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
Q9BYB0	P48058	2	binding	up-regulates quantity	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-264604
P35452	Q9Y5Q3	2	binding	down-regulates activity	0.378	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221896
P49841	P24071	1	phosphorylation	down-regulates activity	0.2	GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state.	SIGNOR-264857
Q2M2Z5	P53350	0	phosphorylation	up-regulates	0.519	Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz.	SIGNOR-149630
Q8IVP5	O75385	0	phosphorylation	up-regulates activity	0.595	Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3.	SIGNOR-273606
P25098	P30989	1	phosphorylation	up-regulates activity	0.2	Here we report the unique phosphorylation\nof NTSR1 by GRK2 and GRK5, which belong to the GRK2 and GRK4 subfamilies,\nrespectively.	SIGNOR-278280
P09543	P02686	1	null	down-regulates activity	0.455	We provide evidence that CNP directly associates with and organizes the actin cytoskeleton, thereby providing an intracellular strut that counteracts membrane compaction by myelin basic protein (MBP).	SIGNOR-269269
P16220	O75582	0	phosphorylation	up-regulates	0.731	Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb.	SIGNOR-59458
Q15831	Q9Y2K2	1	phosphorylation	up-regulates	0.488	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122835
P06493	P15172	1	phosphorylation	down-regulates	0.364	Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21.	SIGNOR-121601
P15311	P07332	1	relocalization	up-regulates	0.395	The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin.	SIGNOR-159496
P00519	Q15746	1	phosphorylation	up-regulates	0.3	Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity	SIGNOR-167989
P53350	O95251	1	phosphorylation	up-regulates	0.503	Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.	SIGNOR-160751
Q9UM11	Q9NQW6	2	binding	down-regulates quantity by destabilization	0.265	Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin.	SIGNOR-272654
P03372	Q99728	0	ubiquitination	down-regulates quantity	0.427	As shown in xref , both FOXK2 and BARD1 enhanced the ubiquitination of ER\u03b1, with the extent of ubiquitination being enhanced when both FOXK2 and BARD1 were overexpressed.\|These findings suggested that FOXK2 might act as a negative regulator of Estrogen receptor\u03b1, and its association with both Estrogen receptor\u03b1 and BRCA1/BARD1 could lead to the down-regulation of Estrogen receptor\u03b1 transcriptional activity, effectively regulating the function of Estrogen receptor\u03b1.	SIGNOR-278803
Q9Y6E0	Q9Y6E0	2	phosphorylation	up-regulates	0.2	Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (mst3) involves paxillin and protein-tyrosine phosphatase-pest.	SIGNOR-150131
P28482	Q07343-2	1	phosphorylation	up-regulates activity	0.268	The short-form PDE4B2 isoenzyme was activated by Erk2 phosphorylation. These functional changes in PDE activity were mimicked by mutation of the target serine for Erk2 phosphorylation to the negatively charged amino acid, aspartic acid.	SIGNOR-275971
P17655	Q15078	1	cleavage	up-regulates activity	0.565	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251610
P60484	P53671	0	phosphorylation	down-regulates activity	0.274	LIMK2 inhibits PTEN phosphatase activity in vitro and in cells.\|PTEN phosphorylation and downregulation by LIMK2 promotes tumorigenesis and EMT in vivo.	SIGNOR-278363
P12931	O00401	1	phosphorylation	up-regulates activity	0.759	An Src family tyrosine kinase, v-Src, phosphorylates and activates N-WASP.	SIGNOR-279487
P03372	Q96FW1	0	deubiquitination	down-regulates activity	0.546	OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.\|We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells.	SIGNOR-276529
Q9UM73	P23471	0	dephosphorylation	down-regulates	0.545	Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation.	SIGNOR-157227
P37173	O95405	2	binding	up-regulates activity	0.57	Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex	SIGNOR-245093
Q02156	P78352	1	phosphorylation	up-regulates quantity	0.285	PKCepsilon directly phosphorylated PSD-95 and JNK1 in vitro Inhibiting PKCepsilon, JNK, or calcium/calmodulin dependent kinase II activity prevented the effects of PKCepsilon activators on PSD-95 phosphorylation.\|These results indicate that PKCepsilon promotes synaptogenesis by activating PSD-95 phosphorylation directly through JNK1 and calcium/calmodulin dependent kinase II and also by inducing expression of PSD-95 and synaptophysin.	SIGNOR-280087
P42345	P06213	1	phosphorylation	up-regulates activity	0.391	Both recombinant mTOR and immunoprecipitated mTORC2 phosphorylate IGF-IR and InsR on Tyr1131/1136 and Tyr1146/1151, respectively.\|Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF-IR and InsR.	SIGNOR-280045
