	2	binding	up-regulates activity	0.765	P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation.	SIGNOR-256522
P06493	O94901	1	phosphorylation	down-regulates activity	0.358	Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions.	SIGNOR-263099
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
P21453	P09471	2	binding	up-regulates activity	0.385	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-256992
O95243	P17252	0	phosphorylation	up-regulates activity	0.2	Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]	SIGNOR-275672
O43663	Q15058	2	binding	up-regulates activity	0.634	KIF14 interacts with PRC1 and citron kinase. We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. I	SIGNOR-266423
Q99612	P49841	0	phosphorylation	up-regulates activity	0.2	Functionally, GSK3beta enhanced KLF6 mediated growth suppression, which was abrogated by the KLF6-4A phosphomutant.\|These data establish that GSK3\u03b2 directly phosphorylates KLF6, which augments its induction of p21 and resultant growth suppression.	SIGNOR-279373
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
P16220	P49841	0	phosphorylation	up-regulates activity	0.691	GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant	SIGNOR-251233
P03372	Q00526	0	phosphorylation	up-regulates activity	0.259	CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3	SIGNOR-273187
Q9ULV8	P12931	0	phosphorylation	up-regulates	0.537	Phosphorylation of a critical tyrosine (tyr-341) in the linker region of cbl-c by src or a phosphomimetic mutation of this tyrosine (y341e) is sufficient to increase the e3 activity of cbl-c.	SIGNOR-165862
Q9P0U3	Q16665	1	desumoylation	up-regulates	0.325	Sumo-specific protease 1 is essential for stabilization of hif1alpha during hypoxia / our results support a model in which sumoylated hif1_ is unstable but can be stabilized when sumo is removed by senp1	SIGNOR-158891
Q13588	P15498	2	binding	up-regulates	0.297	Here we report that both in cell extracts and within intact mammalian cells vav binds to grb2 (sem-5/ash/drk), an adaptor molecule which plays a key role in ras activation.	SIGNOR-33840
O15105	Q9NYJ8	2	binding	up-regulates	0.569	The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling	SIGNOR-153917
Q12857	P15172	1	transcriptional regulation	up-regulates quantity by expression	0.246	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma\|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263982
Q9Y243	P29474	1	phosphorylation	up-regulates activity	0.485	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-251626
P15172	Q06413	2	binding	up-regulates activity	0.743	Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis.	SIGNOR-54089
O43166	Q05086	0	polyubiquitination	down-regulates quantity by destabilization	0.365	the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation.	SIGNOR-272608
Q15848	Q86V24	2	binding	up-regulates	0.773	Expression of adipor1/r2 or suppression of adipor1/r2 expression by small-interfering rna supports our conclusion that they serve as receptors for globular and full-length adiponectin,	SIGNOR-101809
Q02078	Q13164	0	phosphorylation	up-regulates	0.711	We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.	SIGNOR-236579
P51608	Q9H2X6	0	phosphorylation	up-regulates activity	0.478	Here, we identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo.	SIGNOR-264549
Q16512	P10275	1	phosphorylation	up-regulates	0.587	Rho can sensitize the ar to low levels of circulating androgens by promoting the nuclear translocation of a transcriptional co-activator, fhl2 (four and a half lim domains 2), which binds ar, and by stimulating protein kinase n (pkn), which phosphorylates ar directly.	SIGNOR-152762
Q6ZMJ4	P07333	2	binding	up-regulates activity	0.912	CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK	SIGNOR-277714
P43034	Q14204	2	binding	up-regulates activity	0.886	We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex	SIGNOR-252158
Q14814	Q00535	0	phosphorylation	down-regulates activity	0.415	In this case, cdk5 phosphorylates MEF2D on Ser444 suppressing its transcriptional activity.	SIGNOR-279509
Q9HD43	P10912	1	dephosphorylation	down-regulates activity	0.295	Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR	SIGNOR-248802
Q9BYP7	Q9UP95	1	phosphorylation	down-regulates activity	0.464	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities\|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264627
P18031	P11274	1	dephosphorylation	down-regulates	0.33	These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo.	SIGNOR-56818
P17612	Q9GZU1	1	phosphorylation	down-regulates	0.2	The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1.	SIGNOR-158946
Q96AQ6	Q00987	0	polyubiquitination	down-regulates quantity by destabilization	0.29	. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.	SIGNOR-272850
