GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 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
P61088	Q969Q1	1	ubiquitination	up-regulates activity	0.539	We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s.	SIGNOR-272737
P78536	P05067	1	cleavage	up-regulates activity	0.539	By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulated alpha-cleavage in cultured cells.	SIGNOR-262829
Q13535	O75717	1	phosphorylation	up-regulates activity	0.539	And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR.	SIGNOR-262664
Q16539	P06400	1	phosphorylation	down-regulates	0.539	P38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates rb on ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not cdks, triggers an interaction between rb and the human homolog of murine double minute 2 (hdm2), leading to degradation of rb, release of e2f1 and cell death.	SIGNOR-168178
P41002	O43303	1	ubiquitination	down-regulates quantity by destabilization	0.539	Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation.	SIGNOR-266364
P53350	Q96CV9	1	phosphorylation	up-regulates	0.539	Here we show that at mitotic entry, plk1 phosphorylates optineurin (optn) at serine 177 and that this dissociates optn from the golgi-localized gtpase rab8, inducing its translocation into the nucleus.	SIGNOR-196367
Q00535	Q16643	1	phosphorylation	up-regulates activity	0.539	Phosphorylation of drebrin at S142 by Cdk5 relieves the intramolecular inhibition of F-actin bundling.	SIGNOR-279452
P41240	P06239	1	phosphorylation	down-regulates	0.538	P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity.	SIGNOR-20371
P41002	Q9UM11	1	ubiquitination	down-regulates quantity by destabilization	0.538	We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1.	SIGNOR-266363
O00560	Q06945	1	binding	up-regulates activity	0.538	Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5induced Sox4 activation.	SIGNOR-223089
P35813	Q15797	1	dephosphorylation	down-regulates	0.538	In this study, we have found that ppm1a, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates smad1 both in vitro and in vivo. considering the highly conserved nature of the sxs motif in all r-smads, we reasoned that ppm1a might also recognize the sxs motif in the bmp-activated smad1.	SIGNOR-149077
P12931	P00519	1	phosphorylation	up-regulates activity	0.538	c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function.	SIGNOR-246311
Q02763	P27986	1	binding	up-regulates activity	0.538	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242634
Q13535	Q9NZC9	1	phosphorylation	down-regulates activity	0.538	ATR phosphorylates SMARCAL1 on S652, thereby limiting its fork regression activities and preventing aberrant fork processing. Thus, phosphorylation of SMARCAL1 is one mechanism by which ATR prevents fork collapse, promotes the completion of DNA replication, and maintains genome integrity.	SIGNOR-273516
Q13315	Q8N0Z6	1	phosphorylation	up-regulates activity	0.538	Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex.	SIGNOR-262645
Q6GQQ9	Q13546	1	deubiquitination	down-regulates activity	0.538	NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne\|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination.	SIGNOR-268411
Q86YC2	Q9Y253	1	binding	up-regulates	0.538	Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates	SIGNOR-204541
O00743	P78527	1	dephosphorylation	up-regulates activity	0.538	In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation.\|PP6 may dephosphorylate sites in DNA-PKcs to reduce binding with heterodimer Ku proteins, because DNA-PK activation completely depends on Ku-mediated complex formation with DNA.	SIGNOR-277164
Q9UKT8	Q9NP62	1	binding	down-regulates quantity	0.538	FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system	SIGNOR-271524
Q15759	Q06413	1	phosphorylation	up-regulates activity	0.538	In this study, we demonstrate that among the different Mitogen-activated protein kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta2.	SIGNOR-280025
Q92934	Q92843	1	binding	down-regulates	0.538	Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2.	SIGNOR-133805
P02511	P22914	1	binding	up-regulates activity	0.538	Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age.	SIGNOR-253623
Q05209	Q05397	1	dephosphorylation	down-regulates activity	0.538	We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.\| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis.	SIGNOR-248661
P51812	P67809	1	phosphorylation	up-regulates	0.538	We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue.	SIGNOR-182165
Q08209	Q12968	1	dephosphorylation	up-regulates	0.538	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-176376
Q15797	Q13950	1	binding	up-regulates	0.538	Smad1 interacts with runx2 on the promoter of target genes and controls osteoblast gene expression and differentiation	SIGNOR-195642