P00519	Q9Y6W5	1	phosphorylation	up-regulates activity	0.698	Furthermore, Abl phosphorylates WAVE2 on tyrosine 150, and WAVE2 deficient cells rescued with a Y150F mutant fail to regain their ability to ruffle and form microspikes, unlike cells rescued with wild-type WAVE2.\|Together, these data show that c-Abl activates WAVE2 via tyrosine phosphorylation to promote actin remodeling in vivo and that Abi-1 forms the crucial link between these two factors.	SIGNOR-279390
P35611	P17612	0	phosphorylation	down-regulates activity	0.311	Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin.	SIGNOR-250331
P38936	Q96J87	0	post transcriptional regulation	up-regulates quantity by stabilization	0.2	CELF6 binds to the 3'UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest.	SIGNOR-269044
Q7Z6Z7	P38398	1	ubiquitination	down-regulates quantity by destabilization	0.397	Collectively, these data indicate that HUWE1 targets BRCA1, but not BARD1, for polyubiquitination and degradation.Because HUWE1 promotes BRCA1 ubiquitination and degradation, we wondered whether it might contribute to the reduced BRCA1 protein levels in sporadic breast cancer.	SIGNOR-278583
P35354	Q14934	0	transcriptional regulation	up-regulates quantity by expression	0.282	NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration	SIGNOR-264027
P19793	P13631	2	binding	up-regulates	0.686	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16671
P20273	P15907	0	glycosylation	down-regulates activity	0.471	CD22-ligand interaction is regulated by the activity of a b-galactoside a2,6- sialyltransferase that can inactivate CD22-mediated binding by sialylating the CD22 receptor itself. These observations suggest that N-linked glycosylation sites on the CD22 molecule may play a role in the regulation of CD22-mediated adhesion.	SIGNOR-261741
P14651	P32243	1	transcriptional regulation	up-regulates quantity by expression	0.2	Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. \| Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively	SIGNOR-261635
O60260	Q9UL15	2	binding	down-regulates activity	0.2	Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity Immunoprecipitation (IP) of GFP-parkin resulted in the coimmunoprecipitation of both Hsp70 and BAG5 or BAG5(DARA) (Figure 4A). Furthermore, IP of GFP-parkin resulted in the coimmunoprecipitation of BAG5 or BAG5 (DARA) in the absence of overexpressed Hsp70. Taken together, these data demonstrate that BAG5 can directly inhibit parkin-mediated autoubiquitinylation independently of Hsp70.	SIGNOR-261198
Q00535	O94916	1	phosphorylation	up-regulates	0.2	High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. n hek293 cells, mass spectrometry shows phosphorylation of tonebp/orebp-s120, -s134, -t135, and -s155.	SIGNOR-170886
P19784	P60484	1	phosphorylation	down-regulates activity	0.704	We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).	SIGNOR-251025
Q9Y371	Q07812	2	binding	up-regulates	0.329	Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change.	SIGNOR-141166
P24864	Q969H0	2	binding	down-regulates quantity by destabilization	0.567	Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme	SIGNOR-271643
P54132	O14757	0	phosphorylation	down-regulates quantity by destabilization	0.781	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges.	SIGNOR-276909
Q9HB89	Q5H8A3	2	binding	up-regulates	0.729	Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus.	SIGNOR-133074
O00141	P21796	1	phosphorylation	down-regulates quantity	0.2	As hypothesized based upon our observation that activated SGK-1 reduces VDAC-1 protein levels, sgk-1 overexpression normalizes the shortened lifespan of vdac-1 transgenics .\|Taken together, these data indicate that Ser104 phosphorylation of VDAC1 by SGK1 increases its ubiquitination and subsequent cellular clearance.	SIGNOR-278988
P17480	P01106	0	transcriptional regulation	up-regulates quantity by expression	0.356	MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation\|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter.	SIGNOR-269644
O43347	P49757	2	binding	down-regulates	0.445	The study confirmed p21(cip1) and numb proteins as targets of musashi1, suggesting additionally p27(kip1) in cell-cycle regulation and jagged-1 in notch .	SIGNOR-165617
Q8WV22	Q96MG7	2	binding	up-regulates activity	0.2	MAGE-G1 enhances NSE1 ubiquitin ligase activity in vitro.	SIGNOR-265489
Q96R06	O14965	0	phosphorylation	up-regulates activity	0.511	We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids.	SIGNOR-276648
P12931	P49841	0	phosphorylation	up-regulates activity	0.383	P -Ser9 GSK-3\u03b2 phosphorylates Ser43, Ser51, and Ser493 residues of src, regulating src activity.	SIGNOR-278444
Q9BYM8	O14867	1	ubiquitination	down-regulates quantity by destabilization	0.345	HOIL-1 bound Bach1 in vivo and thus stimulated its polyubiquitination in vitro. These results suggest that heme regulates the polyubiquitination of Bach1 and subsequent degradation and that HOIL-1 may function as an E3 ligase in this process.	SIGNOR-236971
