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
Q13043	Q96EB6	1	phosphorylation	down-regulates activity	0.344	We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity.	SIGNOR-279574
Q9UHD2	O75688	0	dephosphorylation	down-regulates activity	0.352	PPM1B dephosphorylates TBK1 in vivo and in vitro.\|These results demonstrate that PPM1B inhibits TBK1 mediated antiviral signaling by directly dephosphorylating TBK1 at Ser172.	SIGNOR-276985
P29372	Q13315	0	phosphorylation	up-regulates activity	0.265	ATM phosphorylates MPG at serine 172 (XREF_FIG).\|In summary, our results show that ATM and MPG are directly associated in vitro and in vivo, phosphorylation of MPG at serine 172 is dependent on ATM and that of loss of phospho ATM reduces MPG glycosylase activity.	SIGNOR-279004
P35813	Q04206	1	dephosphorylation	down-regulates activity	0.353	23 Here we show that PPM1A directly dephosphorylated RelA at S536 and S276, with resultant inhibition of NF-kappaB transactivation and decreased expression of target genes, notably including MCP-1 and CCL2.\|Taken together, these data suggest that dephosphorylation of S276 by PPM1A may contribute to inhibit RelA transcriptional activity, but the majority of PPM1A activity to inhibit RelA transcription relies on dephos phorylation of S536 of RelA.\|We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited Nuclear factor-\u03baB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis.	SIGNOR-276963
P51812	P35916	0	phosphorylation	down-regulates	0.2	Upon truncation of this c-terminal stretch, or mutation of the tyr-707 residue alone, autoinhibition is attenuated, and the kinase becomes constitutively active. Based on these findings we propose that phosphorylation of the tyr-707 represents a novel alternative regulatory mechanism for p90rsk activation.	SIGNOR-98708
O43583	Q9ULC4	2	binding	up-regulates activity	0.746	The MCT-1 protein modifies mRNA translational profiles through its interaction with DENR/DRP, a protein containing an SUI1 domain involved in recognition of the translation initiation codon.	SIGNOR-269674
O60674	Q5VWK5	2	binding	up-regulates	0.701	Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12.	SIGNOR-87808
O95613	Q76N32	0	relocalization	up-regulates activity	0.34	We also found that Cep68 forms a complex with Cep215 (also known as Cdk5Rap2) and PCNT (also known as pericentrin), two PCM (pericentriolar material) proteins involved in centriole engagement. \|Cep68 stabilization increases the amount of PCNT at metaphase centrosomes, but does not affect its removal at the end of mitosis	SIGNOR-275623
Q15139	P53367	1	phosphorylation	up-regulates	0.385	We report that arfaptins contain an amphipathic helix (ah) preceding the bar domain, which is essential for their binding to phosphatidylinositol 4-phosphate (pi(4)p)-containing liposomes and the tgn of mammalian cells. The binding of arfaptin1, but not arfaptin2, to pi(4)p is regulated by protein kinase d (pkd) mediated phosphorylation at ser100 within the ah. We also found that only arfaptin1 is required for the pkd-dependent trafficking of chromogranin a by the regulated secretory pathway.	SIGNOR-202101
Q92858	Q7Z6Z7	0	ubiquitination	down-regulates quantity	0.304	Huwe1 ubiquitinates and degrades Atoh1, and robustly affects development of GNPs that express this transcription factor [ xref ].\|This provides further evidence that phosphorylation of Atoh1 affects Huwe1-mediated degradation, and demonstrates that Huwe1 inhibits Atoh1 to affect cellular differentiation in multiple cell types.	SIGNOR-278693
P11912	P07948	0	phosphorylation	up-regulates activity	0.738	Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b. phosphorylation of Y182 alone can lead to further kinase activation and/or effector focusing necessary for phosphorylation of certain downstream targets, such as p62, p110, and Shc, but not others, such as Vav.	SIGNOR-251397
Q03112	O15123	1	transcriptional regulation	up-regulates quantity by expression	0.2	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2	SIGNOR-266060
Q16566	P46531	1	phosphorylation	up-regulates quantity by stabilization	0.36	In summary, we have found that phosphorylation of Notch1-IC by CaMKIV inhibits the proteasomal degradation of Notch1-IC through Fbw7 ( Fig.\u00a07 ).	SIGNOR-279596
P51787	Q9Y6H6	2	binding	up-regulates activity	0.66	Sexual dimorphism and oestrogen regulation of KCNE3 expression modulates the functional properties of KCNQ1 K⁺ channels\|The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation	SIGNOR-275923
Q9H461	P56704	2	binding	up-regulates	0.797	Structural basis of wnt recognition by frizzled.	SIGNOR-197638
P52294	Q14974	2	binding	up-regulates activity	0.86	Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization.	SIGNOR-260273
P01579	Q9UL17	0	transcriptional regulation	up-regulates quantity by expression	0.475	T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells	SIGNOR-266234
P51610	Q06547	2	binding	down-regulates activity	0.328	The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1GABP interaction can inhibit GABP_dependent transcriptional activation	SIGNOR-221377