O14757	Q13164	0	phosphorylation	up-regulates activity	0.276	Moreover, we demonstrate that ERK5 facilitates Chk1 phosphorylation induced by IR.\|Since we have found that ERK5 was able to accelerate the phosphorylation and activation of IR-induced Chk1, therapeutic targeting of Chk1 in NSCLC cells with high ERK5 expression might be an effective strategy for overcoming radioresistance.	SIGNOR-280028
O75581	Q9Y6M4	0	phosphorylation	up-regulates activity	0.288	Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493	SIGNOR-275401
Q04727	Q96QT6	2	binding	up-regulates activity	0.2	We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.	SIGNOR-266989
P12830	P20794	0	phosphorylation	down-regulates	0.283	Finally, we speculate that there are two mechanisms whereby MAK inactivates CDH1 : the first is kinase dependent inactivation, modeled after CDK, where phosphorylation dissociates CDH1 from APC/C; the second is through physical binding of CDH1 with MAK.\|These results suggest a cell cycle-dependent phosphorylation of CDH1 by MAK.	SIGNOR-278486
P51451	O15524	1	phosphorylation	down-regulates activity	0.2	These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors.	SIGNOR-277889
P41970	P45983	0	phosphorylation	down-regulates activity	0.323	JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export.	SIGNOR-250139
Q8IUQ4	Q9Y6H5	1	ubiquitination	down-regulates	0.676	Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system	SIGNOR-140612
Q9H2X6	P16220	1	phosphorylation	up-regulates	0.389	Ere we found that homeodomain-interacting protein kinase 2 (hipk2), a dna-damage responsive nuclear kinase, is a new creb kinase for phosphorylation at ser-271 but not ser-133, and activates creb transactivation function	SIGNOR-166338
O14939	Q05655	0	phosphorylation	up-regulates	0.463	Finally, we show that thr566 of pld2 is directly phosphorylated by pkc and that pld2 mutation in this region prevents pld2 activation, pld2 translocation to the edge of lamellipodia, rac translocation, and cell spreading after integrin activation	SIGNOR-167577
P19525	P25963	1	phosphorylation	down-regulates quantity by destabilization	0.532	As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation.	SIGNOR-249335
O60462	Q13275	2	binding	up-regulates	0.612	In the nervous system, neuropilins mediate axon retraction and guidance by binding class iii semaphorins. We found that sema3f could compete with metabolically labeled vegf-c for the binding to np1-ig and np2-ig fusion proteins.	SIGNOR-147608
P17612	P26678	1	phosphorylation	up-regulates activity	0.492	Phospholamban (PLB) can be phosphorylated at Ser(16) by cyclic AMP-dependent protein kinase. phosphorylation of Ser(16) is sufficient for mediating the maximal cardiac responses to beta-adrenergic stimulation.	SIGNOR-250030
P27540	P81133	2	binding	up-regulates activity	0.531	We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer.	SIGNOR-240759
P78536	P05067	1	cleavage	up-regulates activity	0.539	By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulated alpha-cleavage in cultured cells.	SIGNOR-262829
P08047	P45983	0	phosphorylation	up-regulates	0.705	In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed.	SIGNOR-184194
Q16566	Q9UQL6	1	phosphorylation	down-regulates	0.51	Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs.	SIGNOR-236571
Q9Y484	Q8IWQ3	0	phosphorylation	up-regulates activity	0.248	WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes.	SIGNOR-268482
O95817	P27361	0	phosphorylation	down-regulates quantity by destabilization	0.312	We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377.	SIGNOR-277318
Q6VAB6	P16298	0	dephosphorylation	up-regulates activity	0.259	These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.\|the negative regulators 14-3-3	SIGNOR-248381
P07949	P56159	2	binding	up-regulates	0.754	Gdnfr-alpha-ligand complex, together with the tyrosine kinase receptor (cret) forms a functional receptor that activates downstream signal transduction pathways	SIGNOR-77587
Q8WTT2	Q14469	0	transcriptional regulation	down-regulates quantity	0.2	The expression level of FAD24 is inversely associated with that of HES1 in porcine MSCs after adipogenic induction. Enforced overexpression of HES1 in MSCs during the early stage of adipogenesis significantly repressed the transcription of FAD24 (P < 0.01) and the other pro-adipogenic genes	SIGNOR-253059
P50148	P08908	2	binding	up-regulates activity	0.3	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-257088
P19784	Q13547	1	phosphorylation	up-regulates activity	0.398	Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1.	SIGNOR-250999
