GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P35226	P31749	0	phosphorylation	up-regulates activity	0.437	The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate	SIGNOR-252559
Q13114	Q99558	1	ubiquitination	down-regulates quantity by destabilization	0.668	TRAF2 and TRAF3 mediate NIK ubiquitination by forming a complex with the E3 ligase cIAP (cIAP1 or cIAP2).\|We demonstrated further that TRAF3 mediates the degradation of NIK and thereby serves as a pivotal negative regulator of noncanonical NF-kappaB signaling.	SIGNOR-278673
O75170	P06493	0	phosphorylation	down-regulates activity	0.261	We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit.	SIGNOR-273587
Q13224	Q96AX9	0	ubiquitination	down-regulates quantity	0.366	Mib2 is localized to the PSD of dendrites in hippocampal neurons and directly ubiquitinates GluN2B in a manner dependent on the non receptor tyrosine kinase Fyn.\|These findings suggest that Mib2 mediates proteasome dependent degradation of GluN2B subunits, which may provide a reciprocal mechanism to SCF Fbx2 regulation of GluN2A.	SIGNOR-278762
O75962	P06241	0	phosphorylation	up-regulates activity	0.2	Here, we demonstrate that Trio is phosphorylated by Src family kinases in the embryonic rat cortex in response to netrin-1. In vitro, Trio was predominantly phosphorylated at Tyr(2622) by the Src kinase Fyn.	SIGNOR-273855
P02671	P45452	0	cleavage	down-regulates quantity by destabilization	0.2	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII\| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.\|MMP-13 27YVATRDN g-chain\| 20ADSGEGD a-chain\| 124RNSVDXLNXN b-chain\| 442LRTGKEKV a-chain	SIGNOR-263613
P49841	P10070	1	phosphorylation	down-regulates quantity by destabilization	0.562	The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3.	SIGNOR-249590
P49716	P68400	0	phosphorylation	up-regulates activity	0.2	Here, we have identified the CCAAT/enhancer binding protein δ (C/EBPδ) as a new substrate for CK2. Using point mutants of C/EBPδ the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPδ. For proper functioning as a transcription factor C/EBPδ has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPδ nor its interaction with C/EBPβ, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPδ.	SIGNOR-276886
Q13485	Q93008	0	deubiquitination	up-regulates	0.648	Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4.	SIGNOR-236855
Q13976	Q9UI08	1	phosphorylation	down-regulates activity	0.2	Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts	SIGNOR-268290
Q00535	P14416	1	phosphorylation	down-regulates activity	0.383	These results indicate that Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling.	SIGNOR-259401
P46527	Q12778	0	transcriptional regulation	up-regulates quantity by expression	0.627	To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter.	SIGNOR-277739
P05114	P17612	0	phosphorylation	down-regulates activity	0.307	PKA preferentially phosphorylates serine 6 in human HMGN1. specific phosphorylation of the NBD of HMGN proteins serves to prevent the interaction of these proteins with their chromatin targets during mitosis.	SIGNOR-249993
P01308	P14735	0	cleavage	down-regulates quantity by destabilization	0.719	IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds	SIGNOR-260986
Q5S007	P15311	1	phosphorylation	up-regulates activity	0.411	LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558.	SIGNOR-279202
Q15418	P30304	1	phosphorylation	down-regulates	0.366	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-202117
Q13043	Q06830	1	phosphorylation	down-regulates activity	0.2	Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183.	SIGNOR-276486
Q13950	Q9HCE7	0	ubiquitination	down-regulates activity	0.504	Recently we have found that smurf1 mediates the protein degradation of the osteoblast-specific transcription factor runx2/cbfa1.	SIGNOR-95233
P60484	P29375	0	transcriptional regulation	down-regulates quantity by destabilization	0.289	The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL.	SIGNOR-260079
O14757	P62745	1	phosphorylation	up-regulates activity	0.328	We identified that Thr173 and Thr175 of RhoB was phosphorylated by Chk1 using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) (Supplementary Fig.\u00a06f).	SIGNOR-279727
Q93009	Q8TB45	1	deubiquitination	up-regulates quantity by stabilization	0.2	Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay.	SIGNOR-277588
O60825	P54646	0	phosphorylation	up-regulates activity	0.443	AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. activation of PFK-2 was due to the phosphorylation of Ser466	SIGNOR-250323
Q9NRM7	P11908	1	phosphorylation	down-regulates quantity by destabilization	0.2	Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness.	SIGNOR-276507
Q96BR9	Q8TBB1	0	polyubiquitination	down-regulates quantity by destabilization	0.2	LNX (ligand of Numb protein-X) is a RING finger and four PDZ domain-containing E3 ubiquitin ligase. Lnx-l induced K48-linked polyubiquitylation of Boz, leading to its proteasomal degradation in human 293T cells and in zebrafish embryos.	SIGNOR-272777
Q8IWU9	P17612	0	phosphorylation	up-regulates	0.254	We also demonstrate that phosphorylation of serine 19, a protein kinase a consensus site located in this n-terminal domain, results in increased tph2 stability and consequent increases in enzyme output in cell culture systems	SIGNOR-178018
P49585	P08047	0	transcriptional regulation	up-regulates quantity by expression	0.2	Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter	SIGNOR-266231
P84022	P35813	0	dephosphorylation	down-regulates activity	0.622	Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.	SIGNOR-232110
P08575	P23458	1	dephosphorylation	up-regulates	0.454	These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3,	SIGNOR-87154