Q02556	P10914	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
P52789	P31749	0	phosphorylation	up-regulates activity	0.445	K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization	SIGNOR-259984
P06239	P08575	0	dephosphorylation	up-regulates activity	0.797	CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity.	SIGNOR-259933
P11678	P12724	1	post translational modification	up-regulates activity	0.477	Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.	SIGNOR-261705
P36507	O15530	0	phosphorylation	up-regulates	0.256	The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation.	SIGNOR-125176
Q92913	Q9Y5Y9	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-253439
P16499	P18545	2	binding	down-regulates activity	0.866	Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B	SIGNOR-260010
Q13546	O43318	2	binding	up-regulates activity	0.553	RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex	SIGNOR-256022
Q9UL54	P46734	2	binding	up-regulates activity	0.67	Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7.	SIGNOR-70947
P23769	P17947	2	binding	down-regulates activity	0.577	Here we demonstrate that a region of the PU.1 Ets domain (the winged helix–turn–helix wing) interacts with the conserved carboxyl-terminal zinc finger of GATA-1 and GATA-2 and that GATA proteins inhibit PU.1 transactivation of critical myeloid target genes.	SIGNOR-256071
O95837	P43657	2	binding	up-regulates activity	0.422	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-257212
Q9Y4K3	Q9BVN2	1	polyubiquitination	down-regulates quantity by destabilization	0.32	We demonstrated that NESCA and NEMO interact by their N-terminal region. Beside to NEMO, we revealed that NESCA directly associates to the E3 ubiquitin ligase TRAF6, which in turn catalyzes NESCA polyubiquitination. Finally, we demonstrated that NESCA overexpression strongly inhibits TRAF6-mediated polyubiquitination of NEMO.	SIGNOR-272774
P19022	P35222	2	binding	up-regulates activity	0.818	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265864
Q13042	P06493	0	phosphorylation	up-regulates	0.638	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119762
Q13309	P24385	2	binding	down-regulates quantity by destabilization	0.594	We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line.	SIGNOR-272575
Q2M1P5	Q99835	0	relocalization	up-regulates activity	0.632	Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins.	SIGNOR-209605
P17252	P17812	1	phosphorylation	down-regulates	0.2	These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity.	SIGNOR-154621
P21860	P62993	2	binding	up-regulates	0.839	All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3.	SIGNOR-121971
P68400	Q9NYV6	1	phosphorylation	down-regulates	0.206	Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation.	SIGNOR-178943
P27361	P04150	1	phosphorylation	down-regulates	0.542	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.\|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-154409
P14778	P18510	2	binding	down-regulates activity	0.897	Homozygous truncating mutations result in lack of secreted interleukin-1–receptor antagonist protein, which inhibits the proinflammatory cytokines interleukin-1α and interleukin-1β	SIGNOR-262302
Q92823	P16157	1	relocalization	up-regulates quantity	0.544	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266721
P78527	P04637	1	phosphorylation	up-regulates	0.793	We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage.	SIGNOR-53030
P10275	Q15466	2	binding	down-regulates	0.415	We demonstrated that shp inhibited both ar-lbd and ntd-dependent transactivation, which evidenced for the first time a protein capable of inhibiting a steroid receptor amino-terminal-dependent transactivation. We further characterized the shp mechanism of action by showing that shp reversed ar coactivator-mediated activation	SIGNOR-112589
P63000	O75044	0	gtpase-activating protein	down-regulates activity	0.588	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-260516
Q9NYY3	P05067	1	phosphorylation	up-regulates activity	0.348	Here we show that Polo-like kinase 2 (Plk2), an activity-inducible regulator of homeostatic plasticity, directly binds and phosphorylates threonine-668 and serine-675 of APP in\u00a0vitro and associates with APP in\u00a0vivo.\|Plk2 was necessary and sufficient to induce BACE-1-mediated APP amyloidogenic processing following overexcitation, associated intimately with APP, and directly phosphorylated the APP C-terminus.	SIGNOR-279424
P17252	P09758	1	phosphorylation	down-regulates activity	0.2	Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation.	SIGNOR-273821
Q9BYB0	Q15398	0	relocalization	up-regulates activity	0.2	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-264600
Q9Y490	P05107	2	binding	up-regulates activity	0.719	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257618
P20265	O75030	1	transcriptional regulation	up-regulates quantity by expression	0.437	We further demonstrate that BRN2 induces MITF transcription through a binding site located at 50/36 of the MITF promoter	SIGNOR-249616
