GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q06187	P00519	phosphorylation	down-regulates activity	0.336	In this report we describe for the first time that ABL1 and Btk physically interact and that ABL1 can phosphorylate tyrosine 223 in the SH3 domain of Btk. \| This is presumably due to the negative regulatory effectof Btk SH3 domain phosphorylation caused by ABL1,which would result in a decreased catalytic activity ofBtk resulting in impaired autophosphorylation.	SIGNOR-260801
Q8IX03	Q15418	phosphorylation	up-regulates	0.335	Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2.	SIGNOR-203298
P07951	P48736	phosphorylation	up-regulates activity	0.335	Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization.	SIGNOR-263028
P12814	P18031	dephosphorylation	up-regulates	0.335	Here we report that protein-tyrosine phosphatase 1b (ptp 1b) is an ?-Actinin phosphatase.	SIGNOR-141634
Q00536	Q00535	phosphorylation	up-regulates activity	0.335	Taken together, our findings demonstrate that Pctaire1 interacts with p35, both in vitro and in vivo, and that phosphorylation of Pctaire1 by Cdk5 enhances its kinase activity.	SIGNOR-279149
Q92934	Q13153	phosphorylation	down-regulates	0.335	Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau.	SIGNOR-73533
P49427	Q15418	phosphorylation	down-regulates quantity by destabilization	0.335	RSK1 phosphorylated Thr162 on UBE2R1.RSK1 induced self-ubiquitination and destabilisation of UBE2R1 by phosphorylation.	SIGNOR-277330
P55283	P07737	null	up-regulates activity	0.335	Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation.	SIGNOR-253111
P60484	Q9H4B4	phosphorylation	down-regulates activity	0.335	Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis	SIGNOR-168473
Q00613	Q9H422	phosphorylation	up-regulates activity	0.335	We show that Yak1 directly phosphorylates Hsf1 in vitro, leading to the increase in DNA binding activity of Hsf1.	SIGNOR-279054
O43639	Q16620	binding	up-regulates	0.335	We identified the nck2 adaptor protein as a novel interaction partner of the active form of trkb. Additionally, we identified three tyrosines in icd-trkb (y694, y695, and y771) that are crucial for this interaction.	SIGNOR-89764
P09917	P17612	phosphorylation	down-regulates activity	0.335	These results indicate that PKA phosphorylates 5-LO on Ser-523, which inhibits the catalytic activity of 5-LO and reduces cellular LT generation.	SIGNOR-264410
Q08345	P02452	binding	up-regulates activity	0.335	The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.\|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.	SIGNOR-272340
Q9UBP6	P31749	phosphorylation	down-regulates	0.335	The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells	SIGNOR-24994
P04637	Q92481	binding	up-regulates quantity by stabilization	0.335	These data suggest that AP-2Œ≤ enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2Œ≤ interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2Œ≤ up-regulates the transcription of the CRYAB gene through stabilizing p53.	SIGNOR-255422
P17844	P17252	phosphorylation	down-regulates activity	0.335	We report that p68 is phosphorylated by protein kinase C in vitro and binds calmodulin in a Ca(2+)-dependent manner. Both phosphorylation and calmodulin binding inhibited p68 ATPase activity \| In addition, a 20-amino acid peptide corresponding to residues 549-568 of p68 was phosphorylated in a Ca- and phospholipid-dependent manner hy PKC	SIGNOR-248896
P19086	P30542	binding	up-regulates activity	0.335	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257092
Q9UGP5	P24941	phosphorylation	up-regulates quantity by stabilization	0.335	Phosphorylation of DNA polymerase λ is required to maintain its stability. Recently, we identified Pol lambda as an interaction partner of cyclin-dependent kinase 2 (CDK2) that is central to the cell cycle G1/S transition and S-phase progression. Experiments with phosphorylation-defective mutants suggest that phosphorylation of Thr 553 is important for maintaining Pol lambda stability, as it is targeted to the proteasomal degradation pathway through ubiquitination unless this residue is phosphorylated.	SIGNOR-276169
P51813	Q06187	phosphorylation	up-regulates	0.335	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism.	SIGNOR-98028
P30519	P68400	phosphorylation	up-regulates activity	0.335	Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. \| CK2 activation is abolished by the S79A mutation but preserved in S179A and T248A mutations, indicating that S79 is the target of CK2-dependent activation of HO2	SIGNOR-250895
Q14938	P55317	binding	up-regulates	0.335	Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex.	SIGNOR-205082
O15126	P00533	phosphorylation	up-regulates activity	0.335	In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation	SIGNOR-262857