O14965	P07195	1	phosphorylation	up-regulates activity	0.2	Aurora-A-mediated phosphorylation of LDHB serine 162 significantly increases its activity in reducing pyruvate to lactate, which efficiently promotes NAD+ regeneration, glycolytic flux, lactate production and bio-synthesis with glycolytic intermediates.	SIGNOR-277493
P06241	P78352	1	phosphorylation	up-regulates	0.562	Psd-95 is phosphorylated either by purified src/fyn kinases in vitro or by co-expression of constitutively active src/fyn in cos7 cells. psd-95 tyr(523) phosphorylation contributes to the post-ischaemic over-activation of nmda receptors.	SIGNOR-180449
Q9BRQ8	P04637	0	transcriptional regulation	up-regulates quantity by expression	0.503	The p53 tumor suppressor protein induces cell cycle arrest or apoptosis in response to cellular stresses. We have identified PRG3 (p53-responsive gene 3), which is induced specifically under p53-dependent apoptotic conditions in human colon cancer cells, and encodes a novel polypeptide of 373 amino acids with a predicted molecular mass of 40.5 kDa. these results support the hypothesis that the expression of the PRG3 gene in cells undergoing p53‐dependent apoptosis involves direct activation of its promoter by p53.	SIGNOR-261808
P17010	P09467	1	transcriptional regulation	down-regulates quantity by repression	0.2	For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma	SIGNOR-267595
P30281	P15172	0	transcriptional regulation	up-regulates quantity by expression	0.374	Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator.	SIGNOR-238526
Q15654	Q12923	0	dephosphorylation	down-regulates activity	0.434	PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration.\|Here we further demonstrate that a switch from c-Src-mediated phosphorylation to PTPL1/Fas-associated phosphatase-1-dependent dephosphorylation serves as an inhibitory feedback control mechanism of TRIP6 function in LPA-induced cell migration. PTPL1 dephosphorylates phosphotyrosine 55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells.	SIGNOR-248713
P28482	P12036	1	phosphorylation	up-regulates activity	0.368	The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. \|Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation.	SIGNOR-249424
Q9UPX8	Q9P1A6	0	relocalization	up-regulates activity	0.849	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-264590
Q04864	Q9UHD2	0	phosphorylation	up-regulates	0.579	The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel.	SIGNOR-148623
O15111	P20749	1	phosphorylation	up-regulates activity	0.429	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.	SIGNOR-277362
P46939	Q7KZI7	0	phosphorylation	up-regulates	0.424	Par-1b, interacts with the utrophin-dg complex, and positively regulates the interaction between utrophin and dg. Ser1258 within r9 is specifically phosphorylated by par-1b.	SIGNOR-161915
P68400	P06744	1	phosphorylation	down-regulates activity	0.333	It is known that human PGI/AMF is phosphorylated at Ser(185) by protein kinase CK2 (CK2) \| These results demonstrate that phosphorylation affects the allosteric kinetic properties of the enzyme, resulting in a less active form of PGI, whereas non-phosphorylated protein species retain cytokine activity.	SIGNOR-250869
P09651	Q9UBS0	0	phosphorylation	up-regulates activity	0.416	Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export.	SIGNOR-279569
Q9NX76	Q9NZQ7	1	stabilization	up-regulates quantity by stabilization	0.47	Furthermore, the observations that (i) CMTM6 affects PD-L1 protein stability at late time points after biosynthesis; (ii) CMTM6, CMTM4 and PD-L1 interact, as shown by co-immunoprecipitation; and that (iii) CMTM6 is largely located at the cell surface, collectively suggest a model in which CMTM6 interacts with PD-L1 at the tumour cell surface and thereby protects it from degradation	SIGNOR-274980
Q8N9L9	P31749	0	phosphorylation	up-regulates quantity by stabilization	0.2	HSPA1A was found to associate with ACOT4. Furthermore, we found that phosphorylation of ACOT4 at S392 by AKT decreased the binding of ACOT4 to HSPA1A, resulting in ACOT4 accumulation. \|AKT phosphorylates ACOT4 at S392 and promotes ACOT4 stability	SIGNOR-271820
P22894	P02671	1	cleavage	down-regulates quantity by destabilization	0.2	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII\| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. \|Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.\|MMP-8 20ADSGEGD a-chain \| 442LRTGKEKV a-chain	SIGNOR-263625
P27169	Q12772	0	transcriptional regulation	up-regulates quantity by expression	0.297	we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity.	SIGNOR-255224
Q14258	P31947	1	ubiquitination	down-regulates quantity by destabilization	0.571	Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest.	SIGNOR-271548
Q99259	Q02156	0	phosphorylation	down-regulates activity	0.321	We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF. Site-directed mutation of T91 to alanine abolished PKA-mediated phosphorylation and inhibition of GAD activity.	SIGNOR-249264
P38936	Q16539	0	phosphorylation	up-regulates quantity by stabilization	0.445	The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.\|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro.	SIGNOR-89436
O75385	Q969V5	0	ubiquitination	down-regulates quantity	0.347	MUL1 promotes ubiquitination of ULK1.\|Overexpression of MUL1 and treatment with selenite promotes ULK1 degradation through the proteasome pathway.	SIGNOR-278759
Q14493	P0C0S5	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265408