O60260	O95140	1	ubiquitination	down-regulates quantity	0.2	Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2. Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy.	SIGNOR-272780
P31749	P21453	1	phosphorylation	up-regulates activity	0.704	Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis	SIGNOR-252467
P08754	P41968	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256891
P50548	P06493	0	phosphorylation	down-regulates	0.2	Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf	SIGNOR-29501
Q9UMX1	Q9BZE0	1	relocalization	down-regulates	0.266	Negative regulation of gli1 and gli2 activator function by suppressor of fused through multiple mechanisms.Together, these observations reveal that su(fu) regulates the activity of gli1 and gli2 through distinct cytoplasmic and nuclear mechanisms.	SIGNOR-142608
Q9UPZ9	Q9UPZ9	2	phosphorylation	up-regulates	0.2	Ick is activated by dual phosphorylation of the tdy motif. Phosphorylation of tyr-159 in the tdy motif requires ick autokinase activity	SIGNOR-138424
P01024	Q03591	2	binding	up-regulates activity	0.833	Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.\|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. \|these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b	SIGNOR-263475
Q13490	Q15628	2	binding	up-regulates activity	0.698	The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD. N-terminal domain of tradd may become accessible to traf2, thereby permitting recruitment of the traf2/ciap1 heterocomplex.	SIGNOR-45134
Q6ZNA4	P12757	1	polyubiquitination	down-regulates quantity by destabilization	0.723	Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.	SIGNOR-272885
Q86X29	Q14289	0	phosphorylation	up-regulates activity	0.2	Pyk2 enhances LSR and tricellulin localization to tTJs.\|Pyk2-dependent phosphorylation of LSR enhances localization of LSR and tricellulin at tricellular tight junctions.	SIGNOR-280101
P12931	P01135	1	cleavage	up-regulates	0.3	Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network.	SIGNOR-235888
Q9UKT9	Q96SW2	0	ubiquitination	down-regulates quantity by destabilization	0.581	IMiD compounds cause selective ubiquitination and degradation of IKZF1 in CD34+ cells by the CRBN E3 ubiquitin ligase.	SIGNOR-272319
P68400	Q9Y6W5	1	phosphorylation	down-regulates	0.2	Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo.	SIGNOR-182350
P00533	P51692	1	phosphorylation	up-regulates	0.829	Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor.	SIGNOR-113393
Q96EV8	Q13049	0	ubiquitination	down-regulates quantity	0.537	TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation.	SIGNOR-265658
P00742	P38435	0	carboxylation	up-regulates activity	0.615	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. \|We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.\|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; \| 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263667
P0DP23	P55040	2	binding	up-regulates activity	0.332	Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.	SIGNOR-261726
P26010	O14713	2	binding	down-regulates activity	0.287	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257664
P84022	P12931	0	phosphorylation	up-regulates activity	0.377	Although the role of ERK in mediating phosphorylation of Smad2/3 remains to be investigated, our data indicate that early Smad3 phosphorylation is independent of transient EGFR transactivation and ERK1/2 activation initiated by HB-EGF release, whereas Src mediated chronic EGFR transactivation and ERK1/2 activation involve late Smad3 activation induced by TGF-beta1.\|Inhibition of Src not only decreases Smad3 phosphorylation but also decreases phosphorylation dependent nuclear translocation of Smad2/3, suggesting that Src kinase could modulate Smad3 activity.	SIGNOR-279292
P28482	Q15672	1	phosphorylation	up-regulates	0.304	We identified the serine 68 (s68) as a major phosphorylation site of twist1 by mass spectrometry and with specific antibodies. This s68 is phosphorylated by p38, jnk and erk1/2 in vitro, and its phosphorylation levels positively correlate with twist1 protein levels in hek293 and breast cancer cells.	SIGNOR-173401
P38398	P42574	0	cleavage	down-regulates quantity by destabilization	0.473	We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable.	SIGNOR-256326
P00441	Q16236	0	transcriptional regulation	up-regulates quantity by expression	0.408	BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2	SIGNOR-254653
P04626	O14672	0	cleavage	up-regulates activity	0.344	The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin.	SIGNOR-259845
O60825	P17252	0	phosphorylation	up-regulates activity	0.439	The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. \| Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme.	SIGNOR-248844