P02511	P07315	2	binding	up-regulates activity	0.531	Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age.	SIGNOR-253622
O15273	Q8WZ42	2	binding	up-regulates activity	0.908	TCAP, a core sarcomeric component capping the titin proteins, was identified as a positive hit (Figure 1A). TCAP is a small (19 kDa), highly abundant cytoplasmic protein expressed exclusively in skeletal muscle and the heart (Valle et al., 1997). TCAP interacts with titin through its N-terminal beta sheet to anchor titin to the Z-disc	SIGNOR-264854
Q9HAU4	Q9Y3C5	2	binding	up-regulates activity	0.54	RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.	SIGNOR-272952
Q9UNE7	P11142	1	polyubiquitination	down-regulates quantity by destabilization	0.728	BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association	SIGNOR-272588
Q16820	Q05655	0	phosphorylation	down-regulates quantity	0.307	These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.	SIGNOR-263171
P41221	Q01973	2	binding	up-regulates	0.747	Ror1 and ror2 bind wnt5a.	SIGNOR-196133
Q92997	Q9NQ66	1	null	up-regulates activity	0.347	Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin	SIGNOR-258980
O76064	P16104	1	ubiquitination	up-regulates	0.2	Rnf8 can ubiquitylate histone h2a and h2ax,	SIGNOR-159309
P04637	P51955	0	phosphorylation	down-regulates	0.318	NEK2 Phosphorylates p53 at Ser315 and Reduces Its Stability.\|These results are consistent with NEK2 inhibiting p53 transcriptional activation functions.	SIGNOR-278488
P61586	Q9NPG1	2	binding	up-regulates activity	0.344	Upon ligand binding, non-canonical wnt signaling controls tissue polarity and cell movement through the activation of rhoa, c-jun n-terminal kinase (jnk), and nemo-like kinase (nlk) signaling cascades.	SIGNOR-167865
Q99996	P20701	2	binding	up-regulates activity	0.2	However, association of CG-NAP/AKAP450 was signifi-cantly enhanced at 37°C in LFA-1-activated cells triggered toundergo motility. Taken together, our findings provide the first definitiveevidence that the protein CG-NAP/AKAP450 is a key scaffoldingcomponent of the multimolecular complex assembled in T cellsupon LFA cross-linking and is functionally indispensable for cellpolarity and migration induced by this integrin.	SIGNOR-260304
O95863	Q13131	0	phosphorylation	up-regulates quantity by stabilization	0.2	Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively.	SIGNOR-161779
Q96PY6	Q13535	2	binding	up-regulates activity	0.2	It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents	SIGNOR-275841
Q9Y3F4	O15105	2	binding	up-regulates	0.61	Strap recruits smad7 to the activated type i receptor and forms a complex	SIGNOR-76771
Q05655	P52757	1	phosphorylation	down-regulates	0.269	A novel cross-talk in diacylglycerol signaling: the rac-gap beta2-chimaerin is negatively regulated by protein kinase cdelta-mediated phosphorylation. phosphorylation of beta2-chimaerin on ser(169) located in the sh2-c1 domain linker region via protein kinase cdelta, which retained beta2-chimaerin in the cytosol and prevented its c1 domain-mediated translocation to membranes	SIGNOR-164687
Q5S007	P62841	1	phosphorylation	up-regulates activity	0.485	Taken together, these results suggest that phosphorylation of s15 on T136 by LRRK2 mediates enhanced cap-dependent and cap-independent reporter translation and that a stimulatory effect of LRRK2 on mRNA translation contributes to LRRK2 toxicity.	SIGNOR-279058
P25100	P38405	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-256951
Q8TAB3	P47869	2	binding	up-regulates quantity by stabilization	0.2	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.	SIGNOR-267218
O95271	O15169	1	ubiquitination	down-regulates quantity by destabilization	0.774	Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.	SIGNOR-187972
P35222	P55290	2	binding	up-regulates activity	0.534	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265853
Q13627	P01106	1	phosphorylation	down-regulates quantity	0.374	We also found that DYRK1A phosphorylated c-Myc on Ser62, priming phosphorylation on Thr58 by GSK3\u03b2 and subsequent degradation.\|c-Myc expression is down-regulated by DYRK1A.	SIGNOR-279609
P24385	Q13547	2	binding	up-regulates	0.697	Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.	SIGNOR-134059
P35226	P42771	1	transcriptional regulation	down-regulates quantity by repression	0.455	In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity,	SIGNOR-253385
P06899	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265381
P08237	Q8IYT8	0	phosphorylation	down-regulates activity	0.2	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274044
P61586	Q8IW93	0	guanine nucleotide exchange factor	up-regulates activity	0.636	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-260543
Q15365	P31751	0	phosphorylation	down-regulates activity	0.429	We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs.	SIGNOR-262625
P29320	P20827	2	binding	up-regulates	0.817	Transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells.	SIGNOR-52005