Q86U70	P50458	1	binding	up-regulates activity	0.538	Cofactor CLIM2 promotes the repressive action of LIM homeodomain transcription factor Lhx2 in the expression of porcine pituitary glycoprotein hormone alpha subunit gene.	SIGNOR-223962
P35222	P37231	1	binding	down-regulates activity	0.538	Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain	SIGNOR-256072
Q13153	Q13233	1	phosphorylation	up-regulates activity	0.538	We found that pak1 phosphorylated mekk1 on serine 67 of its amino-terminal regulatory domain. mekk1 activity was increased modestly following pak phosphorylation.	SIGNOR-236006
Q6STE5	P15172	2	binding	up-regulates activity	0.538	We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes.	SIGNOR-238289
P15172	Q6STE5	2	binding	up-regulates	0.538	This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion	SIGNOR-136130
P41240	P07948	1	phosphorylation	down-regulates	0.538	Lyn tyr507 kinase, csk, is recruited by pag, which targets lipid rafts by palmitoylation.Thus, our data suggest that il-6 treatment induces the translocation of cd45 to lipid rafts sequentially, followed by the association of cd45 with lyn and pag;dephosphorylation of lyn tyr507 and pag tyr314;lyn activation;and csk release from lipid rafts	SIGNOR-132912
Q15382	Q13393	1	binding	up-regulates	0.537	Rheb binds and activates pld1 in vitro in a gtp-dependent manner, strongly suggesting that pld1 is a bona fide effector for rheb.	SIGNOR-178892
P49841	P10071	1	phosphorylation	down-regulates quantity by destabilization	0.537	We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog.	SIGNOR-219231
Q9C0D0	P62136	1	binding	up-regulates activity	0.537	Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process.	SIGNOR-260062
P12931	Q9ULV8	1	phosphorylation	up-regulates	0.537	Phosphorylation of a critical tyrosine (tyr-341) in the linker region of cbl-c by src or a phosphomimetic mutation of this tyrosine (y341e) is sufficient to increase the e3 activity of cbl-c.	SIGNOR-165862
Q16539	P84022	1	phosphorylation	up-regulates activity	0.537	Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways.	SIGNOR-250112
P45985	P05412	1	phosphorylation	up-regulates activity	0.537	SEK1 phosphorylates and activates both p38 and c-Jun NH(2)-terminal kinase (JNK), whereas MKK3 and MKK6 selectively phosphorylate and activate p38.	SIGNOR-279063
Q16690	Q16539	1	dephosphorylation	down-regulates	0.537	The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues.	SIGNOR-166574
P48740	P06681	1	cleavage	up-regulates activity	0.537	The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase	SIGNOR-263420
Q9H2X6	Q00987	1	phosphorylation	down-regulates activity	0.537	HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations.\|This p53-independent effect is likely mediated by HIPK2 catalytic activity and we found that HIPK2 phosphorylates MDM2 in vitro.	SIGNOR-279465
Q96GD4	Q15555	1	phosphorylation	up-regulates activity	0.537	Together, these data indicate that Aurora B and CDK1 phosphorylate EB2 at distinct sites and maintain the hyperphosphorylation of EB2 and its binding affinity to MTs while SAC activity is sustained.	SIGNOR-279591
P51965	Q9H6Y7	1	binding	up-regulates activity	0.537	Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop.	SIGNOR-271552
Q9NRD5	P78348	1	relocalization	up-regulates activity	0.537	we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction	SIGNOR-223417
P50750	P10275	1	phosphorylation	up-regulates activity	0.537	AR S81 phosphorylation by CDK9 is tightly linked to chromatin binding and transcriptional activation.	SIGNOR-279456
Q13049	Q96EV8	1	ubiquitination	down-regulates quantity	0.537	TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation.	SIGNOR-265658
P78527	Q9NUW8	1	phosphorylation	up-regulates	0.537	Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk)	SIGNOR-188776
Q86X55	Q92922	1	methylation	up-regulates activity	0.537	CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.	SIGNOR-251708
Q9Y478	O75385	1	phosphorylation	up-regulates	0.537	Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition	SIGNOR-173044
P41240	P09769	1	phosphorylation	down-regulates activity	0.537	CSK catalyzed phosphorylation affects Tyr-511 of c-Fgr, homologous to Tyr-527 of c-Src and it prevents the autophosphorylation normally occurring at c-Fgr Tyr-400, homologous to c-Src Tyr-416. \| Once phosphorylated at Tyr-511 and down-regulated by CSK, c-Fgr is no more susceptible to polylysine stimulation.	SIGNOR-250779
Q8IXL6	Q8NBP7	1	phosphorylation	up-regulates activity	0.537	Herein, we report that Fam20C and Fam20A significantly eliminate the Furin-cleavage of PCSK9 (XREF_FIG, lanes 5, 6), thereby enhancing the pPCSK9 activity\|Herein, we show that Fam20C phosphorylates PCSK9 at Serines 47, 666, 668 and 688.	SIGNOR-278935