P33993	P60228	binding	up-regulates quantity by stabilization	0.335	Our data show that INT6 interacts with a C-terminal domain of MCM7. Collectively, our observations suggest that INT6 restrains the increased degradation of MCM7 occurring during DNA replication by protecting its polyubiquitylated derivatives from the proteasome activity.	SIGNOR-259154
Q9UQ13	P27361	phosphorylation	down-regulates quantity by destabilization	0.335	Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation.	SIGNOR-277443
P06493	P22674	binding	up-regulates activity	0.335	CDK2 is the predominant activating complex form of CCNO, but CCNO can bind to CDK1 to form an activating complex in the absence of CDK2.	SIGNOR-275617
Q9H2D6	P53350	phosphorylation	up-regulates	0.335	Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1	SIGNOR-198353
Q12800	P28482	phosphorylation	down-regulates	0.335	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309.	SIGNOR-184168
O75955	P12931	phosphorylation	up-regulates activity	0.335	Taken together, we conclude that mitochondrial c-Src phosphorylates flotillin-1 at Tyr56 and Tyr149, and that these phosphorylations are required for its interaction with CxII and the prevention of ROS production.	SIGNOR-273805
P21127	P50613	phosphorylation	up-regulates activity	0.335	We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase	SIGNOR-245871
P08908	Q5T0F9	transcriptional regulation	down-regulates quantity by repression	0.335	Human Freud-2/CC2D1B: a novel repressor of postsynaptic serotonin-1A receptor expression\|Human Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter in human HEK-293 5-HT1A-negative cells and neuronal SK-N-SH cells, a model of postsynaptic 5-HT1A receptor-positive cells.	SIGNOR-268298
O60763	P67870	phosphorylation	up-regulates activity	0.335	Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. \| Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae	SIGNOR-251082
Q02750	Q16584	phosphorylation	up-regulates activity	0.335	Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells.	SIGNOR-280019
Q13887	Q05655	phosphorylation	up-regulates activity	0.335	Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the CBP interaction region enhances its transactivation function. \| Inhibition of protein kinase activity by H7 or calphostin C blocked both full-length and N-terminal fragment (amino acids 1-238) KLF5 activities. Mutation at a potential protein kinase C phosphorylation site within the CBP interaction domain of KLF5 reduces its transactivation function. Furthermore, using the GST pull-down approach, we showed that phosphorylation of KLF5 enhances its interaction with CBP. The results of the present study provide a mechanism for KLF5 transactivation function. \| We found that KLF5s activity was reduced to half when the serine in the potential PKC phosphorylation site was mutated to alanine (Fig. 6B, S153A) Nonetheless, the S153A mutant still retains significant transactivation activity.	SIGNOR-249206
P14672	P04637	transcriptional regulation	down-regulates quantity by repression	0.335	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-267465
P49675	P49715	transcriptional regulation	up-regulates quantity by expression	0.335	Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.	SIGNOR-254043
P05106	Q99704	binding	down-regulates activity	0.334	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257687
Q8NHW3	P28482	phosphorylation	up-regulates activity	0.334	These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription.	SIGNOR-108564
Q01082	P68400	phosphorylation	down-regulates	0.334	We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment.	SIGNOR-150471
P40189	Q05655	phosphorylation	up-regulates activity	0.334	Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling.	SIGNOR-249177
P08151	Q13131	phosphorylation	down-regulates activity	0.334	AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.	SIGNOR-259862
O43665	P17612	phosphorylation	down-regulates activity	0.334	We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel.	SIGNOR-109173
Q15554	P31943	post transcriptional regulation	down-regulates quantity	0.334	During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels.	SIGNOR-266807
P10415	Q16539	phosphorylation	down-regulates activity	0.334	Bcl-2 phosphorylation by p38 mapkin this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, ser(87) and thr(56) as the bcl-2 residues phosphorylated by p38 mapk and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of bcl-2 protein.	SIGNOR-146786
P28356	P09429	binding	up-regulates activity	0.334	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-236956