Q13153	O15143	1	phosphorylation	up-regulates	0.531	The formation of new branched actin filament networks at the cell cortex of migrating cells is choreographed by the actin-related protein (arp) 2/3 complex. Despite the fundamental role of the arp2/3 complex in actin nucleation and branching, upstream signals that control the functions of p41-arc, a putative regulatory component of the mammalian arp2/3 complex. Pak1 phosphorylation of p41-arc regulates its localization with the arp2/3 complex in the cortical nucleation regions of cells. Pak1 phosphorylates p41-arc on threonine 21	SIGNOR-121642
P46531	P11309	0	phosphorylation	up-regulates activity	0.27	Interestingly, Pim1 phosphorylated Notch1 and Notch3, but not Notch2 ICD (Figure xref ), which was in line with the observed Pearson correlations ( xref ).\|Our data indicate that endogenous Pim1 and Notch1 interact already in the cytoplasm, which supports the notion that Pim1 enhances nuclear localization and activity of Notch1.	SIGNOR-279643
Q92793	Q9H2X6	0	phosphorylation	up-regulates activity	0.424	Moreover, we show that HIPK2 strongly potentiates the transcriptional activity of CREB-binding protein.\|We show that HIPK2 interacts with and phosphorylates several regions of CBP.	SIGNOR-279191
P30305	Q16549	0	phosphorylation	down-regulates	0.2	We propose that regulation of cdc25b phosphorylation by p38 is a critical event for initiating the g2/m checkpoint after ultraviolet radiation	SIGNOR-107423
Q8IWA4	O60260	0	ubiquitination	down-regulates quantity	0.2	Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2. Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy.	SIGNOR-272779
P42336	Q13188	0	phosphorylation	down-regulates activity	0.2	MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061	SIGNOR-277922
Q9UII4	P22392	1	ubiquitination	up-regulates quantity by stabilization	0.307	HERC5 is required for ubiquitination of Nm23B. In summary, Nm23B ubiquitination is mediated by HERC5. Stable Nm23B protein in presence of HERC5 as well as proteasome-independent ubiquitination suggest that ubiquitination of Nm23B serves a different purpose than marking it for degradation.	SIGNOR-271778
O15379	P12931	0	phosphorylation	up-regulates activity	0.385	C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form).	SIGNOR-277485
Q15759	P00533	1	phosphorylation	down-regulates	0.334	P38 map kinase mediates stress-induced internalization of egfrthe underlying mechanism entails phosphorylation of egfr at a short segment (amino acids 1002-1022) containing multiple serines and threonines, as well as phosphorylation of two rab5 effectors, eea1 and gdi.	SIGNOR-149086
O15350	Q00987	2	binding	down-regulates activity	0.837	Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis.	SIGNOR-255470
Q9Y6D9	P33981	0	phosphorylation	up-regulates activity	0.819	Furthermore, although catalytically inactive Mps1 can restore kinetochore localization of Mad1, only the active kinase restores Mad2 localization.\|Indeed, Mps1 can phosphorylate Mad1 in vitro.	SIGNOR-279000
Q02535	O00712	0	transcriptional regulation	down-regulates quantity	0.25	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-268879
Q96GD4	Q9NQS7	2	phosphorylation	up-regulates	0.974	Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites.	SIGNOR-118015
Q9H3R0	O60341	2	binding	up-regulates activity	0.2	JMJD2C was found to be co-localized with AR and LSD1 in the epithelium of prostate carcinoma and normal prostate cells. For the detailed mechanism, JMJD2C, AR and LSD1 assembled on the chromatin to remove the methyl groups from mono-, di- and trimethylated H3K9. Importantly, JMJD2C specifically removed the demethylation of the trimethyl H3K9 marks and modulated the transcriptional activity of AR. Moreover, JMJD2C cooperated with LSD1 and activated AR-mediated gene expression via decreasing H3K9me3 at the promoter of AR targeting genes KLK2 and PSA.	SIGNOR-263880
P09132	Q9UHB9	2	binding	up-regulates activity	0.95	Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.	SIGNOR-261167
Q16236	P15559	1	transcriptional regulation	up-regulates quantity by expression	0.487	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256275
P23560	Q16620	2	binding	up-regulates	0.817	Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb	SIGNOR-31597
P31749	Q06187	1	phosphorylation	down-regulates quantity by destabilization	0.296	The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain.	SIGNOR-276466
P08913	P25098	0	phosphorylation	down-regulates activity	0.2	The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization.	SIGNOR-251440
Q9UM11	P12757	2	binding	down-regulates quantity by destabilization	0.385	We demonstrate that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGF-beta. The destruction box of SnoN is required for its degradation in response to TGF-beta signaling. Furthermore, the APC activator CDH1 and Smad3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, Smad3, and APC.	SIGNOR-272621
P24941	Q9UM11	1	phosphorylation	down-regulates activity	0.745	A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.	SIGNOR-250732