P06493	Q96JH7	1	phosphorylation	down-regulates activity	0.537	We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97.	SIGNOR-265038
P06493	Q07817	1	phosphorylation	down-regulates activity	0.537	Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis\|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis.	SIGNOR-267986
P52333	P23458	2	phosphorylation	up-regulates	0.536	Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.	SIGNOR-152917
O14757	O15350	1	phosphorylation	up-regulates	0.536	We found that endogenous p73alpha is serine phosphorylated by endogenous chk1 upon dna damage, which is a mechanism required for the apoptotic-inducing function of p73alpha.	SIGNOR-118913
Q96G30	Q01718	1	binding	up-regulates activity	0.536	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor.	SIGNOR-252361
P61086	Q8WVD3	1	binding	up-regulates activity	0.536	NARF exhibits E3 ubiquitin-ligase activity in cooperation with the ubiquitin conjugating enzyme, E2-25K. These data show that the auto-ubiquitylating activity of NARF is coordinated with E2-25K, and that the RING finger domain of NARF is indispensable for this reaction.	SIGNOR-271594
P17252	Q16236	1	phosphorylation	up-regulates	0.536	Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress	SIGNOR-91826
P12931	P60484	2	phosphorylation	down-regulates	0.536	Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols.	SIGNOR-103721
P42574	Q92934	1	cleavage	up-regulates activity	0.536	Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant.	SIGNOR-126727
Q9NYY3	P06748	1	phosphorylation	up-regulates	0.536	Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.	SIGNOR-125720
P06493	P02545	1	phosphorylation	up-regulates	0.536	Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm	SIGNOR-181314
P23458	P52333	2	phosphorylation	up-regulates	0.536	Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.	SIGNOR-152914
O95972	Q13873	1	binding	up-regulates	0.536	Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle.	SIGNOR-144098
P04629	P00519	1	binding	up-regulates	0.536	Autophosphorylated trka binds directly to plc?, Abl, and shc.	SIGNOR-75402
Q8TEW6	P06241	1	binding	up-regulates	0.536	Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells.	SIGNOR-100999
P60484	P12931	2	dephosphorylation	down-regulates activity	0.536	Antisense- or shRNA mediated downregulation of PTEN induced SRC Tyr416 phosphorylation, SRC activation, and ultimately elevated TZMB resistance, whereas induction of PTEN phosphatase activity directly dephosphorylated SRC Tyr416 residue and so abolished SRC activity .\|These observations indicate that the loss of PTEN phosphatase activity induces SRC activation and so implicates SRC in shaping de novo TZMB resistance in PTEN deficient cells .	SIGNOR-277009
Q9HB63	Q92859	1	binding	up-regulates activity	0.536	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-268170
Q969U6	Q6UVJ0	1	ubiquitination	down-regulates quantity by destabilization	0.536	We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. \|expression of the wild-type form of FBXW5 accelerated the degradation of HsSAS-6 to a half-life of less than two hours	SIGNOR-275478
Q13618	Q8WZ19	1	binding	up-regulates activity	0.536	BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264233
P63151	P36897	1	binding	up-regulates	0.536	In this report, we show that another WD-40 repeat protein, the B_ subunit of protein phosphatase 2A, associates with the cytoplasmic domain of type I TGF-_ receptors. [...] We therefore conclude that B_ specifically and directly associates with the type I receptor cytoplasmic domain in vitro.	SIGNOR-227517
Q7L0J3	P21579	1	binding	up-regulates quantity	0.535	Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs.	SIGNOR-264116
Q12933	Q12851	1	binding	up-regulates	0.535	Both full-lenght gck and the gck-ctd can form complexes in vivo with traf2.	SIGNOR-59685
P12931	P51813	1	phosphorylation	up-regulates	0.535	Coexpression of v-src and etk led to a transphosphorylation on tyrosine 566 of etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of etk.	SIGNOR-75330
P43146	P12931	1	binding	up-regulates activity	0.535	Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.	SIGNOR-268372
P17252	P17302	1	phosphorylation	down-regulates	0.535	Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes.	SIGNOR-120907
P40818	Q92783	1	binding	up-regulates quantity	0.535	Stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells.	SIGNOR-266904
P06241	P10636	1	phosphorylation	down-regulates	0.535	In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn.	SIGNOR-123099
P50750	P04637	1	phosphorylation	up-regulates	0.535	We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation	SIGNOR-201935
Q15382	Q14318	1	gtpase-activating protein	down-regulates activity	0.535	Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1.	SIGNOR-233568