O94907	Q96MU8	2	binding	up-regulates	0.838	Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/betBeta-catenin. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membrane.	SIGNOR-88838
P30679	Q92633	2	binding	up-regulates activity	0.456	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-257282
O43353	Q13489	0	polyubiquitination	up-regulates activity	0.787	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272715
P17947	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.2	We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7.	SIGNOR-277541
O00634	Q92859	2	binding	up-regulates activity	0.72	Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins.	SIGNOR-268171
P07948	P20273	1	phosphorylation	down-regulates activity	0.743	LYN is a BCR-associated SRC kinase involved in the positive regulation of BCR, but it also functions as a negative regulator by phosphorylating the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of CD22.	SIGNOR-268443
P30559	P01178-PRO_0000020495	2	binding	up-regulates activity	0.2	The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation.\| The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta.	SIGNOR-268545
A8K0Z3	P14373	0	ubiquitination	up-regulates activity	0.2	Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport.	SIGNOR-253514
P62714	P31749	1	dephosphorylation	down-regulates	0.508	These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity	SIGNOR-252636
Q12888	P53778	0	phosphorylation	down-regulates activity	0.2	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.\|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks \|phosphorylation of T1609 is likely to be mediated by p38 MAPK	SIGNOR-264448
Q13164	P15056	0	phosphorylation	up-regulates quantity	0.292	Our data indicate that oncogenic BRAF increases ERK5 protein level, phosphorylation at several residues and kinase activity.\|Overexpression of oncogenic BRAF induced ERK5 phosphorylation at Thr218 and Tyr220, although to a lower level than that induced by MEK5DD.	SIGNOR-278353
Q9HC77	O00444	0	phosphorylation	up-regulates	0.799	Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap	SIGNOR-166007
O43524	Q13043	0	phosphorylation	up-regulates	0.681	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity.	SIGNOR-178190
P48729	Q9UKV8	1	phosphorylation	down-regulates activity	0.369	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276510
P0DMV8	O14727	2	binding	down-regulates	0.431	Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, hsp70, is mediated through its direct association with the caspase-recruitment domain (card) of apaf-1 and through apoptosome formation	SIGNOR-80451
Q68D86	Q96CN5	2	binding	up-regulates activity	0.2	CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis.	SIGNOR-275627
P01178-PRO_0000020495	P16519	0	cleavage	up-regulates quantity	0.2	Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.	SIGNOR-270335
Q9Y6E0	Q9Y2H1	1	phosphorylation	up-regulates	0.441	Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity.	SIGNOR-142510
P61586	Q16513	2	binding	up-regulates activity	0.833	PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome.	SIGNOR-275466
P46783	O96006	0	transcriptional regulation	up-regulates quantity by expression	0.2	HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. \| Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid.	SIGNOR-266083
P23470	P40763	1	dephosphorylation	up-regulates activity	0.259	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254729
P15336	P07954	2	binding	up-regulates activity	0.2	Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes.	SIGNOR-266314
Q9Y4C1	Q16695	1	demethylation	up-regulates activity	0.2	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.	SIGNOR-276846
Q13617	P31941	1	ubiquitination	down-regulates quantity by destabilization	0.251	Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation\|Here, we report that the HPV oncoprotein E7 stabilizes the APOBEC3A (A3A) protein in human keratinocytes by inhibiting ubiquitin-dependent protein degradation in a cullin-dependent manner.	SIGNOR-261325
P56704	Q9H237	0	palmitoylation	up-regulates activity	0.7	And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane.	SIGNOR-256598
O95837	Q92633	2	binding	up-regulates activity	0.435	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-257200
Q96P31	Q06124	2	binding	up-regulates activity	0.383	Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.	SIGNOR-274014
P11912	P06241	0	phosphorylation	up-regulates activity	0.596	Lyn and Fyn phosphorylated the CD79a cytoplasmic portion of the fusion proteins well, with >80% of phosphorylation occurring at Y182. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM).	SIGNOR-251153
O95477	Q96KG7	2	binding	up-regulates activity	0.332	ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level.	SIGNOR-265164