Q969V4

Q92949

0

transcriptional regulation

up-regulates quantity by expression

0.364

FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).

SIGNOR-266936

Q01668

Q86UR5

2

binding

up-regulates activity

0.365

Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells.

SIGNOR-264358

Q96PM5

P50750

0

phosphorylation

down-regulates

0.46

We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr.

SIGNOR-201923

Q13263

O14757

0

phosphorylation

up-regulates activity

0.282

These data suggested that KAP1 Ser473 phosphorylation by Chk1 and Chk2 does not take place predominantly at sites of DNA damage, and are consistent with previous work indicating that, following their DNA-damage-localized phosphorylation and activation by ATR and ATM, Chk1 and Chk2 dissociate from chromatin to phosphorylate their substrates , ].|These results therefore indicated that both Chk1 and Chk2 can target KAP1 Ser473, and are in agreement with IR triggering both the ATM and Chk2 and ATR and Chk1 pathways .

SIGNOR-280226

Q6YBV0

Q6IQ22

0

relocalization

down-regulates quantity by destabilization

0.445

We also found that Rab12 promotes constitutive degradation of PAT4 (proton‐coupled amino‐acid transporter 4|Rab12 regulates lysosomal localization or degradation of amino‐acid transporters.

SIGNOR-264763

Q00532

P42772

1

phosphorylation

up-regulates activity

0.2

We demonstrated that depletion of CDKL1 notably upregulated the protein expression of P15. P15 is shown to be a target of CDKL1 in CRC, either direct or indirect.

SIGNOR-273862

Q92934

P16298

0

dephosphorylation

up-regulates activity

0.364

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

SIGNOR-248384

Q676U5

Q9H082

2

binding

up-regulates

0.751

Olgi-resident small gtpase rab33b interacts with atg16l and modulates autophagosome formation.

SIGNOR-178542

P63096

P41145

2

binding

up-regulates activity

0.475

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-256710

P20042

Q13144

0

guanine nucleotide exchange factor

up-regulates activity

0.877

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269128

Q92585

O60563

1

relocalization

up-regulates

0.2

Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.

SIGNOR-130712

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

P49815

Q05655

0

phosphorylation

down-regulates activity

0.2

In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC.

SIGNOR-277427

Q06413

P51608

0

transcriptional regulation

down-regulates quantity by repression

0.346

MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.