Q05513	Q15831	1	phosphorylation	up-regulates	0.321	Here, we have identified s307 as a novel phosphorylation site in lkb1 and provide evidence that, in multiple cell types, phosphorylation of this site by protein kinase c ? (pkc-?) Induces nucleocytoplasmic transport of lkb1.	SIGNOR-185640
P14618	P24666	0	dephosphorylation	up-regulates activity	0.279	Indeed, it is evident that LMW-PTP, hydrolyzing phosphotyrosine residues, contributes to maintain PKM2 in its active form.\|We speculate that this effect is in large part due to LMW-PTP inhibition, which leads a fast PKM2 phosphorylation and inactivation.\|we demonstrate that in melanoma cells the overexpression of LMW-PTP is functional to maintain PKM2 in its dephosphorylate status – the tetrameric, “full active” form - which is retained in the cytoplasm	SIGNOR-277134
P16949	Q16566	0	phosphorylation	down-regulates	0.49	Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr.	SIGNOR-34743
Q14680	Q08050	1	phosphorylation	up-regulates activity	0.501	MELK Activates FOXM1 Transcriptional Activity Leading to Upregulation of Mitotic Gene Expression.\|The autoradiogram clearly shows in vitro phosphorylation of FOXM1 by MELK and CDK2 and cyclinA.	SIGNOR-278412
P10244	Q13309	0	polyubiquitination	down-regulates quantity by destabilization	0.378	P19Skp1 and Cul-1 bind to the F-box protein p45Skp2 to form a complex (SCF) that functions as E3 ubiquitin ligase.We show that B-Myb physically and functionally interacts with components of the Cdc34-SCFp45Skp2 ubiquitin pathway and propose that B-Myb degradation may be required for controlling the correct alternation of events during progression through the cell division cycle.	SIGNOR-272572
P07948	P40763	1	phosphorylation	up-regulates activity	0.659	An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3.	SIGNOR-279062
Q6NXT2	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265420
P67775	Q7Z2W7	1	dephosphorylation	down-regulates activity	0.2	Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity.	SIGNOR-273793
P10275	P06850	1	transcriptional regulation	down-regulates quantity by repression	0.305	A direct androgenic involvement in the expression of human corticotropin-releasing hormone\|A potential androgen-responsive element (ARE) in the human CRH promoter was subsequently analyzed with bandshifts and cotransfections in neuroblastoma cells. In the presence of testosterone, recombinant human AR bound specifically to the CRH-ARE.	SIGNOR-268723
P14317	P43405	0	phosphorylation	up-regulates	0.667	Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis.	SIGNOR-47342
P31751	Q15672	1	phosphorylation	up-regulates activity	0.398	AKT2 phosphorylates Twist1 at S42 to enhance Twist1 mediated E-cadherin suppression.	SIGNOR-279137
O95750	P18848	0	transcriptional regulation	up-regulates quantity by expression	0.2	Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress	SIGNOR-253727
O00762	P10275	0	transcriptional regulation	up-regulates quantity by expression	0.397	The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint.	SIGNOR-251543
Q7Z6I6	P61586	1	gtpase-activating protein	down-regulates activity	0.449	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260485
P12931	Q96KG7	1	phosphorylation	up-regulates activity	0.378	Our data suggest that c-Src augments the phosphorylation of MEGF10 and helps form a signaling complex.\|These results indicate that overexpressed MEGF10 is phosphorylated by c-Src.	SIGNOR-279290
Q9NZJ5	P23458	0	phosphorylation	up-regulates activity	0.2	JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3.	SIGNOR-276677
P33993	P07948	0	phosphorylation	up-regulates activity	0.453	Lyn phosphorylates MCM7 at Y600.\|These evidences suggest that Lyn mediated Y600 phosphorylation may regulate MCM7 function in DNA replication licensing.	SIGNOR-278407
P27361	Q9UBN7	1	phosphorylation	up-regulates	0.426	Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1	SIGNOR-202702
P55957	P68400	0	phosphorylation	up-regulates activity	0.286	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. \| These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250831
Q16623	Q9NX95	0	relocalization	up-regulates activity	0.421	Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes.	SIGNOR-264812
P15336	P27361	0	phosphorylation	up-regulates	0.739	Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.	SIGNOR-90533
Q14576	Q12955	1	post transcriptional regulation	down-regulates quantity	0.25	NElavl (composed of Elavl2, Elavl3, and Elavl4) proteins are the RNA-binding proteins that is specifically expressed in neurons, regulate the alternative splicing of target RNAs, and promote neuronal differentiation and maturation. Here, we found that the alternative splicing of AnkyrinG exon 34 was misregulated in the cerebella of Elavl3-/- mice. AnkyrinG is an essential factor for the formation of neuronal polarity and is required for normal neuronal functions.	SIGNOR-266861
P04049	P31751	0	phosphorylation	down-regulates activity	0.451	Akt (protein kinase b), a member of a different signaling pathway that also regulates these responses, interacted with raf and phosphorylated this protein at a highly conserved serine residue in its regulatory domain in vivo. This phosphorylation of raf by akt inhibited activation of the raf-mek-erk signaling pathway and shifted the cellular response in a human breast cancer cell line from cell cycle arrest to proliferation.	SIGNOR-235678
P17612	P35568	1	phosphorylation	down-regulates quantity by destabilization	0.2	Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223	SIGNOR-235675
P52179	Q5VST9	1	relocalization	up-regulates quantity	0.3	Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins.	SIGNOR-266727
O60674	Q9P0J1	1	phosphorylation	down-regulates activity	0.264	Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.	SIGNOR-276642