Q9BYB0

P48058

2

binding

up-regulates quantity

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-264604

P35452

Q9Y5Q3

2

binding

down-regulates activity

0.378

Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.

SIGNOR-221896

P49841

P24071

1

phosphorylation

down-regulates activity

0.2

GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state.

SIGNOR-264857

Q2M2Z5

P53350

0

phosphorylation

up-regulates

0.519

Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz.

SIGNOR-149630

Q8IVP5

O75385

0

phosphorylation

up-regulates activity

0.595

Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3.

SIGNOR-273606

P25098

P30989

1

phosphorylation

up-regulates activity

0.2

Here we report the unique phosphorylation\nof NTSR1 by GRK2 and GRK5, which belong to the GRK2 and GRK4 subfamilies,\nrespectively.

SIGNOR-278280

P09543

P02686

1

null

down-regulates activity

0.455

We provide evidence that CNP directly associates with and organizes the actin cytoskeleton, thereby providing an intracellular strut that counteracts membrane compaction by myelin basic protein (MBP).

SIGNOR-269269

P16220

O75582

0

phosphorylation

up-regulates

0.731

Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb.

SIGNOR-59458

Q15831

Q9Y2K2

1

phosphorylation

up-regulates

0.488

Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold

SIGNOR-122835

P06493

P15172

1

phosphorylation

down-regulates

0.364

Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21.

SIGNOR-121601

P15311

P07332

1

relocalization

up-regulates

0.395

The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin.

SIGNOR-159496

P00519

Q15746

1

phosphorylation

up-regulates

0.3

Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity

SIGNOR-167989

P53350

O95251

1

phosphorylation

up-regulates

0.503

Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.

SIGNOR-160751

Q9UM11

Q9NQW6

2

binding

down-regulates quantity by destabilization

0.265

Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin.

SIGNOR-272654

P03372

Q99728

0

ubiquitination

down-regulates quantity

0.427

As shown in xref , both FOXK2 and BARD1 enhanced the ubiquitination of ER\u03b1, with the extent of ubiquitination being enhanced when both FOXK2 and BARD1 were overexpressed.|These findings suggested that FOXK2 might act as a negative regulator of Estrogen receptor\u03b1, and its association with both Estrogen receptor\u03b1 and BRCA1/BARD1 could lead to the down-regulation of Estrogen receptor\u03b1 transcriptional activity, effectively regulating the function of Estrogen receptor\u03b1.

SIGNOR-278803

Q9Y6E0

2

phosphorylation

up-regulates

0.2

Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (mst3) involves paxillin and protein-tyrosine phosphatase-pest.

SIGNOR-150131

P28482

Q07343-2

1

phosphorylation

up-regulates activity

0.268

The short-form PDE4B2 isoenzyme was activated by Erk2 phosphorylation. These functional changes in PDE activity were mimicked by mutation of the target serine for Erk2 phosphorylation to the negatively charged amino acid, aspartic acid.

SIGNOR-275971

P17655

Q15078

1

cleavage

up-regulates activity

0.565

Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain

SIGNOR-251610

P60484

P53671

0

phosphorylation

down-regulates activity

0.274

LIMK2 inhibits PTEN phosphatase activity in vitro and in cells.|PTEN phosphorylation and downregulation by LIMK2 promotes tumorigenesis and EMT in vivo.

SIGNOR-278363

P12931

O00401

1

phosphorylation

up-regulates activity

0.759

An Src family tyrosine kinase, v-Src, phosphorylates and activates N-WASP.

SIGNOR-279487

P03372

Q96FW1

0

deubiquitination

down-regulates activity

0.546

OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.|We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells.

SIGNOR-276529

Q9UM73

P23471

0

dephosphorylation

down-regulates

0.545

Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation.

SIGNOR-157227

P37173

O95405

2

binding

up-regulates activity

0.57

Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex

SIGNOR-245093

Q02156

P78352

1

phosphorylation

up-regulates quantity

0.285

PKCepsilon directly phosphorylated PSD-95 and JNK1 in vitro Inhibiting PKCepsilon, JNK, or calcium/calmodulin dependent kinase II activity prevented the effects of PKCepsilon activators on PSD-95 phosphorylation.|These results indicate that PKCepsilon promotes synaptogenesis by activating PSD-95 phosphorylation directly through JNK1 and calcium/calmodulin dependent kinase II and also by inducing expression of PSD-95 and synaptophysin.