Q05397	P08069	1	phosphorylation	up-regulates quantity	0.535	Taken together, our data suggest that FAK mediates the phosphorylation of IGF-1R and stabilizes the receptor.In this study we demonstrate that FAK, mainly known for its role in integrin signaling pathways, associates with and phosphorylates IGF-1R independently of IGF-1R 's intrinsic tyrosine kinase activity.\|The impact of FAK on the expression levels of IGF-1R could be multilateral	SIGNOR-279565
Q93034	O95376	1	binding	up-regulates activity	0.535	Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin.	SIGNOR-268843
P12931	O15357	1	phosphorylation	up-regulates	0.535	Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo.	SIGNOR-92935
Q92793	P41240	1	binding	up-regulates	0.535	Here we present cbp--a transmembrane phosphoprotein that is ubiquitously expressed and binds specifically to the sh2 domain of csk. Cbp is involved in the membrane localization of csk and in the csk-mediated inhibition of c-src.	SIGNOR-77139
P06493	O00311	1	phosphorylation	up-regulates	0.535	Hucdc7 and ask proteins can also be phosphorylated by cdks in vitro. Among four possible cdk phosphorylation sites of hucdc7, replacement of thr-376, corresponding to the activating threonine of cdk, with alanine (t376a mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue.	SIGNOR-78311
Q15831	Q96L34	1	phosphorylation	up-regulates	0.535	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-122682
P27361	P55211	1	phosphorylation	down-regulates activity	0.535	Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk	SIGNOR-101548
P06241	P12318	1	phosphorylation	up-regulates activity	0.534	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point\|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-249336
P27361	Q15303	1	phosphorylation	down-regulates activity	0.534	We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala) significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation.	SIGNOR-277448
Q12967	Q92963	1	binding	up-regulates activity	0.534	Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.	SIGNOR-220859
Q13153	P03372	1	phosphorylation	up-regulates	0.534	Pak1 directly phosphorylated the activation function-2 domain of the er at the n-terminal residue ser305, and its mutation to ala (s305a) abolished the pak1-mediated phosphorylation and transactivation functions of the er	SIGNOR-94206
Q969V5	O00429	1	sumoylation	up-regulates activity	0.534	Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.	SIGNOR-274128
P05109	O00206	1	binding	down-regulates activity	0.534	Interestingly, in the present study, we report that extracellular S100A9 induces terminal differentiation of myeloid leukemia cells in human and murine AMLs after TLR4 activation, which is highly expressed by primary myelomonocytic and monocytic leukemia cells. In contrast, anti-S100A8 induced the differentiation of AML cells, suggesting that the differentiation-promoting effect of S100A9 is inhibited by S100A8. ) S100A8 could bind to TLR4 and activate different signaling pathways, leading to the inhibition of cellular differentiation induced by S100A9.	SIGNOR-261921
O00444	Q9UPN4	1	phosphorylation	up-regulates activity	0.534	We conclude that PLK4 phosphorylates CEP131 at Ser 78 to maintains centriolar satellite integrity.	SIGNOR-280075
O60674	Q15910	1	phosphorylation	down-regulates	0.534	Oncogenic y641 mutations in ezh2 prevent jak2/beta-trcp-mediated degradationbeta-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs beta-trcp-mediated ezh2 degradation.	SIGNOR-202711
P28482	P19793	1	phosphorylation	down-regulates activity	0.534	In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma\|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE	SIGNOR-262958
P48730	O14641	1	phosphorylation	up-regulates	0.534	Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle	SIGNOR-197547
P55290	P35222	1	binding	up-regulates activity	0.534	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265853
P53350	Q14980	1	phosphorylation	down-regulates activity	0.534	Phosphorylation of NuMA by Plk1 at 1833/34 residue can impact its cortical localization.\|These data strongly suggest that Plk1 negatively regulate cortical NuMA localization and that this impact of Plk1 on NuMA is presumably independent of LGN, at least in the anaphase cells.	SIGNOR-279345
P12931	Q7L0Q8	1	phosphorylation	down-regulates activity	0.534	Regulation of the Rho family small GTPase Wrch-1/RhoU by C-terminal tyrosine phosphorylation requires Src. Phosphorylation at Y254 negatively regulates Wrch-1-mediated biological functions.Serum-stimulated tyrosine phosphorylation and relocalization of Wrch-1 decreases its activation of downstream effectors in a Y254-dependent manner.	SIGNOR-259814