O15524	P07947	0	phosphorylation	up-regulates quantity by stabilization	0.2	Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization.	SIGNOR-277453
Q13322	P06241	0	phosphorylation	down-regulates	0.38	Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir.	SIGNOR-78702
P16671	P25098	0	phosphorylation	down-regulates quantity by destabilization	0.2	We, therefore, propose a pathway by which inhibition of GRK2 in the failing heart prevents CD36 phosphorylation, ubiquitination, and, in turn, induces its proteasomal degradation.\|Our data reveal direct phosphorylation of CD36 by GRK2.	SIGNOR-279524
Q14332	Q68DV7	0	relocalization	up-regulates	0.308	Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation61 (see above), and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane	SIGNOR-199585
P12931	P23470	0	dephosphorylation	down-regulates activity	0.307	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-254725
Q8N5S9	Q13131	1	phosphorylation	up-regulates	0.462	Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.	SIGNOR-176598
P07384	P25116	1	cleavage	up-regulates activity	0.376	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus	SIGNOR-263559
O95600	Q13351	0	transcriptional regulation	up-regulates quantity by expression	0.25	Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.	SIGNOR-266050
P49327	P36956	0	transcriptional regulation	up-regulates quantity by expression	0.495	Ultimately, both the AKT and MAPK transduction pathways regulate FASN expression through the modulation of expression of sterol regulatory element-binding protein (SREBP)-1c, which binds to regulatory elements in the FASN promoter. Proto-oncogene FBI-1 (Pokemon), a transcription factor of the bric--brac tramtrack broad complex/pox viruses and zinc fingers (BTB/POZ) domain family, interacts directly with SREBP-1c through its DNA-binding domain to synergistically activate the transcription of FASN	SIGNOR-242884
Q9UI10	P05198	1	guanine nucleotide exchange factor	up-regulates activity	0.869	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269127
P06213	P35568	1	phosphorylation	up-regulates activity	0.914	All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10).	SIGNOR-235975
P15407	Q04759	0	phosphorylation	up-regulates activity	0.2	PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors.	SIGNOR-260879
P41235	P12931	0	phosphorylation	down-regulates	0.365	Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function.	SIGNOR-195896
O76064	P54132	1	ubiquitination	up-regulates activity	0.337	Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of .	SIGNOR-272115
P31749	P35222	1	phosphorylation	up-regulates	0.805	Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity\|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo.	SIGNOR-252499
P52565	P16591	0	phosphorylation	down-regulates activity	0.2	Fer interferes with binding of RhoGDI\u03b1 and Rac. (A) GST-RhoGDI\u03b1 was pre-incubated with Rac, after which GST-Fer (G-Fer) or GST (G) was added and GST fusion proteins were pulled down with glutathione agarose, followed by kinase reactions. (B) GST-RhoGDI\u03b1 was pre-incubated with GST-Fer or GST in kinase buffer, after which Rac was added and RhoGDI\u03b1 was immunoprecipitated. 50 pmol of RhoGDI\u03b1 and Rac1, with 25 pmol of GST and GST-Fer were used.\|These results identify tyrosine phosphorylation of RhoGDIalpha by Fer as a mechanism to regulate binding of RhoGDIalpha to Rac.	SIGNOR-279042
P17612	O00168	1	phosphorylation	up-regulates activity	0.45	PKA-dependent, alpha 1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct alpha1 subunit phosphorylation. we propose that phosphorylation of the small accessory protein phospholemman (PLM) by PKA at serine 68 is responsible for the observed isoform-specific activation of NKA.	SIGNOR-263117
P48048	P17252	0	phosphorylation	down-regulates activity	0.2	The giant patch clamp together with site direct mutagenesis revealed that Thr-193 is the phosphorylation site on PKC that regulates the pH(i) sensitivity of ROMK1 channels. Mutation of PKC-induced phosphorylation sites (T193A) decreases the pH(i) sensitivity and increases the interaction of channel-PIP(2).	SIGNOR-276389
O43293	P40429	1	phosphorylation	up-regulates	0.402	Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro	SIGNOR-182117
Q96EB6	Q13131	0	phosphorylation	down-regulates activity	0.395	Previous studies have reported that AMP-activated protein kinase phosphorylates and inactivates SIRT1, resulting in increased p53 acetylation in liver cancer [ xref , xref ].	SIGNOR-280076
Q96GD4	Q9UQL6	1	phosphorylation	down-regulates	0.258	We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions	SIGNOR-198650
P00738	Q9NZP8	0	cleavage	up-regulates activity	0.375	We demonstrate that coexpression of the proform of Hp (proHp) and C1r-LP in COS-1 cells effected cleavage of proHp in the endoplasmic reticulum. This cleavage depended on proteolytic activity of C1r-LP because mutation of the putative active-site Ser residue abolished the reaction. Furthermore, incubation of affinity-purified C1r-LP and proHp led to the cleavage of the latter protein. ProHp appeared to be cleaved at the expected site because substitution of Gly for Arg-161 blocked the reaction.	SIGNOR-256358
P43686	Q92630	0	phosphorylation	down-regulates quantity by destabilization	0.284	Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation.	SIGNOR-275845
Q9BZL6	Q13563	1	phosphorylation	up-regulates activity	0.2	Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. These results suggest that growth factor-stimulated, protein kinase D-mediated phosphorylation of polycystin-2 is essential for its ER channel function and links extracellular stimuli to its effects on cell growth and intracellular calcium regulation.	SIGNOR-276284

