GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q13972	P12931	phosphorylation	down-regulates activity	0.47	These proximal Src kinases could potentially directly or indirectly phosphorylate Rasgrf-1 upon BCR activation and thereby further increase its GEF activity.	SIGNOR-280133
Q13363	Q9H2X6	phosphorylation	down-regulates	0.47	Homeodomain-interacting protein kinase-2 mediates ctbp phosphorylation and degradation in uv-triggered apoptosishipk2 phosphorylates ctbp at ser-422	SIGNOR-134040
P08621	P35637	binding	up-regulates activity	0.469	FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP	SIGNOR-262823
Q8N122	P27361	phosphorylation	up-regulates activity	0.469	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-169530
Q13224	P17252	phosphorylation	up-regulates activity	0.469	These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.	SIGNOR-249083
P18031	P49841	phosphorylation	down-regulates quantity	0.469	GSK-3beta phosphorylates PTP1B at serine residues, and activation of GSK-3beta reduces the mRNA level of PTP1B.	SIGNOR-279724
P37231	Q9HAZ2	binding	up-regulates	0.469	Prdm16 stimulates brown adipogenesis by binding to ppar-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function	SIGNOR-180298
Q13224	Q06124	dephosphorylation	down-regulates activity	0.469	In addition, surface expression of GluN2B was not reduced in mutant mice and it remains to be investigated how the direct dephosphorylation of GluN2B Y1252 by Shp2 reduces GluN2B function.\|The increased GluN2B Y1472 phosphorylation was reversed by a Src family kinase inhibitor, suggesting that Shp2 may negatively regulate GluN2B Y1472 phosphorylation through suppressing Src activity .	SIGNOR-276950
P08151	Q92831	acetylation	down-regulates activity	0.469	NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase	SIGNOR-269270
Q96CF2	Q96GD4	phosphorylation	up-regulates	0.469	Moreover, we find that the cpc's catalytic subunit, aurora b kinase, phosphorylates one of the three human snf7 paralogues-chmp4c-in its c-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for chmp4c function because their mutation leads to cytokinesis defects. The introduction of the s214a and s215a mutations together with s210a almost completely abolished aurora b phosphorylation	SIGNOR-197967
P08754	Q9HBW0	binding	up-regulates activity	0.469	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-257169
Q99497	Q8IW41	phosphorylation	up-regulates activity	0.469	PRAK preferentially colocalizes with DJ-1 and leads to DJ-1 activation, which in turn facilitates DJ-1 to sequester Daxx in the nucleus, preventing oxidative stress induced cell death.\|These data clearly demonstrate a PRAK dependent phosphorylation of DJ-1.	SIGNOR-279746
P26012	Q9Y490	binding	up-regulates activity	0.469	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-257636
P05771-2	P62714	dephosphorylation	down-regulates activity	0.469	Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.	SIGNOR-248587
P08754	P08913	binding	up-regulates activity	0.469	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-256841
P46527	O00141	phosphorylation	down-regulates	0.469	Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna.	SIGNOR-179117
P08575	P41240	phosphorylation	up-regulates	0.469	Tyrosine phosphorylation of cd45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase.	SIGNOR-26785
P01106	P00519	phosphorylation	up-regulates activity	0.469	Altogether, our data demonstrate that Pin1 and Abl cooperate to enhance the interaction of Myc with p300 and its resulting acetylation.\|These experiments confirmed that Myc Y74 is phosphorylated by Abl, and provided us with a reagent to detect this form of Myc in cells (see below).	SIGNOR-278196
P35222	P51955	phosphorylation	down-regulates quantity	0.469	NEK2 silencing reduced the phosphorylation of beta-catenin at Ser33 and Ser37, but did not decrease the level of total beta-catenin.\|NEK2 slightly decreased the level of total beta-catenin (XREF_FIG).	SIGNOR-278173
Q15118	Q16665	transcriptional regulation	up-regulates quantity by expression	0.469	Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA.	SIGNOR-267444
P08588	P32121	binding	down-regulates activity	0.469	The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors	SIGNOR-256502
Q9H7Z6	Q13315	phosphorylation	up-regulates activity	0.469	In this study we present evidence that MOF is phosphorylated at the threonine 392 residue (pT392-MOF) by ATM subsequent to IR induced DNA damage.\|Interestingly, ATM dependent-MOF phosphorylation increases MOF retention on DNA post-irradiation in S/G2-phase cells.	SIGNOR-278350
Q9H4A3	O95198	binding	down-regulates quantity by destabilization	0.469	We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body.	SIGNOR-272119
P05771	P62714	dephosphorylation	down-regulates activity	0.469	Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.	SIGNOR-248585