SIGNOR-280087

P42345

P06213

1

phosphorylation

up-regulates activity

0.391

Both recombinant mTOR and immunoprecipitated mTORC2 phosphorylate IGF-IR and InsR on Tyr1131/1136 and Tyr1146/1151, respectively.|Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF-IR and InsR.

SIGNOR-280045

P00519

Q9Y6W5

1

phosphorylation

up-regulates activity

0.698

Furthermore, Abl phosphorylates WAVE2 on tyrosine 150, and WAVE2 deficient cells rescued with a Y150F mutant fail to regain their ability to ruffle and form microspikes, unlike cells rescued with wild-type WAVE2.|Together, these data show that c-Abl activates WAVE2 via tyrosine phosphorylation to promote actin remodeling in vivo and that Abi-1 forms the crucial link between these two factors.

SIGNOR-279390

P35611

P17612

0

phosphorylation

down-regulates activity

0.311

Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin.

SIGNOR-250331

P38936

Q96J87

0

post transcriptional regulation

up-regulates quantity by stabilization

0.2

CELF6 binds to the 3'UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest.

SIGNOR-269044

Q7Z6Z7

P38398

1

ubiquitination

down-regulates quantity by destabilization

0.397

Collectively, these data indicate that HUWE1 targets BRCA1, but not BARD1, for polyubiquitination and degradation.Because HUWE1 promotes BRCA1 ubiquitination and degradation, we wondered whether it might contribute to the reduced BRCA1 protein levels in sporadic breast cancer.

SIGNOR-278583

P35354

Q14934

0

transcriptional regulation

up-regulates quantity by expression

0.282

NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration

SIGNOR-264027

P19793

P13631

2

binding

up-regulates

0.686

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins

SIGNOR-16671

P20273

P15907

0

glycosylation

down-regulates activity

0.471

CD22-ligand interaction is regulated by the activity of a b-galactoside a2,6- sialyltransferase that can inactivate CD22-mediated binding by sialylating the CD22 receptor itself. These observations suggest that N-linked glycosylation sites on the CD22 molecule may play a role in the regulation of CD22-mediated adhesion.

SIGNOR-261741

P14651

P32243

1

transcriptional regulation

up-regulates quantity by expression

0.2

Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively

SIGNOR-261635

O60260

Q9UL15

2

binding

down-regulates activity

0.2

Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity Immunoprecipitation (IP) of GFP-parkin resulted in the coimmunoprecipitation of both Hsp70 and BAG5 or BAG5(DARA) (Figure 4A). Furthermore, IP of GFP-parkin resulted in the coimmunoprecipitation of BAG5 or BAG5 (DARA) in the absence of overexpressed Hsp70. Taken together, these data demonstrate that BAG5 can directly inhibit parkin-mediated autoubiquitinylation independently of Hsp70.

SIGNOR-261198

Q00535

O94916

1

phosphorylation

up-regulates

0.2

High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. n hek293 cells, mass spectrometry shows phosphorylation of tonebp/orebp-s120, -s134, -t135, and -s155.

SIGNOR-170886

P19784

P60484

1

phosphorylation

down-regulates activity

0.704

We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).

SIGNOR-251025

Q9Y371

Q07812

2

binding

up-regulates

0.329

Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change.

SIGNOR-141166

P24864

Q969H0

2

binding

down-regulates quantity by destabilization

0.567

Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme

SIGNOR-271643

P54132

O14757

0

phosphorylation

down-regulates quantity by destabilization

0.781

We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges.

SIGNOR-276909

Q9HB89

Q5H8A3

2

binding

up-regulates

0.729

Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus.

SIGNOR-133074

O00141

P21796

1

phosphorylation

down-regulates quantity

0.2

As hypothesized based upon our observation that activated SGK-1 reduces VDAC-1 protein levels, sgk-1 overexpression normalizes the shortened lifespan of vdac-1 transgenics .|Taken together, these data indicate that Ser104 phosphorylation of VDAC1 by SGK1 increases its ubiquitination and subsequent cellular clearance.

SIGNOR-278988

P17480

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.356

MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter.

SIGNOR-269644

O43347

P49757

2

binding

down-regulates

0.445

The study confirmed p21(cip1) and numb proteins as targets of musashi1, suggesting additionally p27(kip1) in cell-cycle regulation and jagged-1 in notch .

SIGNOR-165617

Q8WV22

Q96MG7

2

binding

up-regulates activity

0.2

MAGE-G1 enhances NSE1 ubiquitin ligase activity in vitro.