Q92831	P0DPK2	1	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269614
P49815	Q92574	2	binding	up-regulates activity	0.934	Furthermore, tsc2 is directly phosphorylated by akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1.	SIGNOR-77400
P13861	P17612	2	binding	down-regulates activity	0.876	Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets	SIGNOR-258752
Q16620	P19174	1	phosphorylation	up-regulates activity	0.647	Both Shc and PLCgamma1 are phosphorylated by TrkB, thereby initiating Shc/Ras/MAP kinase and PLCgamma1 signaling respectively.\|We conclude that activation of pY783 PLCgamma1 is due mainly to TrkB activation in these models and that TrkB induced PLCgamma1 signaling promotes limbic epileptogenesis.	SIGNOR-279241
Q12965	Q05397	2	binding	up-regulates activity	0.2	Myosin-1E (MYO1E), an actin-dependent molecular motor protein, directly interacts with FAK to induce Y397 autophosphorylation, which, in turn, causes changes in gene expression commonly observed in aggressive cancer.	SIGNOR-265427
Q9NQC7	Q14164	0	phosphorylation	down-regulates activity	0.441	CYLD is phosphorylated by IKK\u03b5 at Ser418.\|Together, these observations demonstrate that I\u03baB kinase\u03b5-mediated phosphorylation of CYLD at Ser418 inhibits CYLD deubiquitinase activity.	SIGNOR-278311
Q8IUC6	Q86XR7	2	binding	up-regulates activity	0.586	Tram binds trif directly and recruits it to tlr4	SIGNOR-118367
P35398	P48539	1	transcriptional regulation	up-regulates quantity by expression	0.2	RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice.	SIGNOR-266848
Q9HCK8	O43602	1	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-268915
P49841	P30291	1	phosphorylation	down-regulates quantity by destabilization	0.329	Serine 211 phosphorylation occurred under control conditions in the absence of CK1δ and in the presence of GSK3-β (Fig. 5, D and E).	SIGNOR-276632
P62873	P59768	2	binding	up-regulates activity	0.94	GNB1 dissociates from the receptor, bound with GNG2 as stable dimer	SIGNOR-251105
P27361	P49841	1	phosphorylation	down-regulates activity	0.294	We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels	SIGNOR-262523
P45984	Q9NYV6	1	phosphorylation	down-regulates	0.472	Inactivation is due to phosphorylation of tif-ia by c-jun n-terminal kinase (jnk) at a single threonine residue (thr 200). Phosphorylation at thr 200 impairs the interaction of tif-ia with pol i and the tbp-containing factor tif-ib/sl1, thereby abrogating initiation complex formation.	SIGNOR-134878
P01909	Q86YJ5	0	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271538
P56178	P28360	2	binding	down-regulates activity	0.389	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240921
Q149N8	P12004	1	ubiquitination	up-regulates	0.553	We provide evidence that similar to rad5, shprh physically interacts with the human rad6rad18 and mms2ubc13 protein complexes, and importantly, we show that it exhibits an ubiquitin ligase activity and mediates mms2ubc13-dependent polyubiquitylation of pcna. Thus, shprh is a functional homolog of rad5.	SIGNOR-187757
Q99675	P00533	1	polyubiquitination	down-regulates quantity by destabilization	0.2	CGRRF1 ubiquitinates EGFR through K48-linked ubiquitination, which leads to proteasome degradation.	SIGNOR-272220
Q8TDX7	P52732	1	phosphorylation	up-regulates activity	0.407	NEK7 regulates these processes in part through phosphorylation of the kinesin Eg5/KIF11, promoting its accumulation on microtubules in distal dendrites.	SIGNOR-273890
Q9UQM7	P16615	1	phosphorylation	up-regulates activity	0.397	SERCA2 and SERCA2 mutants S38A, S167A, and S531A were expressed in HEK-293 cells and tested for phosphorylation with CaM kinase. Mutant S38A was not phosphorylated, while mutants S167A and S531A were phosphorylated, suggesting that Ser38 is the site of CaM kinase phosphorylation in SERCA2. This conclusion was supported by the observation that phosphorylation of SERCA2 and mutants S167A and S531A by CaM kinase increased the Vmax for Ca2+ transport, while the Vmax for Ca2+ transport by mutant S38A was unaffected by exposure to a phosphorylation reaction mix.	SIGNOR-250616
P26441	P40189	2	binding	up-regulates	0.682	Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2.	SIGNOR-47991
P12931	P18031	0	dephosphorylation	up-regulates activity	0.781	Incubation of the inactivated c-Src with PTP1B results in a dose-dependent reactivation of c-Src tyrosine kinase activity. Incubation of c-Src with 2 or 10 g of PTP1B results in partial or full restoration of c-Src kinase activity, respectively. The activation is accompanied by dephosphorylation of c-Src, both of Tyr-419 and of Tyr-530	SIGNOR-245299
P38405	P21918	2	binding	up-regulates activity	0.509	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-256914
P60484	Q9BXM7	0	phosphorylation	down-regulates activity	0.47	PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import.	SIGNOR-277915
P56524	Q13131	0	phosphorylation	down-regulates	0.272	We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases.	SIGNOR-173689