P61088

Q969Q1

1

ubiquitination

up-regulates activity

0.539

We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s.

SIGNOR-272737

P78536

P05067

1

cleavage

up-regulates activity

0.539

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

SIGNOR-262829

Q13535

O75717

1

phosphorylation

up-regulates activity

0.539

And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR.

SIGNOR-262664

Q16539

P06400

1

phosphorylation

down-regulates

0.539

P38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates rb on ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not cdks, triggers an interaction between rb and the human homolog of murine double minute 2 (hdm2), leading to degradation of rb, release of e2f1 and cell death.

SIGNOR-168178

P41002

O43303

1

ubiquitination

down-regulates quantity by destabilization

0.539

Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation.

SIGNOR-266364

P53350

Q96CV9

1

phosphorylation

up-regulates

0.539

Here we show that at mitotic entry, plk1 phosphorylates optineurin (optn) at serine 177 and that this dissociates optn from the golgi-localized gtpase rab8, inducing its translocation into the nucleus.

SIGNOR-196367

Q00535

Q16643

1

phosphorylation

up-regulates activity

0.539

Phosphorylation of drebrin at S142 by Cdk5 relieves the intramolecular inhibition of F-actin bundling.

SIGNOR-279452

P41240

P06239

1

phosphorylation

down-regulates

0.538

P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity.

SIGNOR-20371

P41002

Q9UM11

1

ubiquitination

down-regulates quantity by destabilization

0.538

We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1.

SIGNOR-266363

O00560

Q06945

1

binding

up-regulates activity

0.538

Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5induced Sox4 activation.

SIGNOR-223089

P35813

Q15797

1

dephosphorylation

down-regulates

0.538

In this study, we have found that ppm1a, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates smad1 both in vitro and in vivo. considering the highly conserved nature of the sxs motif in all r-smads, we reasoned that ppm1a might also recognize the sxs motif in the bmp-activated smad1.

SIGNOR-149077

P12931

P00519

1

phosphorylation

up-regulates activity

0.538

c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function.

SIGNOR-246311

Q02763

P27986

1

binding

up-regulates activity

0.538

Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival

SIGNOR-242634

Q13535

Q9NZC9

1

phosphorylation

down-regulates activity

0.538

ATR phosphorylates SMARCAL1 on S652, thereby limiting its fork regression activities and preventing aberrant fork processing. Thus, phosphorylation of SMARCAL1 is one mechanism by which ATR prevents fork collapse, promotes the completion of DNA replication, and maintains genome integrity.

SIGNOR-273516

Q13315

Q8N0Z6

1

phosphorylation

up-regulates activity

0.538

Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex.

SIGNOR-262645

Q6GQQ9

Q13546

1

deubiquitination

down-regulates activity

0.538

NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination.

SIGNOR-268411

Q86YC2

Q9Y253

1

binding

up-regulates

0.538

Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates

SIGNOR-204541

O00743

P78527

1

dephosphorylation

up-regulates activity

0.538

In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation.|PP6 may dephosphorylate sites in DNA-PKcs to reduce binding with heterodimer Ku proteins, because DNA-PK activation completely depends on Ku-mediated complex formation with DNA.

SIGNOR-277164

Q9UKT8

Q9NP62

1

binding

down-regulates quantity

0.538

FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system

SIGNOR-271524

Q15759

Q06413

1

phosphorylation

up-regulates activity

0.538

In this study, we demonstrate that among the different Mitogen-activated protein kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta2.

SIGNOR-280025

Q92934

Q92843

1

binding

down-regulates

0.538

Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2.

SIGNOR-133805

P02511

P22914

1

binding

up-regulates activity

0.538

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

SIGNOR-253623

Q05209

Q05397

1

dephosphorylation

down-regulates activity

0.538

We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis.

SIGNOR-248661

P51812

P67809

1

phosphorylation

up-regulates

0.538

We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue.

SIGNOR-182165

Q08209

Q12968

1

dephosphorylation

up-regulates

0.538

Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.

SIGNOR-176376

Q15797

Q13950

1

binding

up-regulates

0.538

Smad1 interacts with runx2 on the promoter of target genes and controls osteoblast gene expression and differentiation

SIGNOR-195642

Q86U70

P50458

1

binding

up-regulates activity

0.538

Cofactor CLIM2 promotes the repressive action of LIM homeodomain transcription factor Lhx2 in the expression of porcine pituitary glycoprotein hormone alpha subunit gene.