SIGNOR-265489

Q96R06

O14965

0

phosphorylation

up-regulates activity

0.511

We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids.

SIGNOR-276648

P12931

P49841

0

phosphorylation

up-regulates activity

0.383

P -Ser9 GSK-3\u03b2 phosphorylates Ser43, Ser51, and Ser493 residues of src, regulating src activity.

SIGNOR-278444

Q9BYM8

O14867

1

ubiquitination

down-regulates quantity by destabilization

0.345

HOIL-1 bound Bach1 in vivo and thus stimulated its polyubiquitination in vitro. These results suggest that heme regulates the polyubiquitination of Bach1 and subsequent degradation and that HOIL-1 may function as an E3 ligase in this process.

SIGNOR-236971

O60260

O95140

1

ubiquitination

down-regulates quantity

0.2

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

SIGNOR-272780

P31749

P21453

1

phosphorylation

up-regulates activity

0.704

Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis

SIGNOR-252467

P08754

P41968

2

binding

up-regulates activity

0.25

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

SIGNOR-256891

P50548

P06493

0

phosphorylation

down-regulates

0.2

Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf

SIGNOR-29501

Q9UMX1

Q9BZE0

1

relocalization

down-regulates

0.266

Negative regulation of gli1 and gli2 activator function by suppressor of fused through multiple mechanisms.Together, these observations reveal that su(fu) regulates the activity of gli1 and gli2 through distinct cytoplasmic and nuclear mechanisms.

SIGNOR-142608

Q9UPZ9

2

phosphorylation

up-regulates

0.2

Ick is activated by dual phosphorylation of the tdy motif. Phosphorylation of tyr-159 in the tdy motif requires ick autokinase activity

SIGNOR-138424

P01024

Q03591

2

binding

up-regulates activity

0.833

Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b

SIGNOR-263475

Q13490

Q15628

2

binding

up-regulates activity

0.698

The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD. N-terminal domain of tradd may become accessible to traf2, thereby permitting recruitment of the traf2/ciap1 heterocomplex.

SIGNOR-45134

Q6ZNA4

P12757

1

polyubiquitination

down-regulates quantity by destabilization

0.723

Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.

SIGNOR-272885

Q86X29

Q14289

0

phosphorylation

up-regulates activity

0.2

Pyk2 enhances LSR and tricellulin localization to tTJs.|Pyk2-dependent phosphorylation of LSR enhances localization of LSR and tricellulin at tricellular tight junctions.

SIGNOR-280101

P12931

P01135

1

cleavage

up-regulates

0.3

Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network.

SIGNOR-235888

Q9UKT9

Q96SW2

0

ubiquitination

down-regulates quantity by destabilization

0.581

IMiD compounds cause selective ubiquitination and degradation of IKZF1 in CD34+ cells by the CRBN E3 ubiquitin ligase.

SIGNOR-272319

P68400

Q9Y6W5

1

phosphorylation

down-regulates

0.2

Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo.

SIGNOR-182350

P00533

P51692

1

phosphorylation

up-regulates

0.829

Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor.

SIGNOR-113393

Q96EV8

Q13049

0

ubiquitination

down-regulates quantity

0.537

TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation.

SIGNOR-265658

P00742

P38435

0

carboxylation

up-regulates activity

0.615

This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).

SIGNOR-263667

P0DP23

P55040

2

binding

up-regulates activity

0.332

Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.

SIGNOR-261726

P26010

O14713

2

binding

down-regulates activity

0.287

Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation

SIGNOR-257664

P84022

P12931

0

phosphorylation

up-regulates activity

0.377

Although the role of ERK in mediating phosphorylation of Smad2/3 remains to be investigated, our data indicate that early Smad3 phosphorylation is independent of transient EGFR transactivation and ERK1/2 activation initiated by HB-EGF release, whereas Src mediated chronic EGFR transactivation and ERK1/2 activation involve late Smad3 activation induced by TGF-beta1.|Inhibition of Src not only decreases Smad3 phosphorylation but also decreases phosphorylation dependent nuclear translocation of Smad2/3, suggesting that Src kinase could modulate Smad3 activity.

SIGNOR-279292

P28482

Q15672

1

phosphorylation

up-regulates

0.304

We identified the serine 68 (s68) as a major phosphorylation site of twist1 by mass spectrometry and with specific antibodies. This s68 is phosphorylated by p38, jnk and erk1/2 in vitro, and its phosphorylation levels positively correlate with twist1 protein levels in hek293 and breast cancer cells.