P36897	P36873	dephosphorylation	down-regulates	0.469	We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI.	SIGNOR-121277
P10071	P17612	phosphorylation	down-regulates quantity	0.468	Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3.	SIGNOR-75359
Q9NQ66	O95837	binding	up-regulates activity	0.468	This suggests that both Gal4 and Gal6 can activate PLC b1.	SIGNOR-278119
P15172	P50461	binding	up-regulates activity	0.468	we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.	SIGNOR-241116
P10070	P17612	phosphorylation	down-regulates	0.468	In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation	SIGNOR-154273
Q9NP62	Q9P0U3	desumoylation	up-regulates activity	0.468	We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.	SIGNOR-262681
P53350	Q96EP1	polyubiquitination	down-regulates quantity by destabilization	0.468	Chfr, a mitotic stress checkpoint, plays an important role in cell cycle progression, tumor suppression and the processes that require the E3 ubiquitin ligase activity mediated by the RING finger domain. Chfr stimulates the formation of polyubiquitin chains by ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins including Plk1 and Aurora A.	SIGNOR-271464
Q13546	Q8WZ73	ubiquitination	down-regulates quantity by destabilization	0.468	We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappaB activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation.	SIGNOR-271482
O95297	P12931	phosphorylation	up-regulates	0.468	Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr	SIGNOR-113410
Q9BYX4	O14730	phosphorylation	down-regulates activity	0.468	RIOK3 mediates phosphorylation of MDA5 Ser-828\|RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response	SIGNOR-264576
Q13547	Q00987	ubiquitination	down-regulates quantity by destabilization	0.468	MDM2 induces ubiquitination of HDAC1 in VSMCs.\|Under calcification inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination.	SIGNOR-278761
Q14249	Q13490	ubiquitination	up-regulates activity	0.468	Alternatively, cIAP1 may mediate a vital function of EndoG other than cell death.\|Cellular inhibitor of apoptosis protein 1 ubiquitinates endonuclease G but does not affect endonuclease G-mediated cell death.	SIGNOR-278605
P48431	Q99986	phosphorylation	up-regulates activity	0.468	VRK1, but not kinase-dead VRK1 (K179E), phosphorylated Sox2 (XREF_FIG).	SIGNOR-279578
P63096	P34972	binding	up-regulates activity	0.468	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-256700
P19793	Q14994	binding	up-regulates	0.468	Therefore, both car-rxr heterodimers and car monomers can contribute to the gene activating function of pbrems in car target genes.	SIGNOR-104441
O95999	Q13315	phosphorylation	up-regulates activity	0.468	Upon DNA damage, ATM phosphorylates the residue T91 of BCL10, promoting binding of BCL10 to RNF8 and simultaneously presenting UBC13 to RNF8.\|When cells were pre-treated with different PIKK inhibitors, the ATM specific inhibitor KU55933 efficiently reduced etoposide induced focus formation of BCL10, whereas pretreatment of cells with NU6027, an ATR specific inhibitor, or NU7026, a DNA-PKcs-specific inhibitor, did not compromise etoposide induced focus formation of BCL10 (XREF_FIG).	SIGNOR-278392
Q9NZQ7	Q9BZS1	transcriptional regulation	up-regulates quantity by expression	0.468	FOXP3 expression additionally increased programmed death ligand 1 (PD-L1) expression, which, when inhibited with CCL5, decreased the tumor burden and Treg infiltration in orthotopic murine, Pan-02 PDAC tumors	SIGNOR-277728
P42229	Q06187	phosphorylation	up-regulates activity	0.467	Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity.	SIGNOR-250603
P63096	P28222	binding	up-regulates activity	0.467	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-256720
Q99961	Q5S007	phosphorylation	down-regulates	0.467	We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association.	SIGNOR-192068
Q14934	P45983	phosphorylation	up-regulates activity	0.467	Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif.\|Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose dependent manner by JNK1 or JNK2.	SIGNOR-280033
Q9BW11	P61244	binding	up-regulates activity	0.467	the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.	SIGNOR-240393
Q9UMX1	P17612	phosphorylation	up-regulates quantity by stabilization	0.467	We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation	SIGNOR-172003
O00327	Q14995	transcriptional regulation	down-regulates quantity by repression	0.467	A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription.	SIGNOR-268006
Q92574	P53350	phosphorylation	down-regulates quantity by destabilization	0.467	The Hsp90 client Plk1 phosphorylates Sgt1, which had a positive impact on Sgt1 function, whereas phosphorylation of Tsc1 by Plk1 led to its ubiquitination and degradation.	SIGNOR-280072
Q96T58	Q9Y618	binding	up-regulates	0.467	Sharp is a potent transcriptional repressor whose repression domain (rd) interacts directly with smrt	SIGNOR-107260