Q13043

Q96EB6

1

phosphorylation

down-regulates activity

0.344

We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity.

SIGNOR-279574

Q9UHD2

O75688

0

dephosphorylation

down-regulates activity

0.352

PPM1B dephosphorylates TBK1 in vivo and in vitro.|These results demonstrate that PPM1B inhibits TBK1 mediated antiviral signaling by directly dephosphorylating TBK1 at Ser172.

SIGNOR-276985

P29372

Q13315

0

phosphorylation

up-regulates activity

0.265

ATM phosphorylates MPG at serine 172 (XREF_FIG).|In summary, our results show that ATM and MPG are directly associated in vitro and in vivo, phosphorylation of MPG at serine 172 is dependent on ATM and that of loss of phospho ATM reduces MPG glycosylase activity.

SIGNOR-279004

P35813

Q04206

1

dephosphorylation

down-regulates activity

0.353

23 Here we show that PPM1A directly dephosphorylated RelA at S536 and S276, with resultant inhibition of NF-kappaB transactivation and decreased expression of target genes, notably including MCP-1 and CCL2.|Taken together, these data suggest that dephosphorylation of S276 by PPM1A may contribute to inhibit RelA transcriptional activity, but the majority of PPM1A activity to inhibit RelA transcription relies on dephos phorylation of S536 of RelA.|We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited Nuclear factor-\u03baB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis.

SIGNOR-276963

P51812

P35916

0

phosphorylation

down-regulates

0.2

Upon truncation of this c-terminal stretch, or mutation of the tyr-707 residue alone, autoinhibition is attenuated, and the kinase becomes constitutively active. Based on these findings we propose that phosphorylation of the tyr-707 represents a novel alternative regulatory mechanism for p90rsk activation.

SIGNOR-98708

O43583

Q9ULC4

2

binding

up-regulates activity

0.746

The MCT-1 protein modifies mRNA translational profiles through its interaction with DENR/DRP, a protein containing an SUI1 domain involved in recognition of the translation initiation codon.

SIGNOR-269674

O60674

Q5VWK5

2

binding

up-regulates

0.701

Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12.

SIGNOR-87808

O95613

Q76N32

0

relocalization

up-regulates activity

0.34

We also found that Cep68 forms a complex with Cep215 (also known as Cdk5Rap2) and PCNT (also known as pericentrin), two PCM (pericentriolar material) proteins involved in centriole engagement. |Cep68 stabilization increases the amount of PCNT at metaphase centrosomes, but does not affect its removal at the end of mitosis

SIGNOR-275623

Q15139

P53367

1

phosphorylation

up-regulates

0.385

We report that arfaptins contain an amphipathic helix (ah) preceding the bar domain, which is essential for their binding to phosphatidylinositol 4-phosphate (pi(4)p)-containing liposomes and the tgn of mammalian cells. The binding of arfaptin1, but not arfaptin2, to pi(4)p is regulated by protein kinase d (pkd) mediated phosphorylation at ser100 within the ah. We also found that only arfaptin1 is required for the pkd-dependent trafficking of chromogranin a by the regulated secretory pathway.

SIGNOR-202101

Q92858

Q7Z6Z7

0

ubiquitination

down-regulates quantity

0.304

Huwe1 ubiquitinates and degrades Atoh1, and robustly affects development of GNPs that express this transcription factor [ xref ].|This provides further evidence that phosphorylation of Atoh1 affects Huwe1-mediated degradation, and demonstrates that Huwe1 inhibits Atoh1 to affect cellular differentiation in multiple cell types.

SIGNOR-278693

P11912

P07948

0

phosphorylation

up-regulates activity

0.738

Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b. phosphorylation of Y182 alone can lead to further kinase activation and/or effector focusing necessary for phosphorylation of certain downstream targets, such as p62, p110, and Shc, but not others, such as Vav.

SIGNOR-251397

Q03112

O15123

1

transcriptional regulation

up-regulates quantity by expression

0.2

We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2

SIGNOR-266060

Q16566

P46531

1

phosphorylation

up-regulates quantity by stabilization

0.36

In summary, we have found that phosphorylation of Notch1-IC by CaMKIV inhibits the proteasomal degradation of Notch1-IC through Fbw7 ( Fig.\u00a07 ).

SIGNOR-279596

P51787

Q9Y6H6

2

binding

up-regulates activity

0.66

Sexual dimorphism and oestrogen regulation of KCNE3 expression modulates the functional properties of KCNQ1 K⁺ channels|The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation

SIGNOR-275923

Q9H461

P56704

2

binding

up-regulates

0.797

Structural basis of wnt recognition by frizzled.

SIGNOR-197638

P52294

Q14974

2

binding

up-regulates activity

0.86

Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization.