SIGNOR-264680

P29372

P51965

2

binding

up-regulates activity

0.2

Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E)

SIGNOR-271929

Q16539

Q13541

1

phosphorylation

down-regulates activity

0.433

4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E.

SIGNOR-250097

P07954

P78527

0

phosphorylation

up-regulates activity

0.2

We show that exposure to ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions.

SIGNOR-266349

P23677

P17252

0

null

down-regulates activity

0.37

In contrast, phosphorylation of the A isoform with PKC caused a significant decrease in activity whether assayed in the presence or absence of calcium/calmodulin (to _25% of the unphosphorylated enzyme activity).

SIGNOR-248991

Q9Y4K3

O43561

1

ubiquitination

up-regulates activity

0.345

Interestingly, this study has demonstrated that the membrane-proximal region of linker for activation of T cells preceding tyrosine-132 mediates its association with TRAF6, which promotes the ubiquitination of linker for activation of T cells and, in turn, the phosphorylation of tyrosine residues on linker for activation of T cells.|Moreover, LAT was ubiquitinated at Lysine 88 by TRAF6 via K63 linked chain.

SIGNOR-278675

P40933

P31785

2

binding

up-regulates

0.853

The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex.

SIGNOR-108815

Q96PY6

P48163

1

phosphorylation

down-regulates activity

0.2

PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation.

SIGNOR-275570

O43464

P31749

0

phosphorylation

down-regulates

0.322

Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212

SIGNOR-252500

P78318

P29372

0

monoubiquitination

down-regulates quantity by destabilization

0.2

We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. MID1 serves as the E3 ligase for α4 (2B), leading to a conformational change in α4 whereby the UIM of α4 binds in cis to the covalently attached ubiquitin (Ub; 3). This structural rearrangement then leads to calpain-mediated cleavage of the C terminus of α4 (4), allowing for polyubiquitination of PP2Ac by a currently unknown E3 ligase (5) and subsequent degradation by the proteasome.

SIGNOR-272040

Q8TDV5

P50148

2

binding

up-regulates activity

0.25

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-257366

P68400

P35226

1

phosphorylation

down-regulates quantity by destabilization

0.269

Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. e-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function.

SIGNOR-277345

P20701

P05362

2

binding

up-regulates

0.922

This leads to further neutrophil-endothelial cell interactions through the binding of LFA-1 to its endothelial counterreceptor ICAM-1 during the slow rolling phase

SIGNOR-255040

Q9NZN5

Q03113

2

binding

up-regulates activity

0.765

P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation.

SIGNOR-256522

P06493

O94901

1

phosphorylation

down-regulates activity

0.358

Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions.

SIGNOR-263099

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

P21453

P09471

2

binding

up-regulates activity

0.385

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-256992

O95243

P17252

0

phosphorylation

up-regulates activity

0.2

Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]

SIGNOR-275672

O43663

Q15058

2

binding

up-regulates activity

0.634

KIF14 interacts with PRC1 and citron kinase. We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. I

SIGNOR-266423

Q99612

P49841

0

phosphorylation

up-regulates activity

0.2

Functionally, GSK3beta enhanced KLF6 mediated growth suppression, which was abrogated by the KLF6-4A phosphomutant.|These data establish that GSK3\u03b2 directly phosphorylates KLF6, which augments its induction of p21 and resultant growth suppression.

SIGNOR-279373

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

P16220

P49841

0

phosphorylation

up-regulates activity

0.691

GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant

SIGNOR-251233

P03372

Q00526

0

phosphorylation

up-regulates activity

0.259

CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3

SIGNOR-273187

Q9ULV8

P12931

0

phosphorylation

up-regulates

0.537

Phosphorylation of a critical tyrosine (tyr-341) in the linker region of cbl-c by src or a phosphomimetic mutation of this tyrosine (y341e) is sufficient to increase the e3 activity of cbl-c.