SIGNOR-223962

P35222

P37231

1

binding

down-regulates activity

0.538

Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain

SIGNOR-256072

Q13153

Q13233

1

phosphorylation

up-regulates activity

0.538

We found that pak1 phosphorylated mekk1 on serine 67 of its amino-terminal regulatory domain. mekk1 activity was increased modestly following pak phosphorylation.

SIGNOR-236006

Q6STE5

P15172

2

binding

up-regulates activity

0.538

We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes.

SIGNOR-238289

P15172

Q6STE5

2

binding

up-regulates

0.538

This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion

SIGNOR-136130

P41240

P07948

1

phosphorylation

down-regulates

0.538

Lyn tyr507 kinase, csk, is recruited by pag, which targets lipid rafts by palmitoylation.Thus, our data suggest that il-6 treatment induces the translocation of cd45 to lipid rafts sequentially, followed by the association of cd45 with lyn and pag;dephosphorylation of lyn tyr507 and pag tyr314;lyn activation;and csk release from lipid rafts

SIGNOR-132912

Q15382

Q13393

1

binding

up-regulates

0.537

Rheb binds and activates pld1 in vitro in a gtp-dependent manner, strongly suggesting that pld1 is a bona fide effector for rheb.

SIGNOR-178892

P49841

P10071

1

phosphorylation

down-regulates quantity by destabilization

0.537

We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog.

SIGNOR-219231

Q9C0D0

P62136

1

binding

up-regulates activity

0.537

Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process.

SIGNOR-260062

P12931

Q9ULV8

1

phosphorylation

up-regulates

0.537

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

SIGNOR-165862

Q16539

P84022

1

phosphorylation

up-regulates activity

0.537

Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways.

SIGNOR-250112

P45985

P05412

1

phosphorylation

up-regulates activity

0.537

SEK1 phosphorylates and activates both p38 and c-Jun NH(2)-terminal kinase (JNK), whereas MKK3 and MKK6 selectively phosphorylate and activate p38.

SIGNOR-279063

Q16690

Q16539

1

dephosphorylation

down-regulates

0.537

The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues.

SIGNOR-166574

P48740

P06681

1

cleavage

up-regulates activity

0.537

The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase

SIGNOR-263420

Q9H2X6

Q00987

1

phosphorylation

down-regulates activity

0.537

HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations.|This p53-independent effect is likely mediated by HIPK2 catalytic activity and we found that HIPK2 phosphorylates MDM2 in vitro.

SIGNOR-279465

Q96GD4

Q15555

1

phosphorylation

up-regulates activity

0.537

Together, these data indicate that Aurora B and CDK1 phosphorylate EB2 at distinct sites and maintain the hyperphosphorylation of EB2 and its binding affinity to MTs while SAC activity is sustained.

SIGNOR-279591

P51965

Q9H6Y7

1

binding

up-regulates activity

0.537

Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop.

SIGNOR-271552

Q9NRD5

P78348

1

relocalization

up-regulates activity

0.537

we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction

SIGNOR-223417

P50750

P10275

1

phosphorylation

up-regulates activity

0.537

AR S81 phosphorylation by CDK9 is tightly linked to chromatin binding and transcriptional activation.

SIGNOR-279456

Q13049

Q96EV8

1

ubiquitination

down-regulates quantity

0.537

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

SIGNOR-265658

P78527

Q9NUW8

1

phosphorylation

up-regulates

0.537

Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk)

SIGNOR-188776

Q86X55

Q92922

1

methylation

up-regulates activity

0.537

CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.

SIGNOR-251708

Q9Y478

O75385

1

phosphorylation

up-regulates

0.537

Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition

SIGNOR-173044

P41240

P09769

1

phosphorylation

down-regulates activity

0.537

CSK catalyzed phosphorylation affects Tyr-511 of c-Fgr, homologous to Tyr-527 of c-Src and it prevents the autophosphorylation normally occurring at c-Fgr Tyr-400, homologous to c-Src Tyr-416. | Once phosphorylated at Tyr-511 and down-regulated by CSK, c-Fgr is no more susceptible to polylysine stimulation.

SIGNOR-250779

Q8IXL6

Q8NBP7

1

phosphorylation

up-regulates activity

0.537

Herein, we report that Fam20C and Fam20A significantly eliminate the Furin-cleavage of PCSK9 (XREF_FIG, lanes 5, 6), thereby enhancing the pPCSK9 activity|Herein, we show that Fam20C phosphorylates PCSK9 at Serines 47, 666, 668 and 688.