O15392	Q16254	transcriptional regulation	down-regulates quantity by repression	0.334	This TGF-beta response is triggered through a Smad2/3-dependent hypophosphorylation of Rb and the subsequent association of the Rb/E2F4 repressive complex to CDE/CHR elements in the proximal region of the survivin promoter.	SIGNOR-271678
O00418	Q16539	phosphorylation	down-regulates activity	0.334	Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%.	SIGNOR-249707
P54253	Q00987	ubiquitination	down-regulates quantity by destabilization	0.334	NICD and MDM2 ubiquitinate and degrade ATXN1.\|These results suggest that NICD and MDM2 synergistically reduce ATXN1 expression at the posttranscriptional level.	SIGNOR-278823
P01106	Q8TEK3	binding	up-regulates activity	0.334	Our data suggest that the c-Myc-dependent transcriptional switch is modulated by DOT1L, as in the presence of DOT1L c-Myc preferentially forms an active complex with p300 rather than a repressive complex containing HDAC1 and DNMT1	SIGNOR-239362
Q9GZR7	Q00987	polyubiquitination	up-regulates activity	0.334	MDM2 mediates nonproteolytic polyubiquitylation of the DEAD-Box RNA helicase DDX24. Unexpectedly, however, the polyubiquitylation of DDX24 did not elicit its proteasomal degradation but rather promoted its association with preribosomal ribonucleoprotein (pre-rRNP) processing complexes that are required for the early steps of pre-rRNA processing.	SIGNOR-272845
Q9UM73	P23467	dephosphorylation	down-regulates	0.334	Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation.	SIGNOR-157175
P19086	P55085	binding	up-regulates activity	0.334	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257232
P23760	P49841	phosphorylation	up-regulates quantity	0.334	The ubiquitously expressed CK2 often provides the priming phosphorylation for GSK-3, however, we found that GSK-3beta alone was sufficient to phosphorylate PAX3 at both Ser205 and Ser197 and Ser201 in-vitro.	SIGNOR-278482
Q9Y385	P49137	phosphorylation	down-regulates quantity by destabilization	0.334	Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production. These findings strongly suggest that MK2 directly phosphorylates Ube2j1 at Ser(184) upon p38-activating stress in vivo.	SIGNOR-263091
Q15858	Q96PU5	ubiquitination	down-regulates quantity by destabilization	0.334	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253458
P49757	Q14012	phosphorylation	down-regulates	0.334	Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2.	SIGNOR-149993
P00533	Q15759	phosphorylation	down-regulates	0.334	P38 map kinase mediates stress-induced internalization of egfrthe underlying mechanism entails phosphorylation of egfr at a short segment (amino acids 1002-1022) containing multiple serines and threonines, as well as phosphorylation of two rab5 effectors, eea1 and gdi.	SIGNOR-149086
Q8TDI8	O75838	binding	up-regulates activity	0.334	Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia.	SIGNOR-269664
P17600	O75914	phosphorylation	up-regulates activity	0.334	Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release	SIGNOR-250246
O75475	O00311	phosphorylation	up-regulates	0.334	We now report identification of the cdc7-activator of s-phase kinase (ask) heterodimer as a novel interactor of ledgf. the kinase phosphorylated ledgf in vitro, with ser-206 being the major target, and ledgf phosphorylated at this residue could be detected during s phase of the cell cycle. Ledgf potently stimulated the enzymatic activity of cdc7-ask, increasing phosphorylation of mcm2 in vitro by more than 10-fold.	SIGNOR-25763
O43255	P12931	phosphorylation	up-regulates activity	0.334	In human breast cancer cell lines, the protein kinase Src has been shown to activate Siah2 by phosphorylation of tyrosines 86, 140, and 263.\|This function is promoted by Src phosphorylation of Siah2, which increases C/EBPdelta binding, ubiquitination, and degradation.	SIGNOR-279555
P47712	Q8IW41	phosphorylation	up-regulates activity	0.334	The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells.	SIGNOR-250162
O14921	P17612	phosphorylation	up-regulates quantity by stabilization	0.334	Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry.	SIGNOR-259835
O75807	P07948	phosphorylation	up-regulates	0.334	Gadd34 was tyrosine-phosphorylated in vivo in a lyn-dependent manner.	SIGNOR-109934
P51813	Q08881	phosphorylation	up-regulates activity	0.334	Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.	SIGNOR-251331
O15304	P42684	phosphorylation	up-regulates	0.334	Our results also demonstrate that mutation of the siva-1 tyr48 site abrogates the apoptotic function of siva-1 and that apoptosis induced by siva-1 is dependent on expression of kinase-active arg.	SIGNOR-104992
P32942	Q04759	phosphorylation	up-regulates activity	0.334	Ser489 was a phosphorylation site in vitro for recombinant protein kinase Ctheta. Finally, treatment of Jurkat cells with chelerythrine chloride, a protein kinase C inhibitor, prevented ICAM-3-triggered spreading.	SIGNOR-248979