Q99490	P06241	phosphorylation	up-regulates	0.467	We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival.	SIGNOR-147936
Q16611	Q92843	binding	down-regulates	0.467	Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax.	SIGNOR-152989
O15360	O14965	phosphorylation	up-regulates activity	0.467	E detected interactions between Aurora A kinase and FANCA protein, one of the components of the FA nuclear core complex. These results suggest that S165 phosphorylation by Aurora A kinase is required for proper activation of the FA/BRCA pathway in response to DNA damage.	SIGNOR-277263
O95239	P53350	phosphorylation	down-regulates activity	0.467	Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome.\|These results suggest that Plk1 negatively regulates the loading of both KIF4 and condensin to the chromosome.	SIGNOR-280069
Q03113	Q9UBY5	binding	up-regulates	0.467	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2.	SIGNOR-198544
Q08828	P19086	binding	down-regulates activity	0.467	Activated a z inhibits the activity of type I and type V adenylyl cyclases.	SIGNOR-278044
P13631	P31749	phosphorylation	up-regulates activity	0.467	S379 of RARγ is indispensable for the CLDN6-triggered cellular events. The most important finding of the present study is that the CLDN6/SFK/PI3K/AKT signaling controls the RARγ and ERα activities (Fig. 6).	SIGNOR-277492
Q14247	P28482	phosphorylation	up-regulates	0.467	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-165200
P14921	P31314	binding	down-regulates activity	0.467	We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement.	SIGNOR-259097
P09017	O15550	transcriptional regulation	up-regulates quantity by expression	0.467	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260030
P63000	Q92997	binding	up-regulates	0.467	Wnt/fz activation of rac and rho is inhibited by rac-n17 and rho-n19, respectively (figs. _(figs.1d,1d, _d,5c,d;5c,d;habas et al. 2001), and requires different dvl domains wnt signaling induces complex formation between dvl and rac.	SIGNOR-97409
O43156	Q9UK97	binding	down-regulates quantity by destabilization	0.467	Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins.	SIGNOR-271997
Q9UGP5	P78527	phosphorylation	up-regulates activity	0.467	We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ.	SIGNOR-273835
P46379	O43765	binding	up-regulates activity	0.467	USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.	SIGNOR-272859
Q9NPB6	P37173	phosphorylation	up-regulates	0.466	We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. [...] These data suggest that T_RII phosphorylates Par6 at its penultimate residue, Ser345.	SIGNOR-227484
Q00987	P46934	ubiquitination	up-regulates quantity by stabilization	0.466	NEDD4 promotes MDM2 ubiquitination in a dose- and time-dependent manner, whereas depletion of NEDD4 reduced the half-life of endogenous MDM2 [ xref ].	SIGNOR-278769
Q9Y4K3	Q9UNE7	ubiquitination	down-regulates quantity by destabilization	0.466	CHIP promotes TRAF6 ubiquitination and degradation.\|These results suggest that CHIP negatively regulates the stability of TRAF6.	SIGNOR-278670
O14974	Q9H093	phosphorylation	down-regulates activity	0.466	NUAK2 phosphorylates and inhibits MYPT1, the regulatory subunit of MLC phosphatase, stabilizing actin filaments and mediating contraction of smooth muscle cells ( xref ).	SIGNOR-279081
O00429	P06493	phosphorylation	up-regulates activity	0.466	Drp1 is phosphorylated at the Ser616 position and activated predominantly by CDK1.	SIGNOR-279394
P10636	P43405	phosphorylation	down-regulates	0.466	We established that tyrosine 18 was the primary residue in tau phosphorylated by sykphosphorylation of tau by syk could be involved in neurite outgrowth.	SIGNOR-159648
Q8NHZ8	O95835	phosphorylation	up-regulates activity	0.466	LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C\|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C\|Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly	SIGNOR-275472
Q09472	P28482	phosphorylation	up-regulates	0.466	Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression.	SIGNOR-156891
P49789	P12931	phosphorylation	up-regulates activity	0.466	The human tumor suppressor Fhit is a homodimeric histidine triad (HIT) protein of 147 amino acids which has Ap3A hydrolase activity. We have recently discovered that Fhit is phosphorylated in vivo and is phosphorylated in vitro by Src kinaseMALDI-TOF and HPLC-ESI tandem mass spectrometry of intact Fhit and proteolytic peptides of Fhit demonstrated that Fhit is phosphorylated on Y114 on either one or both subunitsThe decreases in the values of Km and kcat for the phosphorylated forms in comparison to those of unphosphorylated Fhit favor the formation and lifetime of the Fhit_Ap3A complex, which may enhance the tumor suppressor activity of Fhit.	SIGNOR-247134
P15509	P09919	binding	up-regulates	0.466	Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta).	SIGNOR-72511