SIGNOR-278935

P06493

Q96JH7

1

phosphorylation

down-regulates activity

0.537

We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97.

SIGNOR-265038

P06493

Q07817

1

phosphorylation

down-regulates activity

0.537

Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis.

SIGNOR-267986

P52333

P23458

2

phosphorylation

up-regulates

0.536

Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.

SIGNOR-152917

O14757

O15350

1

phosphorylation

up-regulates

0.536

We found that endogenous p73alpha is serine phosphorylated by endogenous chk1 upon dna damage, which is a mechanism required for the apoptotic-inducing function of p73alpha.

SIGNOR-118913

Q96G30

Q01718

1

binding

up-regulates activity

0.536

We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor.

SIGNOR-252361

P61086

Q8WVD3

1

binding

up-regulates activity

0.536

NARF exhibits E3 ubiquitin-ligase activity in cooperation with the ubiquitin conjugating enzyme, E2-25K. These data show that the auto-ubiquitylating activity of NARF is coordinated with E2-25K, and that the RING finger domain of NARF is indispensable for this reaction.

SIGNOR-271594

P17252

Q16236

1

phosphorylation

up-regulates

0.536

Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress

SIGNOR-91826

P12931

P60484

2

phosphorylation

down-regulates

0.536

Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols.

SIGNOR-103721

P42574

Q92934

1

cleavage

up-regulates activity

0.536

Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant.

SIGNOR-126727

Q9NYY3

P06748

1

phosphorylation

up-regulates

0.536

Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.

SIGNOR-125720

P06493

P02545

1

phosphorylation

up-regulates

0.536

Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm

SIGNOR-181314

P23458

P52333

2

phosphorylation

up-regulates

0.536

Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.

SIGNOR-152914

O95972

Q13873

1

binding

up-regulates

0.536

Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle.

SIGNOR-144098

P04629

P00519

1

binding

up-regulates

0.536

Autophosphorylated trka binds directly to plc?, Abl, and shc.

SIGNOR-75402

Q8TEW6

P06241

1

binding

up-regulates

0.536

Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells.

SIGNOR-100999

P60484

P12931

2

dephosphorylation

down-regulates activity

0.536

Antisense- or shRNA mediated downregulation of PTEN induced SRC Tyr416 phosphorylation, SRC activation, and ultimately elevated TZMB resistance, whereas induction of PTEN phosphatase activity directly dephosphorylated SRC Tyr416 residue and so abolished SRC activity .|These observations indicate that the loss of PTEN phosphatase activity induces SRC activation and so implicates SRC in shaping de novo TZMB resistance in PTEN deficient cells .

SIGNOR-277009

Q9HB63

Q92859

1

binding

up-regulates activity

0.536

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-268170

Q969U6

Q6UVJ0

1

ubiquitination

down-regulates quantity by destabilization

0.536

We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. |expression of the wild-type form of FBXW5 accelerated the degradation of HsSAS-6 to a half-life of less than two hours

SIGNOR-275478

Q13618

Q8WZ19

1

binding

up-regulates activity

0.536

BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.

SIGNOR-264233

P63151

P36897

1

binding

up-regulates

0.536

In this report, we show that another WD-40 repeat protein, the B_ subunit of protein phosphatase 2A, associates with the cytoplasmic domain of type I TGF-_ receptors. [...] We therefore conclude that B_ specifically and directly associates with the type I receptor cytoplasmic domain in vitro.

SIGNOR-227517

Q7L0J3

P21579

1

binding

up-regulates quantity

0.535

Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs.

SIGNOR-264116

Q12933

Q12851

1

binding

up-regulates

0.535

Both full-lenght gck and the gck-ctd can form complexes in vivo with traf2.

SIGNOR-59685

P12931

P51813

1

phosphorylation

up-regulates

0.535

Coexpression of v-src and etk led to a transphosphorylation on tyrosine 566 of etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of etk.

SIGNOR-75330

P43146

P12931

1

binding

up-regulates activity

0.535

Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.

SIGNOR-268372

P17252

P17302

1

phosphorylation

down-regulates

0.535

Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes.

SIGNOR-120907

P40818

Q92783

1

binding

up-regulates quantity

0.535

Stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells.

SIGNOR-266904

P06241

P10636

1

phosphorylation

down-regulates

0.535

In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn.

SIGNOR-123099

P50750

P04637

1

phosphorylation

up-regulates

0.535

We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation

SIGNOR-201935

Q15382

Q14318

1

gtpase-activating protein

down-regulates activity

0.535

Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1.