SIGNOR-260273

P01579

Q9UL17

0

transcriptional regulation

up-regulates quantity by expression

0.475

T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells

SIGNOR-266234

P51610

Q06547

2

binding

down-regulates activity

0.328

The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1GABP interaction can inhibit GABP_dependent transcriptional activation

SIGNOR-221377

Q02556

P10914

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

P52789

P31749

0

phosphorylation

up-regulates activity

0.445

K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization

SIGNOR-259984

P06239

P08575

0

dephosphorylation

up-regulates activity

0.797

CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity.

SIGNOR-259933

P11678

P12724

1

post translational modification

up-regulates activity

0.477

Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.

SIGNOR-261705

P36507

O15530

0

phosphorylation

up-regulates

0.256

The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation.

SIGNOR-125176

Q92913

Q9Y5Y9

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-253439

P16499

P18545

2

binding

down-regulates activity

0.866

Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B

SIGNOR-260010

Q13546

O43318

2

binding

up-regulates activity

0.553

RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex

SIGNOR-256022

Q9UL54

P46734

2

binding

up-regulates activity

0.67

Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7.

SIGNOR-70947

P23769

P17947

2

binding

down-regulates activity

0.577

Here we demonstrate that a region of the PU.1 Ets domain (the winged helix–turn–helix wing) interacts with the conserved carboxyl-terminal zinc finger of GATA-1 and GATA-2 and that GATA proteins inhibit PU.1 transactivation of critical myeloid target genes.

SIGNOR-256071

O95837

P43657

2

binding

up-regulates activity

0.422

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-257212

Q9Y4K3

Q9BVN2

1

polyubiquitination

down-regulates quantity by destabilization

0.32

We demonstrated that NESCA and NEMO interact by their N-terminal region. Beside to NEMO, we revealed that NESCA directly associates to the E3 ubiquitin ligase TRAF6, which in turn catalyzes NESCA polyubiquitination. Finally, we demonstrated that NESCA overexpression strongly inhibits TRAF6-mediated polyubiquitination of NEMO.

SIGNOR-272774

P19022

P35222

2

binding

up-regulates activity

0.818

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265864

Q13042

P06493

0

phosphorylation

up-regulates

0.638

Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation

SIGNOR-119762

Q13309

P24385

2

binding

down-regulates quantity by destabilization

0.594

We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line.

SIGNOR-272575

Q2M1P5

Q99835

0

relocalization

up-regulates activity

0.632

Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins.

SIGNOR-209605

P17252

P17812

1

phosphorylation

down-regulates

0.2

These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity.

SIGNOR-154621

P21860

P62993

2

binding

up-regulates

0.839

All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3.

SIGNOR-121971

P68400

Q9NYV6

1

phosphorylation

down-regulates

0.206

Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation.

SIGNOR-178943

P27361

P04150

1

phosphorylation

down-regulates

0.542

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

SIGNOR-154409

P14778

P18510

2

binding

down-regulates activity

0.897

Homozygous truncating mutations result in lack of secreted interleukin-1–receptor antagonist protein, which inhibits the proinflammatory cytokines interleukin-1α and interleukin-1β

SIGNOR-262302

Q92823

P16157

1

relocalization

up-regulates quantity

0.544

Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.

SIGNOR-266721

P78527

P04637

1

phosphorylation

up-regulates

0.793

We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage.

SIGNOR-53030

P10275

Q15466

2

binding

down-regulates

0.415

We demonstrated that shp inhibited both ar-lbd and ntd-dependent transactivation, which evidenced for the first time a protein capable of inhibiting a steroid receptor amino-terminal-dependent transactivation. We further characterized the shp mechanism of action by showing that shp reversed ar coactivator-mediated activation

SIGNOR-112589

P63000

O75044

0

gtpase-activating protein

down-regulates activity

0.588

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-260516

Q9NYY3

P05067

1

phosphorylation

up-regulates activity

0.348

Here we show that Polo-like kinase 2 (Plk2), an activity-inducible regulator of homeostatic plasticity, directly binds and phosphorylates threonine-668 and serine-675 of APP in\u00a0vitro and associates with APP in\u00a0vivo.|Plk2 was necessary and sufficient to induce BACE-1-mediated APP amyloidogenic processing following overexcitation, associated intimately with APP, and directly phosphorylated the APP C-terminus.

SIGNOR-279424

P17252

P09758

1

phosphorylation

down-regulates activity

0.2

Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation.

SIGNOR-273821

Q9BYB0

Q15398

0

relocalization

up-regulates activity

0.2

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-264600

Q9Y490

P05107

2

binding

up-regulates activity

0.719

Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.

SIGNOR-257618

P20265

O75030

1

transcriptional regulation

up-regulates quantity by expression

0.437

We further demonstrate that BRN2 induces MITF transcription through a binding site located at 50/36 of the MITF promoter

SIGNOR-249616

P02511

P07315

2

binding

up-regulates activity

0.531

Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age.