Q8N122	Q9Y478	phosphorylation	down-regulates	0.466	Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2.	SIGNOR-173041
O95863	Q15139	phosphorylation	down-regulates activity	0.466	Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba.	SIGNOR-168537
P50148	O43613	binding	up-regulates activity	0.466	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-257220
P27449	Q8N6D2	polyubiquitination	down-regulates quantity by destabilization	0.466	The data indicated that RNF182 targeted ATP6V0C for degradation by the ubiquitin-proteosome pathway.	SIGNOR-271771
P31431	O43184	binding	up-regulates	0.466	The adam12 cysteine-rich domain (radam12-cys) supports cell attachment using syndecan-4 as a primary cell surface receptor that subsequently triggers beta(1) integrin-dependent cell spreading, stress fiber assembly, and focal adhesion formation.	SIGNOR-96931
Q01130	Q92993	acetylation	down-regulates	0.466	In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation.	SIGNOR-170594
Q13114	Q86VP1	binding	down-regulates activity	0.466	ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi.	SIGNOR-275737
O14641	Q96GF1	polyubiquitination	down-regulates quantity by destabilization	0.466	The E3 ligase RNF185 negatively regulates osteogenic differentiation by targeting Dvl2 for degradation. Overexpression of RNF185 decreases the exogenous and endogenous level of Dvl2, promotes the ubiquitination and degradation of Dvl2	SIGNOR-272173
Q99081	Q02535	binding	down-regulates activity	0.466	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241152
P78527	P07948	phosphorylation	down-regulates activity	0.466	The interaction between Lyn and DNA-PKcs inhibits DNA-PKcs activity and the ability of DNA-PKcs to form a complex with Ku/DNA.\|We also show that Lyn phosphorylates DNA-PKcs but not Ku in vitro.	SIGNOR-279061
P06850	P51608	transcriptional regulation	down-regulates quantity by repression	0.466	Collectively, these results point to a specific association between WT MeCP2 and the methylated promoter region of Crh in vivo. In contrast, the MeCP2308 protein was not detected at the Crh promoter. \| Thus, the results of seqChIP indicate that MeCP2 preferentially associates with a transcriptionally inactive, dimethyl-histone H3 Lys-9-rich form of the Crh promoter in mice.	SIGNOR-264548
O15519	P31749	phosphorylation	down-regulates quantity	0.466	TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling.	SIGNOR-252548
Q06609	P42574	cleavage	down-regulates quantity by destabilization	0.466	The RAD51 protein has been shown to be a substrate for caspase-3\|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin	SIGNOR-271709
P42336	Q9UQC2	binding	up-regulates	0.466	The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival	SIGNOR-204966
P35568	Q12923	dephosphorylation	down-regulates activity	0.466	Finally, we report that PTPL1 expression is sufficient to block the IRS-1/phosphatidylinositol 3-kinase/Akt signaling pathway, to inhibit the insulin-like growth factor-I effect on cell survival, and to induce apoptosis.\|We first show by complementary approaches that PTPL1 specifically dephosphorylates insulin receptor substrate-1 (IRS-1) in vitro and in cellulo.	SIGNOR-277053
P19022	O00192	binding	up-regulates quantity by stabilization	0.466	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252128
P50148	P32238	binding	up-regulates activity	0.465	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-257303
Q8NBP7	Q12772	transcriptional regulation	up-regulates quantity by expression	0.465	Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes.	SIGNOR-254459
P10997	P16519	cleavage	up-regulates activity	0.465	The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule	SIGNOR-261791
P48436	P17612	phosphorylation	up-regulates	0.465	We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta.	SIGNOR-137085
P54252	P49841	phosphorylation	up-regulates quantity by stabilization	0.465	Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3\|	SIGNOR-264821
Q13107	P31749	phosphorylation	up-regulates quantity by stabilization	0.465	AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability.	SIGNOR-273482
O00562	P06493	phosphorylation	up-regulates	0.465	T287 is phosphorylated by cdk1 during mitosis. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis.	SIGNOR-124642
Q96SN8	Q96R06	relocalization	up-regulates activity	0.465	By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically.	SIGNOR-271719
P78362	P31749	phosphorylation	up-regulates	0.465	Here we show that srpk2, a protein kinase specific for the serine/arginine (sr) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin d1. Akt phosphorylates srpk2 on thr-492 and promotes its nuclear translocation leading to cyclin d1 up-regulation, cell cycle reentry, and neuronal apoptosis.	SIGNOR-186760
O00418	P0DP23	binding	up-regulates	0.465	The calmodulin-binding region is located between amino acids 51 and 96	SIGNOR-82505