P10276	Q8IZD2	binding	up-regulates activity	0.334	MLL5 binds to retinoic acid receptor α (RARα) and induces transcriptional activation of RARα target genes by methylation of lysine residues of histone H3.	SIGNOR-260041
Q13501	Q12981	binding	up-regulates activity	0.334	RNF185 functions as a ubiquitin E3 ligase, enabling BNIP1-p62 interaction. BNIP1 is polyubiquitinated by RNF185 and associates with autophagy receptor p62. In addition, we checked the endogenous localization of BNIP1 and p62 in HeLa cells (Fig. 7F). Alexa Fluor 488 conjugated endogenous BNIP1 and TRITIC conjugated endogenous p62 overlapped well in the cytoplasm, further providing the locational evidence for the recruitment of p62 by BNIP1.	SIGNOR-271932
P31749	P41134	binding	up-regulates	0.334	We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation;	SIGNOR-255658
O43918	Q9UER7	binding	down-regulates activity	0.334	The interaction between AIRE and DAXX has been validated by in vivo coimmunoprecipitation analysis and colocalization study in mammalian cells. The interaction has been further confirmed by showing in transactivation assays that DAXX exerts a strong repressive role on the transcriptional activity of AIRE.	SIGNOR-239287
Q12778	O15021	phosphorylation	down-regulates activity	0.334	MAST4 phosphorylation of FOXO1 regulates RTKN2 expression.	SIGNOR-279079
Q04912	P00533	phosphorylation	up-regulates activity	0.334	This showed that EGFR activation transphosphorylated Ron.\|Together, these data suggested that (1) Ron activation transphosphorylated EGFR and vice versa and (2) activated Ron biochemically interacted with EGFR.	SIGNOR-280000
Q9UEY8	P17252	phosphorylation	down-regulates quantity by destabilization	0.334	Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. \| Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. \| The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin	SIGNOR-249143
P23528	Q15139	phosphorylation	down-regulates activity	0.334	PKD1 regulates cofilin S3-phosphorylation\|Both, oxidative stress as well as RhoA activation enhanced cofilin phosphorylation at S3, implicating an increased inhibition due to PKD1-mediated signalling events	SIGNOR-275944
P06744	P68400	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
P30304	P48729	phosphorylation	down-regulates	0.333	Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a	SIGNOR-164734
P12004	P00519	phosphorylation	up-regulates activity	0.333	In the current study, we are able to establish a new pathway in which the Ron receptor tyrosine kinase activates c-Abl which in turn catalyzes Y211 phosphorylation of PCNA.\|We previously showed that Y211 phosphorylation stabilized chromatin bound PCNA, which in turn promoted cell proliferation, and that c-Abl functioned to enhance chromatin association of PCNA in cancer cells.	SIGNOR-279389
O14640	P46937	binding	down-regulates	0.333	Yap restricts elevated wnt independently of the axinapcgsk-3beta complex partly by limiting the activity of dishevelled (dvl).	SIGNOR-199806
Q13315	P67775	dephosphorylation	down-regulates activity	0.333	Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro.	SIGNOR-248644
Q8IWB6	P06493	phosphorylation	down-regulates quantity by destabilization	0.333	Cdk1 phosphorylation of Tex14 is required for the Tex14-Plk1 interaction	SIGNOR-273524
Q15417	P06241	phosphorylation	down-regulates activity	0.333	We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin	SIGNOR-251159
P53041	P48730	phosphorylation	up-regulates activity	0.333	Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90.	SIGNOR-277373
O15169	P62136	dephosphorylation	down-regulates activity	0.333	The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin\| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity\| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated	SIGNOR-248551
Q9UJA2	Q8NCQ5	binding	down-regulates quantity by destabilization	0.333	Fbxo15 Targets CLS1 Protein for Ubiquitination and Degradation to Disrupt Mitochondrial Function. S. aureus infection induces expression of a kinase, PINK1, that phosphorylates an indispensable protein CLS1, which in turn triggers CLS1 ubiquitination and degradation by the F box protein (SCFFbxo15).	SIGNOR-272170
Q9NRF2	P48357	binding	up-regulates activity	0.333	The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex	SIGNOR-253077
P57078	P98170	polyubiquitination	up-regulates activity	0.333	In this study, we report that in addition to RIP1 and RIP2, also RIP3 and RIP4 directly interact with XIAP, cIAP1 and cIAP2. When comparing the ability of these IAPs to directly conjugate RIP1–RIP4 with ubiquitin chains, we found that cIAP1 was the most effective E3 and was capable of ubiquitinating all four RIPs in the presence of the E2 component UbcH5a. On the contrary, XIAP was only capable of inducing weak ubiquitination of RIP4.	SIGNOR-272716