SIGNOR-253622

O15273

Q8WZ42

2

binding

up-regulates activity

0.908

TCAP, a core sarcomeric component capping the titin proteins, was identified as a positive hit (Figure 1A). TCAP is a small (19 kDa), highly abundant cytoplasmic protein expressed exclusively in skeletal muscle and the heart (Valle et al., 1997). TCAP interacts with titin through its N-terminal beta sheet to anchor titin to the Z-disc

SIGNOR-264854

Q9HAU4

Q9Y3C5

2

binding

up-regulates activity

0.54

RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.

SIGNOR-272952

Q9UNE7

P11142

1

polyubiquitination

down-regulates quantity by destabilization

0.728

BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association

SIGNOR-272588

Q16820

Q05655

0

phosphorylation

down-regulates quantity

0.307

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

SIGNOR-263171

P41221

Q01973

2

binding

up-regulates

0.747

Ror1 and ror2 bind wnt5a.

SIGNOR-196133

Q92997

Q9NQ66

1

null

up-regulates activity

0.347

Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin

SIGNOR-258980

O76064

P16104

1

ubiquitination

up-regulates

0.2

Rnf8 can ubiquitylate histone h2a and h2ax,

SIGNOR-159309

P04637

P51955

0

phosphorylation

down-regulates

0.318

NEK2 Phosphorylates p53 at Ser315 and Reduces Its Stability.|These results are consistent with NEK2 inhibiting p53 transcriptional activation functions.

SIGNOR-278488

P61586

Q9NPG1

2

binding

up-regulates activity

0.344

Upon ligand binding, non-canonical wnt signaling controls tissue polarity and cell movement through the activation of rhoa, c-jun n-terminal kinase (jnk), and nemo-like kinase (nlk) signaling cascades.

SIGNOR-167865

Q99996

P20701

2

binding

up-regulates activity

0.2

However, association of CG-NAP/AKAP450 was signifi-cantly enhanced at 37°C in LFA-1-activated cells triggered toundergo motility. Taken together, our findings provide the first definitiveevidence that the protein CG-NAP/AKAP450 is a key scaffoldingcomponent of the multimolecular complex assembled in T cellsupon LFA cross-linking and is functionally indispensable for cellpolarity and migration induced by this integrin.

SIGNOR-260304

O95863

Q13131

0

phosphorylation

up-regulates quantity by stabilization

0.2

Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively.

SIGNOR-161779

Q96PY6

Q13535

2

binding

up-regulates activity

0.2

It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents

SIGNOR-275841

Q9Y3F4

O15105

2

binding

up-regulates

0.61

Strap recruits smad7 to the activated type i receptor and forms a complex

SIGNOR-76771

Q05655

P52757

1

phosphorylation

down-regulates

0.269

A novel cross-talk in diacylglycerol signaling: the rac-gap beta2-chimaerin is negatively regulated by protein kinase cdelta-mediated phosphorylation. phosphorylation of beta2-chimaerin on ser(169) located in the sh2-c1 domain linker region via protein kinase cdelta, which retained beta2-chimaerin in the cytosol and prevented its c1 domain-mediated translocation to membranes

SIGNOR-164687

Q5S007

P62841

1

phosphorylation

up-regulates activity

0.485

Taken together, these results suggest that phosphorylation of s15 on T136 by LRRK2 mediates enhanced cap-dependent and cap-independent reporter translation and that a stimulatory effect of LRRK2 on mRNA translation contributes to LRRK2 toxicity.

SIGNOR-279058

P25100

P38405

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-256951

Q8TAB3

P47869

2

binding

up-regulates quantity by stabilization

0.2

Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.

SIGNOR-267218

O95271

O15169

1

ubiquitination

down-regulates quantity by destabilization

0.774

Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.

SIGNOR-187972

P35222

P55290

2

binding

up-regulates activity

0.534

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265853

Q13627

P01106

1

phosphorylation

down-regulates quantity

0.374

We also found that DYRK1A phosphorylated c-Myc on Ser62, priming phosphorylation on Thr58 by GSK3\u03b2 and subsequent degradation.|c-Myc expression is down-regulated by DYRK1A.

SIGNOR-279609

P24385

Q13547

2

binding

up-regulates

0.697

Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.

SIGNOR-134059

P35226

P42771

1

transcriptional regulation

down-regulates quantity by repression

0.455

In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity,

SIGNOR-253385

P06899

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265381

P08237

Q8IYT8

0

phosphorylation

down-regulates activity

0.2

Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).

SIGNOR-274044

P61586

Q8IW93

0

guanine nucleotide exchange factor

up-regulates activity

0.636

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-260543

Q15365

P31751

0

phosphorylation

down-regulates activity

0.429

We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs.

SIGNOR-262625

P29320

P20827

2

binding

up-regulates

0.817

Transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells.

SIGNOR-52005

Q92831

P0DPK2

1

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269614

P49815

Q92574

2

binding

up-regulates activity

0.934

Furthermore, tsc2 is directly phosphorylated by akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1.