P35226

P31749

0

phosphorylation

up-regulates activity

0.437

The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate

SIGNOR-252559

Q13114

Q99558

1

ubiquitination

down-regulates quantity by destabilization

0.668

TRAF2 and TRAF3 mediate NIK ubiquitination by forming a complex with the E3 ligase cIAP (cIAP1 or cIAP2).|We demonstrated further that TRAF3 mediates the degradation of NIK and thereby serves as a pivotal negative regulator of noncanonical NF-kappaB signaling.

SIGNOR-278673

O75170

P06493

0

phosphorylation

down-regulates activity

0.261

We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit.

SIGNOR-273587

Q13224

Q96AX9

0

ubiquitination

down-regulates quantity

0.366

Mib2 is localized to the PSD of dendrites in hippocampal neurons and directly ubiquitinates GluN2B in a manner dependent on the non receptor tyrosine kinase Fyn.|These findings suggest that Mib2 mediates proteasome dependent degradation of GluN2B subunits, which may provide a reciprocal mechanism to SCF Fbx2 regulation of GluN2A.

SIGNOR-278762

O75962

P06241

0

phosphorylation

up-regulates activity

0.2

Here, we demonstrate that Trio is phosphorylated by Src family kinases in the embryonic rat cortex in response to netrin-1. In vitro, Trio was predominantly phosphorylated at Tyr(2622) by the Src kinase Fyn.

SIGNOR-273855

P02671

P45452

0

cleavage

down-regulates quantity by destabilization

0.2

Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain

SIGNOR-263613

P49841

P10070

1

phosphorylation

down-regulates quantity by destabilization

0.562

The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3.

SIGNOR-249590

P49716

P68400

0

phosphorylation

up-regulates activity

0.2

Here, we have identified the CCAAT/enhancer binding protein δ (C/EBPδ) as a new substrate for CK2. Using point mutants of C/EBPδ the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPδ. For proper functioning as a transcription factor C/EBPδ has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPδ nor its interaction with C/EBPβ, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPδ.

SIGNOR-276886

Q13485

Q93008

0

deubiquitination

up-regulates

0.648

Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4.

SIGNOR-236855

Q13976

Q9UI08

1

phosphorylation

down-regulates activity

0.2

Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts

SIGNOR-268290

Q00535

P14416

1

phosphorylation

down-regulates activity

0.383

These results indicate that Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling.

SIGNOR-259401

P46527

Q12778

0

transcriptional regulation

up-regulates quantity by expression

0.627

To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter.

SIGNOR-277739

P05114

P17612

0

phosphorylation

down-regulates activity

0.307

PKA preferentially phosphorylates serine 6 in human HMGN1. specific phosphorylation of the NBD of HMGN proteins serves to prevent the interaction of these proteins with their chromatin targets during mitosis.

SIGNOR-249993

P01308

P14735

0

cleavage

down-regulates quantity by destabilization

0.719

IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds

SIGNOR-260986

Q5S007

P15311

1

phosphorylation

up-regulates activity

0.411

LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558.

SIGNOR-279202

Q15418

P30304

1

phosphorylation

down-regulates

0.366

Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.

SIGNOR-202117

Q13043

Q06830

1

phosphorylation

down-regulates activity

0.2

Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183.

SIGNOR-276486

Q13950

Q9HCE7

0

ubiquitination

down-regulates activity

0.504

Recently we have found that smurf1 mediates the protein degradation of the osteoblast-specific transcription factor runx2/cbfa1.

SIGNOR-95233

P60484

P29375

0

transcriptional regulation

down-regulates quantity by destabilization

0.289

The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL.

SIGNOR-260079

O14757

P62745

1

phosphorylation

up-regulates activity

0.328

We identified that Thr173 and Thr175 of RhoB was phosphorylated by Chk1 using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) (Supplementary Fig.\u00a06f).

SIGNOR-279727

Q93009

Q8TB45

1

deubiquitination

up-regulates quantity by stabilization

0.2

Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay.

SIGNOR-277588

O60825

P54646

0

phosphorylation

up-regulates activity

0.443

AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. activation of PFK-2 was due to the phosphorylation of Ser466

SIGNOR-250323

Q9NRM7

P11908

1

phosphorylation

down-regulates quantity by destabilization

0.2

Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness.

SIGNOR-276507

Q96BR9

Q8TBB1

0

polyubiquitination

down-regulates quantity by destabilization

0.2

LNX (ligand of Numb protein-X) is a RING finger and four PDZ domain-containing E3 ubiquitin ligase. Lnx-l induced K48-linked polyubiquitylation of Boz, leading to its proteasomal degradation in human 293T cells and in zebrafish embryos.

SIGNOR-272777

Q8IWU9

P17612

0

phosphorylation

up-regulates

0.254

We also demonstrate that phosphorylation of serine 19, a protein kinase a consensus site located in this n-terminal domain, results in increased tph2 stability and consequent increases in enzyme output in cell culture systems

SIGNOR-178018

P49585

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.2

Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter

SIGNOR-266231

P84022

P35813

0

dephosphorylation

down-regulates activity

0.622

Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.