SIGNOR-173401

P38398

P42574

0

cleavage

down-regulates quantity by destabilization

0.473

We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable.

SIGNOR-256326

P00441

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.408

BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2

SIGNOR-254653

P04626

O14672

0

cleavage

up-regulates activity

0.344

The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin.

SIGNOR-259845

O60825

P17252

0

phosphorylation

up-regulates activity

0.439

The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme.

SIGNOR-248844

O94907

Q96MU8

2

binding

up-regulates

0.838

Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/betBeta-catenin. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membrane.

SIGNOR-88838

P30679

Q92633

2

binding

up-regulates activity

0.456

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-257282

O43353

Q13489

0

polyubiquitination

up-regulates activity

0.787

CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.

SIGNOR-272715

P17947

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7.

SIGNOR-277541

O00634

Q92859

2

binding

up-regulates activity

0.72

Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins.

SIGNOR-268171

P07948

P20273

1

phosphorylation

down-regulates activity

0.743

LYN is a BCR-associated SRC kinase involved in the positive regulation of BCR, but it also functions as a negative regulator by phosphorylating the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of CD22.

SIGNOR-268443

P30559

P01178-PRO_0000020495

2

binding

up-regulates activity

0.2

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation.| The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta.

SIGNOR-268545

A8K0Z3

P14373

0

ubiquitination

up-regulates activity

0.2

Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport.

SIGNOR-253514

P62714

P31749

1

dephosphorylation

down-regulates

0.508

These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity

SIGNOR-252636

Q12888

P53778

0

phosphorylation

down-regulates activity

0.2

Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK

SIGNOR-264448

Q13164

P15056

0

phosphorylation

up-regulates quantity

0.292

Our data indicate that oncogenic BRAF increases ERK5 protein level, phosphorylation at several residues and kinase activity.|Overexpression of oncogenic BRAF induced ERK5 phosphorylation at Thr218 and Tyr220, although to a lower level than that induced by MEK5DD.

SIGNOR-278353

Q9HC77

O00444

0

phosphorylation

up-regulates

0.799

Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap

SIGNOR-166007

O43524

Q13043

0

phosphorylation

up-regulates

0.681

Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity.

SIGNOR-178190

P48729

Q9UKV8

1

phosphorylation

down-regulates activity

0.369

Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.

SIGNOR-276510

P0DMV8

O14727

2

binding

down-regulates

0.431

Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, hsp70, is mediated through its direct association with the caspase-recruitment domain (card) of apaf-1 and through apoptosome formation

SIGNOR-80451

Q68D86

Q96CN5

2

binding

up-regulates activity

0.2

CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis.

SIGNOR-275627

P01178-PRO_0000020495

P16519

0

cleavage

up-regulates quantity

0.2

Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.

SIGNOR-270335

Q9Y6E0

Q9Y2H1

1

phosphorylation

up-regulates

0.441

Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity.

SIGNOR-142510

P61586

Q16513

2

binding

up-regulates activity

0.833

PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome.

SIGNOR-275466

P46783

O96006

0

transcriptional regulation

up-regulates quantity by expression

0.2

HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid.

SIGNOR-266083

P23470

P40763

1

dephosphorylation

up-regulates activity

0.259

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254729

P15336

P07954

2

binding

up-regulates activity

0.2

Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes.

SIGNOR-266314

Q9Y4C1

Q16695

1

demethylation

up-regulates activity

0.2

Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.

SIGNOR-276846

Q13617

P31941

1

ubiquitination

down-regulates quantity by destabilization

0.251

Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation|Here, we report that the HPV oncoprotein E7 stabilizes the APOBEC3A (A3A) protein in human keratinocytes by inhibiting ubiquitin-dependent protein degradation in a cullin-dependent manner.

SIGNOR-261325

P56704

Q9H237

0

palmitoylation

up-regulates activity

0.7

And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane.

SIGNOR-256598

O95837

Q92633

2

binding

up-regulates activity

0.435

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-257200

Q96P31

Q06124

2

binding

up-regulates activity

0.383

Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.

SIGNOR-274014

P11912

P06241

0

phosphorylation

up-regulates activity

0.596

Lyn and Fyn phosphorylated the CD79a cytoplasmic portion of the fusion proteins well, with >80% of phosphorylation occurring at Y182. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM).

SIGNOR-251153

O95477

Q96KG7

2

binding

up-regulates activity

0.332

ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level.

SIGNOR-265164