SIGNOR-77400

P13861

P17612

2

binding

down-regulates activity

0.876

Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets

SIGNOR-258752

Q16620

P19174

1

phosphorylation

up-regulates activity

0.647

Both Shc and PLCgamma1 are phosphorylated by TrkB, thereby initiating Shc/Ras/MAP kinase and PLCgamma1 signaling respectively.|We conclude that activation of pY783 PLCgamma1 is due mainly to TrkB activation in these models and that TrkB induced PLCgamma1 signaling promotes limbic epileptogenesis.

SIGNOR-279241

Q12965

Q05397

2

binding

up-regulates activity

0.2

Myosin-1E (MYO1E), an actin-dependent molecular motor protein, directly interacts with FAK to induce Y397 autophosphorylation, which, in turn, causes changes in gene expression commonly observed in aggressive cancer.

SIGNOR-265427

Q9NQC7

Q14164

0

phosphorylation

down-regulates activity

0.441

CYLD is phosphorylated by IKK\u03b5 at Ser418.|Together, these observations demonstrate that I\u03baB kinase\u03b5-mediated phosphorylation of CYLD at Ser418 inhibits CYLD deubiquitinase activity.

SIGNOR-278311

Q8IUC6

Q86XR7

2

binding

up-regulates activity

0.586

Tram binds trif directly and recruits it to tlr4

SIGNOR-118367

P35398

P48539

1

transcriptional regulation

up-regulates quantity by expression

0.2

RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice.

SIGNOR-266848

Q9HCK8

O43602

1

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-268915

P49841

P30291

1

phosphorylation

down-regulates quantity by destabilization

0.329

Serine 211 phosphorylation occurred under control conditions in the absence of CK1δ and in the presence of GSK3-β (Fig. 5, D and E).

SIGNOR-276632

P62873

P59768

2

binding

up-regulates activity

0.94

GNB1 dissociates from the receptor, bound with GNG2 as stable dimer

SIGNOR-251105

P27361

P49841

1

phosphorylation

down-regulates activity

0.294

We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels

SIGNOR-262523

P45984

Q9NYV6

1

phosphorylation

down-regulates

0.472

Inactivation is due to phosphorylation of tif-ia by c-jun n-terminal kinase (jnk) at a single threonine residue (thr 200). Phosphorylation at thr 200 impairs the interaction of tif-ia with pol i and the tbp-containing factor tif-ib/sl1, thereby abrogating initiation complex formation.

SIGNOR-134878

P01909

Q86YJ5

0

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.

SIGNOR-271538

P56178

P28360

2

binding

down-regulates activity

0.389

We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.

SIGNOR-240921

Q149N8

P12004

1

ubiquitination

up-regulates

0.553

We provide evidence that similar to rad5, shprh physically interacts with the human rad6rad18 and mms2ubc13 protein complexes, and importantly, we show that it exhibits an ubiquitin ligase activity and mediates mms2ubc13-dependent polyubiquitylation of pcna. Thus, shprh is a functional homolog of rad5.

SIGNOR-187757

Q99675

P00533

1

polyubiquitination

down-regulates quantity by destabilization

0.2

CGRRF1 ubiquitinates EGFR through K48-linked ubiquitination, which leads to proteasome degradation.

SIGNOR-272220

Q8TDX7

P52732

1

phosphorylation

up-regulates activity

0.407

NEK7 regulates these processes in part through phosphorylation of the kinesin Eg5/KIF11, promoting its accumulation on microtubules in distal dendrites.

SIGNOR-273890

Q9UQM7

P16615

1

phosphorylation

up-regulates activity

0.397

SERCA2 and SERCA2 mutants S38A, S167A, and S531A were expressed in HEK-293 cells and tested for phosphorylation with CaM kinase. Mutant S38A was not phosphorylated, while mutants S167A and S531A were phosphorylated, suggesting that Ser38 is the site of CaM kinase phosphorylation in SERCA2. This conclusion was supported by the observation that phosphorylation of SERCA2 and mutants S167A and S531A by CaM kinase increased the Vmax for Ca2+ transport, while the Vmax for Ca2+ transport by mutant S38A was unaffected by exposure to a phosphorylation reaction mix.

SIGNOR-250616

P26441

P40189

2

binding

up-regulates

0.682

Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2.

SIGNOR-47991

P12931

P18031

0

dephosphorylation

up-regulates activity

0.781

Incubation of the inactivated c-Src with PTP1B results in a dose-dependent reactivation of c-Src tyrosine kinase activity. Incubation of c-Src with 2 or 10 g of PTP1B results in partial or full restoration of c-Src kinase activity, respectively. The activation is accompanied by dephosphorylation of c-Src, both of Tyr-419 and of Tyr-530

SIGNOR-245299

P38405

P21918

2

binding

up-regulates activity

0.509

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-256914

P60484

Q9BXM7

0

phosphorylation

down-regulates activity

0.47

PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import.

SIGNOR-277915

P56524

Q13131

0

phosphorylation

down-regulates

0.272

We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases.

SIGNOR-173689