SIGNOR-232110

P08575

P23458

1

dephosphorylation

up-regulates

0.454

These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3,

SIGNOR-87154

O14965

P07195

1

phosphorylation

up-regulates activity

0.2

Aurora-A-mediated phosphorylation of LDHB serine 162 significantly increases its activity in reducing pyruvate to lactate, which efficiently promotes NAD+ regeneration, glycolytic flux, lactate production and bio-synthesis with glycolytic intermediates.

SIGNOR-277493

P06241

P78352

1

phosphorylation

up-regulates

0.562

Psd-95 is phosphorylated either by purified src/fyn kinases in vitro or by co-expression of constitutively active src/fyn in cos7 cells. psd-95 tyr(523) phosphorylation contributes to the post-ischaemic over-activation of nmda receptors.

SIGNOR-180449

Q9BRQ8

P04637

0

transcriptional regulation

up-regulates quantity by expression

0.503

The p53 tumor suppressor protein induces cell cycle arrest or apoptosis in response to cellular stresses. We have identified PRG3 (p53-responsive gene 3), which is induced specifically under p53-dependent apoptotic conditions in human colon cancer cells, and encodes a novel polypeptide of 373 amino acids with a predicted molecular mass of 40.5 kDa. these results support the hypothesis that the expression of the PRG3 gene in cells undergoing p53‐dependent apoptosis involves direct activation of its promoter by p53.

SIGNOR-261808

P17010

P09467

1

transcriptional regulation

down-regulates quantity by repression

0.2

For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma

SIGNOR-267595

P30281

P15172

0

transcriptional regulation

up-regulates quantity by expression

0.374

Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator.

SIGNOR-238526

Q15654

Q12923

0

dephosphorylation

down-regulates activity

0.434

PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration.|Here we further demonstrate that a switch from c-Src-mediated phosphorylation to PTPL1/Fas-associated phosphatase-1-dependent dephosphorylation serves as an inhibitory feedback control mechanism of TRIP6 function in LPA-induced cell migration. PTPL1 dephosphorylates phosphotyrosine 55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells.

SIGNOR-248713

P28482

P12036

1

phosphorylation

up-regulates activity

0.368

The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation.

SIGNOR-249424

Q9UPX8

Q9P1A6

0

relocalization

up-regulates activity

0.849

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-264590

Q04864

Q9UHD2

0

phosphorylation

up-regulates

0.579

The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel.

SIGNOR-148623

O15111

P20749

1

phosphorylation

up-regulates activity

0.429

Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.

SIGNOR-277362

P46939

Q7KZI7

0

phosphorylation

up-regulates

0.424

Par-1b, interacts with the utrophin-dg complex, and positively regulates the interaction between utrophin and dg. Ser1258 within r9 is specifically phosphorylated by par-1b.

SIGNOR-161915

P68400

P06744

1

phosphorylation

down-regulates activity

0.333

It is known that human PGI/AMF is phosphorylated at Ser(185) by protein kinase CK2 (CK2) | These results demonstrate that phosphorylation affects the allosteric kinetic properties of the enzyme, resulting in a less active form of PGI, whereas non-phosphorylated protein species retain cytokine activity.

SIGNOR-250869

P09651

Q9UBS0

0

phosphorylation

up-regulates activity

0.416

Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export.

SIGNOR-279569

Q9NX76

Q9NZQ7

1

stabilization

up-regulates quantity by stabilization

0.47

Furthermore, the observations that (i) CMTM6 affects PD-L1 protein stability at late time points after biosynthesis; (ii) CMTM6, CMTM4 and PD-L1 interact, as shown by co-immunoprecipitation; and that (iii) CMTM6 is largely located at the cell surface, collectively suggest a model in which CMTM6 interacts with PD-L1 at the tumour cell surface and thereby protects it from degradation

SIGNOR-274980

Q8N9L9

P31749

0

phosphorylation

up-regulates quantity by stabilization

0.2

HSPA1A was found to associate with ACOT4. Furthermore, we found that phosphorylation of ACOT4 at S392 by AKT decreased the binding of ACOT4 to HSPA1A, resulting in ACOT4 accumulation. |AKT phosphorylates ACOT4 at S392 and promotes ACOT4 stability

SIGNOR-271820

P22894

P02671

1

cleavage

down-regulates quantity by destabilization

0.2

Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-8 20ADSGEGD a-chain | 442LRTGKEKV a-chain

SIGNOR-263625

P27169

Q12772

0

transcriptional regulation

up-regulates quantity by expression

0.297

we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity.

SIGNOR-255224

Q14258

P31947

1

ubiquitination

down-regulates quantity by destabilization

0.571

Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest.

SIGNOR-271548

Q99259

Q02156

0

phosphorylation

down-regulates activity

0.321

We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF. Site-directed mutation of T91 to alanine abolished PKA-mediated phosphorylation and inhibition of GAD activity.

SIGNOR-249264

P38936

Q16539

0

phosphorylation

up-regulates quantity by stabilization

0.445

The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro.

SIGNOR-89436

O75385

Q969V5

0

ubiquitination

down-regulates quantity

0.347

MUL1 promotes ubiquitination of ULK1.|Overexpression of MUL1 and treatment with selenite promotes ULK1 degradation through the proteasome pathway.

SIGNOR-278759

Q14493

P0C0S5

1

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265408

Q05513

Q15831

1

phosphorylation

up-regulates

0.321

Here, we have identified s307 as a novel phosphorylation site in lkb1 and provide evidence that, in multiple cell types, phosphorylation of this site by protein kinase c ? (pkc-?) Induces nucleocytoplasmic transport of lkb1.