Q13972

P12931

0

phosphorylation

down-regulates activity

0.47

These proximal Src kinases could potentially directly or indirectly phosphorylate Rasgrf-1 upon BCR activation and thereby further increase its GEF activity.

SIGNOR-280133

Q13363

Q9H2X6

0

phosphorylation

down-regulates

0.47

Homeodomain-interacting protein kinase-2 mediates ctbp phosphorylation and degradation in uv-triggered apoptosishipk2 phosphorylates ctbp at ser-422

SIGNOR-134040

P08621

P35637

0

binding

up-regulates activity

0.469

FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP

SIGNOR-262823

Q8N122

P27361

0

phosphorylation

up-regulates activity

0.469

We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.

SIGNOR-169530

Q13224

P17252

0

phosphorylation

up-regulates activity

0.469

These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.

SIGNOR-249083

P18031

P49841

0

phosphorylation

down-regulates quantity

0.469

GSK-3beta phosphorylates PTP1B at serine residues, and activation of GSK-3beta reduces the mRNA level of PTP1B.

SIGNOR-279724

P37231

Q9HAZ2

0

binding

up-regulates

0.469

Prdm16 stimulates brown adipogenesis by binding to ppar-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function

SIGNOR-180298

Q13224

Q06124

0

dephosphorylation

down-regulates activity

0.469

In addition, surface expression of GluN2B was not reduced in mutant mice and it remains to be investigated how the direct dephosphorylation of GluN2B Y1252 by Shp2 reduces GluN2B function.|The increased GluN2B Y1472 phosphorylation was reversed by a Src family kinase inhibitor, suggesting that Shp2 may negatively regulate GluN2B Y1472 phosphorylation through suppressing Src activity .

SIGNOR-276950

P08151

Q92831

0

acetylation

down-regulates activity

0.469

NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase

SIGNOR-269270

Q96CF2

Q96GD4

0

phosphorylation

up-regulates

0.469

Moreover, we find that the cpc's catalytic subunit, aurora b kinase, phosphorylates one of the three human snf7 paralogues-chmp4c-in its c-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for chmp4c function because their mutation leads to cytokinesis defects. The introduction of the s214a and s215a mutations together with s210a almost completely abolished aurora b phosphorylation

SIGNOR-197967

P08754

Q9HBW0

0

binding

up-regulates activity

0.469

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-257169

Q99497

Q8IW41

0

phosphorylation

up-regulates activity

0.469

PRAK preferentially colocalizes with DJ-1 and leads to DJ-1 activation, which in turn facilitates DJ-1 to sequester Daxx in the nucleus, preventing oxidative stress induced cell death.|These data clearly demonstrate a PRAK dependent phosphorylation of DJ-1.

SIGNOR-279746

P26012

Q9Y490

0

binding

up-regulates activity

0.469

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-257636

P05771-2

P62714

0

dephosphorylation

down-regulates activity

0.469

Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.

SIGNOR-248587

P08754

P08913

0

binding

up-regulates activity

0.469

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-256841

P46527

O00141

0

phosphorylation

down-regulates

0.469

Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna.

SIGNOR-179117

P08575

P41240

0

phosphorylation

up-regulates

0.469

Tyrosine phosphorylation of cd45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase.

SIGNOR-26785

P01106

P00519

0

phosphorylation

up-regulates activity

0.469

Altogether, our data demonstrate that Pin1 and Abl cooperate to enhance the interaction of Myc with p300 and its resulting acetylation.|These experiments confirmed that Myc Y74 is phosphorylated by Abl, and provided us with a reagent to detect this form of Myc in cells (see below).

SIGNOR-278196

P35222

P51955

0

phosphorylation

down-regulates quantity

0.469

NEK2 silencing reduced the phosphorylation of beta-catenin at Ser33 and Ser37, but did not decrease the level of total beta-catenin.|NEK2 slightly decreased the level of total beta-catenin (XREF_FIG).

SIGNOR-278173

Q15118

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.469

Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA.

SIGNOR-267444

P08588

P32121

0

binding

down-regulates activity

0.469

The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors

SIGNOR-256502

Q9H7Z6

Q13315

0

phosphorylation

up-regulates activity

0.469

In this study we present evidence that MOF is phosphorylated at the threonine 392 residue (pT392-MOF) by ATM subsequent to IR induced DNA damage.|Interestingly, ATM dependent-MOF phosphorylation increases MOF retention on DNA post-irradiation in S/G2-phase cells.

SIGNOR-278350

Q9H4A3

O95198

0

binding

down-regulates quantity by destabilization

0.469

We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body.

SIGNOR-272119

P05771

P62714

0

dephosphorylation

down-regulates activity

0.469

Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.

SIGNOR-248585

P36897

P36873

0

dephosphorylation

down-regulates

0.469

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

SIGNOR-121277

P10071

P17612

0

phosphorylation

down-regulates quantity

0.468

Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3.