SIGNOR-165862

Q9P0U3

Q16665

1

desumoylation

up-regulates

0.325

Sumo-specific protease 1 is essential for stabilization of hif1alpha during hypoxia / our results support a model in which sumoylated hif1_ is unstable but can be stabilized when sumo is removed by senp1

SIGNOR-158891

Q13588

P15498

2

binding

up-regulates

0.297

Here we report that both in cell extracts and within intact mammalian cells vav binds to grb2 (sem-5/ash/drk), an adaptor molecule which plays a key role in ras activation.

SIGNOR-33840

O15105

Q9NYJ8

2

binding

up-regulates

0.569

The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling

SIGNOR-153917

Q12857

P15172

1

transcriptional regulation

up-regulates quantity by expression

0.246

NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,

SIGNOR-263982

Q9Y243

P29474

1

phosphorylation

up-regulates activity

0.485

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-251626

P15172

Q06413

2

binding

up-regulates activity

0.743

Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis.

SIGNOR-54089

O43166

Q05086

0

polyubiquitination

down-regulates quantity by destabilization

0.365

the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation.

SIGNOR-272608

Q15848

Q86V24

2

binding

up-regulates

0.773

Expression of adipor1/r2 or suppression of adipor1/r2 expression by small-interfering rna supports our conclusion that they serve as receptors for globular and full-length adiponectin,

SIGNOR-101809

Q02078

Q13164

0

phosphorylation

up-regulates

0.711

We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.

SIGNOR-236579

P51608

Q9H2X6

0

phosphorylation

up-regulates activity

0.478

Here, we identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo.

SIGNOR-264549

Q16512

P10275

1

phosphorylation

up-regulates

0.587

Rho can sensitize the ar to low levels of circulating androgens by promoting the nuclear translocation of a transcriptional co-activator, fhl2 (four and a half lim domains 2), which binds ar, and by stimulating protein kinase n (pkn), which phosphorylates ar directly.

SIGNOR-152762

Q6ZMJ4

P07333

2

binding

up-regulates activity

0.912

CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK

SIGNOR-277714

P43034

Q14204

2

binding

up-regulates activity

0.886

We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex

SIGNOR-252158

Q14814

Q00535

0

phosphorylation

down-regulates activity

0.415

In this case, cdk5 phosphorylates MEF2D on Ser444 suppressing its transcriptional activity.

SIGNOR-279509

Q9HD43

P10912

1

dephosphorylation

down-regulates activity

0.295

Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR

SIGNOR-248802

Q9BYP7

Q9UP95

1

phosphorylation

down-regulates activity

0.464

We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs

SIGNOR-264627

P18031

P11274

1

dephosphorylation

down-regulates

0.33

These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo.

SIGNOR-56818

P17612

Q9GZU1

1

phosphorylation

down-regulates

0.2

The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1.

SIGNOR-158946

Q96AQ6

Q00987

0

polyubiquitination

down-regulates quantity by destabilization

0.29

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

SIGNOR-272850

O14757

Q13164

0

phosphorylation

up-regulates activity

0.276

Moreover, we demonstrate that ERK5 facilitates Chk1 phosphorylation induced by IR.|Since we have found that ERK5 was able to accelerate the phosphorylation and activation of IR-induced Chk1, therapeutic targeting of Chk1 in NSCLC cells with high ERK5 expression might be an effective strategy for overcoming radioresistance.

SIGNOR-280028

O75581

Q9Y6M4

0

phosphorylation

up-regulates activity

0.288

Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493

SIGNOR-275401

Q04727

Q96QT6

2

binding

up-regulates activity

0.2

We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.

SIGNOR-266989

P12830

P20794

0

phosphorylation

down-regulates

0.283

Finally, we speculate that there are two mechanisms whereby MAK inactivates CDH1 : the first is kinase dependent inactivation, modeled after CDK, where phosphorylation dissociates CDH1 from APC/C; the second is through physical binding of CDH1 with MAK.|These results suggest a cell cycle-dependent phosphorylation of CDH1 by MAK.

SIGNOR-278486

P51451

O15524

1

phosphorylation

down-regulates activity

0.2

These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors.

SIGNOR-277889

P41970

P45983

0

phosphorylation

down-regulates activity

0.323

JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export.