SIGNOR-185640

P14618

P24666

0

dephosphorylation

up-regulates activity

0.279

Indeed, it is evident that LMW-PTP, hydrolyzing phosphotyrosine residues, contributes to maintain PKM2 in its active form.|We speculate that this effect is in large part due to LMW-PTP inhibition, which leads a fast PKM2 phosphorylation and inactivation.|we demonstrate that in melanoma cells the overexpression of LMW-PTP is functional to maintain PKM2 in its dephosphorylate status – the tetrameric, “full active” form - which is retained in the cytoplasm

SIGNOR-277134

P16949

Q16566

0

phosphorylation

down-regulates

0.49

Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr.

SIGNOR-34743

Q14680

Q08050

1

phosphorylation

up-regulates activity

0.501

MELK Activates FOXM1 Transcriptional Activity Leading to Upregulation of Mitotic Gene Expression.|The autoradiogram clearly shows in vitro phosphorylation of FOXM1 by MELK and CDK2 and cyclinA.

SIGNOR-278412

P10244

Q13309

0

polyubiquitination

down-regulates quantity by destabilization

0.378

P19Skp1 and Cul-1 bind to the F-box protein p45Skp2 to form a complex (SCF) that functions as E3 ubiquitin ligase.We show that B-Myb physically and functionally interacts with components of the Cdc34-SCFp45Skp2 ubiquitin pathway and propose that B-Myb degradation may be required for controlling the correct alternation of events during progression through the cell division cycle.

SIGNOR-272572

P07948

P40763

1

phosphorylation

up-regulates activity

0.659

An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3.

SIGNOR-279062

Q6NXT2

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265420

P67775

Q7Z2W7

1

dephosphorylation

down-regulates activity

0.2

Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity.

SIGNOR-273793

P10275

P06850

1

transcriptional regulation

down-regulates quantity by repression

0.305

A direct androgenic involvement in the expression of human corticotropin-releasing hormone|A potential androgen-responsive element (ARE) in the human CRH promoter was subsequently analyzed with bandshifts and cotransfections in neuroblastoma cells. In the presence of testosterone, recombinant human AR bound specifically to the CRH-ARE.

SIGNOR-268723

P14317

P43405

0

phosphorylation

up-regulates

0.667

Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis.

SIGNOR-47342

P31751

Q15672

1

phosphorylation

up-regulates activity

0.398

AKT2 phosphorylates Twist1 at S42 to enhance Twist1 mediated E-cadherin suppression.

SIGNOR-279137

O95750

P18848

0

transcriptional regulation

up-regulates quantity by expression

0.2

Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress

SIGNOR-253727

O00762

P10275

0

transcriptional regulation

up-regulates quantity by expression

0.397

The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint.

SIGNOR-251543

Q7Z6I6

P61586

1

gtpase-activating protein

down-regulates activity

0.449

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260485

P12931

Q96KG7

1

phosphorylation

up-regulates activity

0.378

Our data suggest that c-Src augments the phosphorylation of MEGF10 and helps form a signaling complex.|These results indicate that overexpressed MEGF10 is phosphorylated by c-Src.

SIGNOR-279290

Q9NZJ5

P23458

0

phosphorylation

up-regulates activity

0.2

JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3.

SIGNOR-276677

P33993

P07948

0

phosphorylation

up-regulates activity

0.453

Lyn phosphorylates MCM7 at Y600.|These evidences suggest that Lyn mediated Y600 phosphorylation may regulate MCM7 function in DNA replication licensing.

SIGNOR-278407

P27361

Q9UBN7

1

phosphorylation

up-regulates

0.426

Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1

SIGNOR-202702

P55957

P68400

0

phosphorylation

up-regulates activity

0.286

Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.

SIGNOR-250831

Q16623

Q9NX95

0

relocalization

up-regulates activity

0.421

Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes.

SIGNOR-264812

P15336

P27361

0

phosphorylation

up-regulates

0.739

Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.

SIGNOR-90533

Q14576

Q12955

1

post transcriptional regulation

down-regulates quantity

0.25

NElavl (composed of Elavl2, Elavl3, and Elavl4) proteins are the RNA-binding proteins that is specifically expressed in neurons, regulate the alternative splicing of target RNAs, and promote neuronal differentiation and maturation. Here, we found that the alternative splicing of AnkyrinG exon 34 was misregulated in the cerebella of Elavl3-/- mice. AnkyrinG is an essential factor for the formation of neuronal polarity and is required for normal neuronal functions.

SIGNOR-266861

P04049

P31751

0

phosphorylation

down-regulates activity

0.451

Akt (protein kinase b), a member of a different signaling pathway that also regulates these responses, interacted with raf and phosphorylated this protein at a highly conserved serine residue in its regulatory domain in vivo. This phosphorylation of raf by akt inhibited activation of the raf-mek-erk signaling pathway and shifted the cellular response in a human breast cancer cell line from cell cycle arrest to proliferation.

SIGNOR-235678

P17612

P35568

1

phosphorylation

down-regulates quantity by destabilization

0.2

Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223

SIGNOR-235675

P52179

Q5VST9

1

relocalization

up-regulates quantity

0.3

Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins.

SIGNOR-266727

O60674

Q9P0J1

1

phosphorylation

down-regulates activity

0.264

Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.

SIGNOR-276642

O15524

P07947

0

phosphorylation

up-regulates quantity by stabilization

0.2

Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization.