SIGNOR-75359

Q9NQ66

O95837

0

binding

up-regulates activity

0.468

This suggests that both Gal4 and Gal6 can activate PLC b1.

SIGNOR-278119

P15172

P50461

0

binding

up-regulates activity

0.468

we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.

SIGNOR-241116

P10070

P17612

0

phosphorylation

down-regulates

0.468

In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation

SIGNOR-154273

Q9NP62

Q9P0U3

0

desumoylation

up-regulates activity

0.468

We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.

SIGNOR-262681

P53350

Q96EP1

0

polyubiquitination

down-regulates quantity by destabilization

0.468

Chfr, a mitotic stress checkpoint, plays an important role in cell cycle progression, tumor suppression and the processes that require the E3 ubiquitin ligase activity mediated by the RING finger domain. Chfr stimulates the formation of polyubiquitin chains by ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins including Plk1 and Aurora A.

SIGNOR-271464

Q13546

Q8WZ73

0

ubiquitination

down-regulates quantity by destabilization

0.468

We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappaB activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation.

SIGNOR-271482

O95297

P12931

0

phosphorylation

up-regulates

0.468

Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr

SIGNOR-113410

Q9BYX4

O14730

0

phosphorylation

down-regulates activity

0.468

RIOK3 mediates phosphorylation of MDA5 Ser-828|RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response

SIGNOR-264576

Q13547

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.468

MDM2 induces ubiquitination of HDAC1 in VSMCs.|Under calcification inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination.

SIGNOR-278761

Q14249

Q13490

0

ubiquitination

up-regulates activity

0.468

Alternatively, cIAP1 may mediate a vital function of EndoG other than cell death.|Cellular inhibitor of apoptosis protein 1 ubiquitinates endonuclease G but does not affect endonuclease G-mediated cell death.

SIGNOR-278605

P48431

Q99986

0

phosphorylation

up-regulates activity

0.468

VRK1, but not kinase-dead VRK1 (K179E), phosphorylated Sox2 (XREF_FIG).

SIGNOR-279578

P63096

P34972

0

binding

up-regulates activity

0.468

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-256700

P19793

Q14994

0

binding

up-regulates

0.468

Therefore, both car-rxr heterodimers and car monomers can contribute to the gene activating function of pbrems in car target genes.

SIGNOR-104441

O95999

Q13315

0

phosphorylation

up-regulates activity

0.468

Upon DNA damage, ATM phosphorylates the residue T91 of BCL10, promoting binding of BCL10 to RNF8 and simultaneously presenting UBC13 to RNF8.|When cells were pre-treated with different PIKK inhibitors, the ATM specific inhibitor KU55933 efficiently reduced etoposide induced focus formation of BCL10, whereas pretreatment of cells with NU6027, an ATR specific inhibitor, or NU7026, a DNA-PKcs-specific inhibitor, did not compromise etoposide induced focus formation of BCL10 (XREF_FIG).

SIGNOR-278392

Q9NZQ7

Q9BZS1

0

transcriptional regulation

up-regulates quantity by expression

0.468

FOXP3 expression additionally increased programmed death ligand 1 (PD-L1) expression, which, when inhibited with CCL5, decreased the tumor burden and Treg infiltration in orthotopic murine, Pan-02 PDAC tumors

SIGNOR-277728

P42229

Q06187

0

phosphorylation

up-regulates activity

0.467

Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity.

SIGNOR-250603

P63096

P28222

0

binding

up-regulates activity

0.467

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-256720

Q99961

Q5S007

0

phosphorylation

down-regulates

0.467

We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association.

SIGNOR-192068

Q14934

P45983

0

phosphorylation

up-regulates activity

0.467

Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif.|Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose dependent manner by JNK1 or JNK2.

SIGNOR-280033

Q9BW11

P61244

0

binding

up-regulates activity

0.467

the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.

SIGNOR-240393

Q9UMX1

P17612

0

phosphorylation

up-regulates quantity by stabilization

0.467

We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation

SIGNOR-172003

O00327

Q14995

0

transcriptional regulation

down-regulates quantity by repression

0.467

A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription.

SIGNOR-268006

Q92574

P53350

0

phosphorylation

down-regulates quantity by destabilization

0.467

The Hsp90 client Plk1 phosphorylates Sgt1, which had a positive impact on Sgt1 function, whereas phosphorylation of Tsc1 by Plk1 led to its ubiquitination and degradation.

SIGNOR-280072

Q96T58

Q9Y618

0

binding

up-regulates

0.467

Sharp is a potent transcriptional repressor whose repression domain (rd) interacts directly with smrt

SIGNOR-107260

Q99490

P06241

0

phosphorylation

up-regulates

0.467

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

SIGNOR-147936

Q16611

Q92843

0

binding

down-regulates

0.467

Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax.