SIGNOR-250139

Q8IUQ4

Q9Y6H5

1

ubiquitination

down-regulates

0.676

Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system

SIGNOR-140612

Q9H2X6

P16220

1

phosphorylation

up-regulates

0.389

Ere we found that homeodomain-interacting protein kinase 2 (hipk2), a dna-damage responsive nuclear kinase, is a new creb kinase for phosphorylation at ser-271 but not ser-133, and activates creb transactivation function

SIGNOR-166338

O14939

Q05655

0

phosphorylation

up-regulates

0.463

Finally, we show that thr566 of pld2 is directly phosphorylated by pkc and that pld2 mutation in this region prevents pld2 activation, pld2 translocation to the edge of lamellipodia, rac translocation, and cell spreading after integrin activation

SIGNOR-167577

P19525

P25963

1

phosphorylation

down-regulates quantity by destabilization

0.532

As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation.

SIGNOR-249335

O60462

Q13275

2

binding

up-regulates

0.612

In the nervous system, neuropilins mediate axon retraction and guidance by binding class iii semaphorins. We found that sema3f could compete with metabolically labeled vegf-c for the binding to np1-ig and np2-ig fusion proteins.

SIGNOR-147608

P17612

P26678

1

phosphorylation

up-regulates activity

0.492

Phospholamban (PLB) can be phosphorylated at Ser(16) by cyclic AMP-dependent protein kinase. phosphorylation of Ser(16) is sufficient for mediating the maximal cardiac responses to beta-adrenergic stimulation.

SIGNOR-250030

P27540

P81133

2

binding

up-regulates activity

0.531

We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer.

SIGNOR-240759

P78536

P05067

1

cleavage

up-regulates activity

0.539

By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulated alpha-cleavage in cultured cells.

SIGNOR-262829

P08047

P45983

0

phosphorylation

up-regulates

0.705

In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed.

SIGNOR-184194

Q16566

Q9UQL6

1

phosphorylation

down-regulates

0.51

Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs.

SIGNOR-236571

Q9Y484

Q8IWQ3

0

phosphorylation

up-regulates activity

0.248

WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes.

SIGNOR-268482

O95817

P27361

0

phosphorylation

down-regulates quantity by destabilization

0.312

We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377.

SIGNOR-277318

Q6VAB6

P16298

0

dephosphorylation

up-regulates activity

0.259

These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3

SIGNOR-248381

P07949

P56159

2

binding

up-regulates

0.754

Gdnfr-alpha-ligand complex, together with the tyrosine kinase receptor (cret) forms a functional receptor that activates downstream signal transduction pathways

SIGNOR-77587

Q8WTT2

Q14469

0

transcriptional regulation

down-regulates quantity

0.2

The expression level of FAD24 is inversely associated with that of HES1 in porcine MSCs after adipogenic induction. Enforced overexpression of HES1 in MSCs during the early stage of adipogenesis significantly repressed the transcription of FAD24 (P < 0.01) and the other pro-adipogenic genes

SIGNOR-253059

P50148

P08908

2

binding

up-regulates activity

0.3

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-257088

P19784

Q13547

1

phosphorylation

up-regulates activity

0.398

Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1.

SIGNOR-250999

Q13153

O15143

1

phosphorylation

up-regulates

0.531

The formation of new branched actin filament networks at the cell cortex of migrating cells is choreographed by the actin-related protein (arp) 2/3 complex. Despite the fundamental role of the arp2/3 complex in actin nucleation and branching, upstream signals that control the functions of p41-arc, a putative regulatory component of the mammalian arp2/3 complex. Pak1 phosphorylation of p41-arc regulates its localization with the arp2/3 complex in the cortical nucleation regions of cells. Pak1 phosphorylates p41-arc on threonine 21

SIGNOR-121642

P46531

P11309

0

phosphorylation

up-regulates activity

0.27

Interestingly, Pim1 phosphorylated Notch1 and Notch3, but not Notch2 ICD (Figure xref ), which was in line with the observed Pearson correlations ( xref ).|Our data indicate that endogenous Pim1 and Notch1 interact already in the cytoplasm, which supports the notion that Pim1 enhances nuclear localization and activity of Notch1.