SIGNOR-277453

Q13322

P06241

0

phosphorylation

down-regulates

0.38

Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir.

SIGNOR-78702

P16671

P25098

0

phosphorylation

down-regulates quantity by destabilization

0.2

We, therefore, propose a pathway by which inhibition of GRK2 in the failing heart prevents CD36 phosphorylation, ubiquitination, and, in turn, induces its proteasomal degradation.|Our data reveal direct phosphorylation of CD36 by GRK2.

SIGNOR-279524

Q14332

Q68DV7

0

relocalization

up-regulates

0.308

Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation61 (see above), and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane

SIGNOR-199585

P12931

P23470

0

dephosphorylation

down-regulates activity

0.307

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-254725

Q8N5S9

Q13131

1

phosphorylation

up-regulates

0.462

Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.

SIGNOR-176598

P07384

P25116

1

cleavage

up-regulates activity

0.376

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus

SIGNOR-263559

O95600

Q13351

0

transcriptional regulation

up-regulates quantity by expression

0.25

Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.

SIGNOR-266050

P49327

P36956

0

transcriptional regulation

up-regulates quantity by expression

0.495

Ultimately, both the AKT and MAPK transduction pathways regulate FASN expression through the modulation of expression of sterol regulatory element-binding protein (SREBP)-1c, which binds to regulatory elements in the FASN promoter. Proto-oncogene FBI-1 (Pokemon), a transcription factor of the bric--brac tramtrack broad complex/pox viruses and zinc fingers (BTB/POZ) domain family, interacts directly with SREBP-1c through its DNA-binding domain to synergistically activate the transcription of FASN

SIGNOR-242884

Q9UI10

P05198

1

guanine nucleotide exchange factor

up-regulates activity

0.869

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

SIGNOR-269127

P06213

P35568

1

phosphorylation

up-regulates activity

0.914

All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10).

SIGNOR-235975

P15407

Q04759

0

phosphorylation

up-regulates activity

0.2

PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors.

SIGNOR-260879

P41235

P12931

0

phosphorylation

down-regulates

0.365

Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function.

SIGNOR-195896

O76064

P54132

1

ubiquitination

up-regulates activity

0.337

Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of .

SIGNOR-272115

P31749

P35222

1

phosphorylation

up-regulates

0.805

Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo.

SIGNOR-252499

P52565

P16591

0

phosphorylation

down-regulates activity

0.2

Fer interferes with binding of RhoGDI\u03b1 and Rac. (A) GST-RhoGDI\u03b1 was pre-incubated with Rac, after which GST-Fer (G-Fer) or GST (G) was added and GST fusion proteins were pulled down with glutathione agarose, followed by kinase reactions. (B) GST-RhoGDI\u03b1 was pre-incubated with GST-Fer or GST in kinase buffer, after which Rac was added and RhoGDI\u03b1 was immunoprecipitated. 50 pmol of RhoGDI\u03b1 and Rac1, with 25 pmol of GST and GST-Fer were used.|These results identify tyrosine phosphorylation of RhoGDIalpha by Fer as a mechanism to regulate binding of RhoGDIalpha to Rac.

SIGNOR-279042

P17612

O00168

1

phosphorylation

up-regulates activity

0.45

PKA-dependent, alpha 1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct alpha1 subunit phosphorylation. we propose that phosphorylation of the small accessory protein phospholemman (PLM) by PKA at serine 68 is responsible for the observed isoform-specific activation of NKA.

SIGNOR-263117

P48048

P17252

0

phosphorylation

down-regulates activity

0.2

The giant patch clamp together with site direct mutagenesis revealed that Thr-193 is the phosphorylation site on PKC that regulates the pH(i) sensitivity of ROMK1 channels. Mutation of PKC-induced phosphorylation sites (T193A) decreases the pH(i) sensitivity and increases the interaction of channel-PIP(2).

SIGNOR-276389

O43293

P40429

1

phosphorylation

up-regulates

0.402

Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro

SIGNOR-182117

Q96EB6

Q13131

0

phosphorylation

down-regulates activity

0.395

Previous studies have reported that AMP-activated protein kinase phosphorylates and inactivates SIRT1, resulting in increased p53 acetylation in liver cancer [ xref , xref ].

SIGNOR-280076

Q96GD4

Q9UQL6

1

phosphorylation

down-regulates

0.258

We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions

SIGNOR-198650

P00738

Q9NZP8

0

cleavage

up-regulates activity

0.375

We demonstrate that coexpression of the proform of Hp (proHp) and C1r-LP in COS-1 cells effected cleavage of proHp in the endoplasmic reticulum. This cleavage depended on proteolytic activity of C1r-LP because mutation of the putative active-site Ser residue abolished the reaction. Furthermore, incubation of affinity-purified C1r-LP and proHp led to the cleavage of the latter protein. ProHp appeared to be cleaved at the expected site because substitution of Gly for Arg-161 blocked the reaction.

SIGNOR-256358

P43686

Q92630

0

phosphorylation

down-regulates quantity by destabilization

0.284

Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation.

SIGNOR-275845

Q9BZL6

Q13563

1

phosphorylation

up-regulates activity

0.2

Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. These results suggest that growth factor-stimulated, protein kinase D-mediated phosphorylation of polycystin-2 is essential for its ER channel function and links extracellular stimuli to its effects on cell growth and intracellular calcium regulation.

SIGNOR-276284