SIGNOR-152989

O15360

O14965

0

phosphorylation

up-regulates activity

0.467

E detected interactions between Aurora A kinase and FANCA protein, one of the components of the FA nuclear core complex. These results suggest that S165 phosphorylation by Aurora A kinase is required for proper activation of the FA/BRCA pathway in response to DNA damage.

SIGNOR-277263

O95239

P53350

0

phosphorylation

down-regulates activity

0.467

Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome.|These results suggest that Plk1 negatively regulates the loading of both KIF4 and condensin to the chromosome.

SIGNOR-280069

Q03113

Q9UBY5

0

binding

up-regulates

0.467

Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2.

SIGNOR-198544

Q08828

P19086

0

binding

down-regulates activity

0.467

Activated a z inhibits the activity of type I and type V adenylyl cyclases.

SIGNOR-278044

P13631

P31749

0

phosphorylation

up-regulates activity

0.467

S379 of RARγ is indispensable for the CLDN6-triggered cellular events. The most important finding of the present study is that the CLDN6/SFK/PI3K/AKT signaling controls the RARγ and ERα activities (Fig. 6).

SIGNOR-277492

Q14247

P28482

0

phosphorylation

up-regulates

0.467

Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.

SIGNOR-165200

P14921

P31314

0

binding

down-regulates activity

0.467

We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement.

SIGNOR-259097

P09017

O15550

0

transcriptional regulation

up-regulates quantity by expression

0.467

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

SIGNOR-260030

P63000

Q92997

0

binding

up-regulates

0.467

Wnt/fz activation of rac and rho is inhibited by rac-n17 and rho-n19, respectively (figs. _(figs.1d,1d, _d,5c,d;5c,d;habas et al. 2001), and requires different dvl domains wnt signaling induces complex formation between dvl and rac.

SIGNOR-97409

O43156

Q9UK97

0

binding

down-regulates quantity by destabilization

0.467

Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins.

SIGNOR-271997

Q9UGP5

P78527

0

phosphorylation

up-regulates activity

0.467

We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ.

SIGNOR-273835

P46379

O43765

0

binding

up-regulates activity

0.467

USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.

SIGNOR-272859

Q9NPB6

P37173

0

phosphorylation

up-regulates

0.466

We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. [...] These data suggest that T_RII phosphorylates Par6 at its penultimate residue, Ser345.

SIGNOR-227484

Q00987

P46934

0

ubiquitination

up-regulates quantity by stabilization

0.466

NEDD4 promotes MDM2 ubiquitination in a dose- and time-dependent manner, whereas depletion of NEDD4 reduced the half-life of endogenous MDM2 [ xref ].

SIGNOR-278769

Q9Y4K3

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.466

CHIP promotes TRAF6 ubiquitination and degradation.|These results suggest that CHIP negatively regulates the stability of TRAF6.

SIGNOR-278670

O14974

Q9H093

0

phosphorylation

down-regulates activity

0.466

NUAK2 phosphorylates and inhibits MYPT1, the regulatory subunit of MLC phosphatase, stabilizing actin filaments and mediating contraction of smooth muscle cells ( xref ).

SIGNOR-279081

O00429

P06493

0

phosphorylation

up-regulates activity

0.466

Drp1 is phosphorylated at the Ser616 position and activated predominantly by CDK1.

SIGNOR-279394

P10636

P43405

0

phosphorylation

down-regulates

0.466

We established that tyrosine 18 was the primary residue in tau phosphorylated by sykphosphorylation of tau by syk could be involved in neurite outgrowth.

SIGNOR-159648

Q8NHZ8

O95835

0

phosphorylation

up-regulates activity

0.466

LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C|Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly

SIGNOR-275472

Q09472

P28482

0

phosphorylation

up-regulates

0.466

Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression.

SIGNOR-156891

P49789

P12931

0

phosphorylation

up-regulates activity

0.466

The human tumor suppressor Fhit is a homodimeric histidine triad (HIT) protein of 147 amino acids which has Ap3A hydrolase activity. We have recently discovered that Fhit is phosphorylated in vivo and is phosphorylated in vitro by Src kinaseMALDI-TOF and HPLC-ESI tandem mass spectrometry of intact Fhit and proteolytic peptides of Fhit demonstrated that Fhit is phosphorylated on Y114 on either one or both subunitsThe decreases in the values of Km and kcat for the phosphorylated forms in comparison to those of unphosphorylated Fhit favor the formation and lifetime of the Fhit_Ap3A complex, which may enhance the tumor suppressor activity of Fhit.

SIGNOR-247134

P15509

P09919

0

binding

up-regulates

0.466

Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta).