SIGNOR-233568

Q05397

P08069

1

phosphorylation

up-regulates quantity

0.535

Taken together, our data suggest that FAK mediates the phosphorylation of IGF-1R and stabilizes the receptor.In this study we demonstrate that FAK, mainly known for its role in integrin signaling pathways, associates with and phosphorylates IGF-1R independently of IGF-1R 's intrinsic tyrosine kinase activity.|The impact of FAK on the expression levels of IGF-1R could be multilateral

SIGNOR-279565

Q93034

O95376

1

binding

up-regulates activity

0.535

Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin.

SIGNOR-268843

P12931

O15357

1

phosphorylation

up-regulates

0.535

Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo.

SIGNOR-92935

Q92793

P41240

1

binding

up-regulates

0.535

Here we present cbp--a transmembrane phosphoprotein that is ubiquitously expressed and binds specifically to the sh2 domain of csk. Cbp is involved in the membrane localization of csk and in the csk-mediated inhibition of c-src.

SIGNOR-77139

P06493

O00311

1

phosphorylation

up-regulates

0.535

Hucdc7 and ask proteins can also be phosphorylated by cdks in vitro. Among four possible cdk phosphorylation sites of hucdc7, replacement of thr-376, corresponding to the activating threonine of cdk, with alanine (t376a mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue.

SIGNOR-78311

Q15831

Q96L34

1

phosphorylation

up-regulates

0.535

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-122682

P27361

P55211

1

phosphorylation

down-regulates activity

0.535

Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk

SIGNOR-101548

P06241

P12318

1

phosphorylation

up-regulates activity

0.534

To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.

SIGNOR-249336

P27361

Q15303

1

phosphorylation

down-regulates activity

0.534

We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala) significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation.

SIGNOR-277448

Q12967

Q92963

1

binding

up-regulates activity

0.534

Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.

SIGNOR-220859

Q13153

P03372

1

phosphorylation

up-regulates

0.534

Pak1 directly phosphorylated the activation function-2 domain of the er at the n-terminal residue ser305, and its mutation to ala (s305a) abolished the pak1-mediated phosphorylation and transactivation functions of the er

SIGNOR-94206

Q969V5

O00429

1

sumoylation

up-regulates activity

0.534

Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.

SIGNOR-274128

P05109

O00206

1

binding

down-regulates activity

0.534

Interestingly, in the present study, we report that extracellular S100A9 induces terminal differentiation of myeloid leukemia cells in human and murine AMLs after TLR4 activation, which is highly expressed by primary myelomonocytic and monocytic leukemia cells. In contrast, anti-S100A8 induced the differentiation of AML cells, suggesting that the differentiation-promoting effect of S100A9 is inhibited by S100A8. ) S100A8 could bind to TLR4 and activate different signaling pathways, leading to the inhibition of cellular differentiation induced by S100A9.

SIGNOR-261921

O00444

Q9UPN4

1

phosphorylation

up-regulates activity

0.534

We conclude that PLK4 phosphorylates CEP131 at Ser 78 to maintains centriolar satellite integrity.

SIGNOR-280075

O60674

Q15910

1

phosphorylation

down-regulates

0.534

Oncogenic y641 mutations in ezh2 prevent jak2/beta-trcp-mediated degradationbeta-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs beta-trcp-mediated ezh2 degradation.

SIGNOR-202711

P28482

P19793

1

phosphorylation

down-regulates activity

0.534

In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE

SIGNOR-262958

P48730

O14641

1

phosphorylation

up-regulates

0.534

Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle

SIGNOR-197547

P55290

P35222

1

binding

up-regulates activity

0.534

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

SIGNOR-265853

P53350

Q14980

1

phosphorylation

down-regulates activity

0.534

Phosphorylation of NuMA by Plk1 at 1833/34 residue can impact its cortical localization.|These data strongly suggest that Plk1 negatively regulate cortical NuMA localization and that this impact of Plk1 on NuMA is presumably independent of LGN, at least in the anaphase cells.

SIGNOR-279345

P12931

Q7L0Q8

1

phosphorylation

down-regulates activity

0.534

Regulation of the Rho family small GTPase Wrch-1/RhoU by C-terminal tyrosine phosphorylation requires Src. Phosphorylation at Y254 negatively regulates Wrch-1-mediated biological functions.Serum-stimulated tyrosine phosphorylation and relocalization of Wrch-1 decreases its activation of downstream effectors in a Y254-dependent manner.

SIGNOR-259814