SIGNOR-279643

Q92793

Q9H2X6

0

phosphorylation

up-regulates activity

0.424

Moreover, we show that HIPK2 strongly potentiates the transcriptional activity of CREB-binding protein.|We show that HIPK2 interacts with and phosphorylates several regions of CBP.

SIGNOR-279191

P30305

Q16549

0

phosphorylation

down-regulates

0.2

We propose that regulation of cdc25b phosphorylation by p38 is a critical event for initiating the g2/m checkpoint after ultraviolet radiation

SIGNOR-107423

Q8IWA4

O60260

0

ubiquitination

down-regulates quantity

0.2

Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2. Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy.

SIGNOR-272779

P42336

Q13188

0

phosphorylation

down-regulates activity

0.2

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

SIGNOR-277922

Q9UII4

P22392

1

ubiquitination

up-regulates quantity by stabilization

0.307

HERC5 is required for ubiquitination of Nm23B. In summary, Nm23B ubiquitination is mediated by HERC5. Stable Nm23B protein in presence of HERC5 as well as proteasome-independent ubiquitination suggest that ubiquitination of Nm23B serves a different purpose than marking it for degradation.

SIGNOR-271778

O15379

P12931

0

phosphorylation

up-regulates activity

0.385

C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form).

SIGNOR-277485

Q15759

P00533

1

phosphorylation

down-regulates

0.334

P38 map kinase mediates stress-induced internalization of egfrthe underlying mechanism entails phosphorylation of egfr at a short segment (amino acids 1002-1022) containing multiple serines and threonines, as well as phosphorylation of two rab5 effectors, eea1 and gdi.

SIGNOR-149086

O15350

Q00987

2

binding

down-regulates activity

0.837

Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis.

SIGNOR-255470

Q9Y6D9

P33981

0

phosphorylation

up-regulates activity

0.819

Furthermore, although catalytically inactive Mps1 can restore kinetochore localization of Mad1, only the active kinase restores Mad2 localization.|Indeed, Mps1 can phosphorylate Mad1 in vitro.

SIGNOR-279000

Q02535

O00712

0

transcriptional regulation

down-regulates quantity

0.25

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-268879

Q96GD4

Q9NQS7

2

phosphorylation

up-regulates

0.974

Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites.

SIGNOR-118015

Q9H3R0

O60341

2

binding

up-regulates activity

0.2

JMJD2C was found to be co-localized with AR and LSD1 in the epithelium of prostate carcinoma and normal prostate cells. For the detailed mechanism, JMJD2C, AR and LSD1 assembled on the chromatin to remove the methyl groups from mono-, di- and trimethylated H3K9. Importantly, JMJD2C specifically removed the demethylation of the trimethyl H3K9 marks and modulated the transcriptional activity of AR. Moreover, JMJD2C cooperated with LSD1 and activated AR-mediated gene expression via decreasing H3K9me3 at the promoter of AR targeting genes KLK2 and PSA.

SIGNOR-263880

P09132

Q9UHB9

2

binding

up-regulates activity

0.95

Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.

SIGNOR-261167

Q16236

P15559

1

transcriptional regulation

up-regulates quantity by expression

0.487

In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).

SIGNOR-256275

P23560

Q16620

2

binding

up-regulates

0.817

Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb

SIGNOR-31597

P31749

Q06187

1

phosphorylation

down-regulates quantity by destabilization

0.296

The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain.

SIGNOR-276466

P08913

P25098

0

phosphorylation

down-regulates activity

0.2

The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization.

SIGNOR-251440

Q9UM11

P12757

2

binding

down-regulates quantity by destabilization

0.385

We demonstrate that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGF-beta. The destruction box of SnoN is required for its degradation in response to TGF-beta signaling. Furthermore, the APC activator CDH1 and Smad3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, Smad3, and APC.

SIGNOR-272621

P24941

Q9UM11

1

phosphorylation

down-regulates activity

0.745

A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.

SIGNOR-250732