SIGNOR-72511

Q8N122

Q9Y478

0

phosphorylation

down-regulates

0.466

Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2.

SIGNOR-173041

O95863

Q15139

0

phosphorylation

down-regulates activity

0.466

Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba.

SIGNOR-168537

P50148

O43613

0

binding

up-regulates activity

0.466

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-257220

P27449

Q8N6D2

0

polyubiquitination

down-regulates quantity by destabilization

0.466

The data indicated that RNF182 targeted ATP6V0C for degradation by the ubiquitin-proteosome pathway.

SIGNOR-271771

P31431

O43184

0

binding

up-regulates

0.466

The adam12 cysteine-rich domain (radam12-cys) supports cell attachment using syndecan-4 as a primary cell surface receptor that subsequently triggers beta(1) integrin-dependent cell spreading, stress fiber assembly, and focal adhesion formation.

SIGNOR-96931

Q01130

Q92993

0

acetylation

down-regulates

0.466

In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation.

SIGNOR-170594

Q13114

Q86VP1

0

binding

down-regulates activity

0.466

ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi.

SIGNOR-275737

O14641

Q96GF1

0

polyubiquitination

down-regulates quantity by destabilization

0.466

The E3 ligase RNF185 negatively regulates osteogenic differentiation by targeting Dvl2 for degradation. Overexpression of RNF185 decreases the exogenous and endogenous level of Dvl2, promotes the ubiquitination and degradation of Dvl2

SIGNOR-272173

Q99081

Q02535

0

binding

down-regulates activity

0.466

All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.

SIGNOR-241152

P78527

P07948

0

phosphorylation

down-regulates activity

0.466

The interaction between Lyn and DNA-PKcs inhibits DNA-PKcs activity and the ability of DNA-PKcs to form a complex with Ku/DNA.|We also show that Lyn phosphorylates DNA-PKcs but not Ku in vitro.

SIGNOR-279061

P06850

P51608

0

transcriptional regulation

down-regulates quantity by repression

0.466

Collectively, these results point to a specific association between WT MeCP2 and the methylated promoter region of Crh in vivo. In contrast, the MeCP2308 protein was not detected at the Crh promoter. | Thus, the results of seqChIP indicate that MeCP2 preferentially associates with a transcriptionally inactive, dimethyl-histone H3 Lys-9-rich form of the Crh promoter in mice.

SIGNOR-264548

O15519

P31749

0

phosphorylation

down-regulates quantity

0.466

TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling.

SIGNOR-252548

Q06609

P42574

0

cleavage

down-regulates quantity by destabilization

0.466

The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin

SIGNOR-271709

P42336

Q9UQC2

0

binding

up-regulates

0.466

The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival

SIGNOR-204966

P35568

Q12923

0

dephosphorylation

down-regulates activity

0.466

Finally, we report that PTPL1 expression is sufficient to block the IRS-1/phosphatidylinositol 3-kinase/Akt signaling pathway, to inhibit the insulin-like growth factor-I effect on cell survival, and to induce apoptosis.|We first show by complementary approaches that PTPL1 specifically dephosphorylates insulin receptor substrate-1 (IRS-1) in vitro and in cellulo.

SIGNOR-277053

P19022

O00192

0

binding

up-regulates quantity by stabilization

0.466

To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.

SIGNOR-252128

P50148

P32238

0

binding

up-regulates activity

0.465

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-257303

Q8NBP7

Q12772

0

transcriptional regulation

up-regulates quantity by expression

0.465

Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes.

SIGNOR-254459

P10997

P16519

0

cleavage

up-regulates activity

0.465

The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule

SIGNOR-261791

P48436

P17612

0

phosphorylation

up-regulates

0.465

We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta.

SIGNOR-137085

P54252

P49841

0

phosphorylation

up-regulates quantity by stabilization

0.465

Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3|

SIGNOR-264821

Q13107

P31749

0

phosphorylation

up-regulates quantity by stabilization

0.465

AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability.

SIGNOR-273482

O00562

P06493

0

phosphorylation

up-regulates

0.465

T287 is phosphorylated by cdk1 during mitosis. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis.

SIGNOR-124642

Q96SN8

Q96R06

0

relocalization

up-regulates activity

0.465

By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically.

SIGNOR-271719

P78362

P31749

0

phosphorylation

up-regulates

0.465

Here we show that srpk2, a protein kinase specific for the serine/arginine (sr) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin d1. Akt phosphorylates srpk2 on thr-492 and promotes its nuclear translocation leading to cyclin d1 up-regulation, cell cycle reentry, and neuronal apoptosis.

SIGNOR-186760

O00418

P0DP23

0

binding

up-regulates

0.465

The calmodulin-binding region is located between amino acids 51 and 96

SIGNOR-82505