Q13562	Q02779	binding	up-regulates activity	0.333	we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2	SIGNOR-234599
O00429	Q14012	phosphorylation	up-regulates activity	0.333	For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission	SIGNOR-262552
Q00839	Q9UHD9	binding	up-regulates quantity by stabilization	0.333	Confirmation of binding of recombinant full-length hnRNPA1 and hnRNPU proteins with ubiquilin-2 by GST-pull-down assays\|Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein	SIGNOR-262271
P10070	Q8N752	phosphorylation	up-regulates	0.333	Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed	SIGNOR-179972
P10071	Q8N752	phosphorylation	up-regulates	0.333	Ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed	SIGNOR-144554
O75581	O94921	phosphorylation	up-regulates	0.333	Low-density lipoprotein receptor related proteins 5 and 6 (lrp5/6) are transmembrane receptors that initiate wnt/beta-catenin signaling. Phosphorylation of pppsp motifs in the lrp6 cytoplasmic domain is crucial for signal transduction. Using a kinome-wide rnai screen, we show that pppsp phosphorylation requires the drosophila cyclin-dependent kinase (cdk) l63. L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6.	SIGNOR-162924
Q13541	P19784	phosphorylation	down-regulates activity	0.333	The kinase is quite distinct from casein kinase 2, which also phosphorylates Ser-111 of 4E-BP1. The possible importance of these kinases in the phosphorylation of 4E-BP1 in fat cells is discussed. It is suggested that the phosphorylation of Ser-111 might be a priming event that facilitates the subsequent phosphorylation of Thr-36, Thr-45, Ser-64 and Thr69 by a rapamycin-sensitive process that initiates the dissociation of 4E-BP1 from eIF4E and hence the formation of the eIF4F complex.	SIGNOR-249334
P08247	Q05193	binding	up-regulates activity	0.333	The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling.	SIGNOR-264119
P51532	Q96EP1	polyubiquitination	down-regulates quantity by destabilization	0.333	Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination.	SIGNOR-271457
P08238	P68400	phosphorylation	down-regulates	0.333	Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation.	SIGNOR-179264
P46527	Q00536	phosphorylation	down-regulates quantity by destabilization	0.333	In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells.\|Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target.	SIGNOR-273016
P10636	P07384	cleavage	down-regulates activity	0.333	Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains	SIGNOR-251584
P78527	P09629	binding	up-regulates activity	0.333	Ku70 and Ku80 associated with HOXB7 in vivo. Ku70/Ku80 heterodimer formation is a prerequisite for HOXB7 binding. interaction between Ku70/80 and HOXB7 may affect the catalytic activity of DNA-PK. HOXB7 stimulates DNA-PK activity	SIGNOR-226063
P06493	Q9Y5B0	dephosphorylation	down-regulates activity	0.333	Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.\|We can not exclude that, in addition to S90 and S453, other Cdk1 phosphorylation sites in Gwl are dephosphorylated by Fcp1; nevertheless, assaying S67-Ensa kinase activity of V5-GwlS90A and V5-GwlS453A mutant proteins, isolated from transfected and prometaphase arrested HeLa cells, revealed that both mutants had significantly reduced S67-Ensa kinase activity compared to V5-GwlWT (XREF_FIG).\|We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells.	SIGNOR-277141

Q06187

P00519

0

phosphorylation

down-regulates activity

0.336

In this report we describe for the first time that ABL1 and Btk physically interact and that ABL1 can phosphorylate tyrosine 223 in the SH3 domain of Btk. | This is presumably due to the negative regulatory effectof Btk SH3 domain phosphorylation caused by ABL1,which would result in a decreased catalytic activity ofBtk resulting in impaired autophosphorylation.

SIGNOR-260801

Q8IX03

Q15418

0

phosphorylation

up-regulates

0.335

Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2.

SIGNOR-203298

P07951

P48736

0

phosphorylation

up-regulates activity

0.335

Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization.

SIGNOR-263028

P12814

P18031

0

dephosphorylation

up-regulates

0.335

Here we report that protein-tyrosine phosphatase 1b (ptp 1b) is an ?-Actinin phosphatase.

SIGNOR-141634

Q00536

Q00535

0

phosphorylation

up-regulates activity

0.335

Taken together, our findings demonstrate that Pctaire1 interacts with p35, both in vitro and in vivo, and that phosphorylation of Pctaire1 by Cdk5 enhances its kinase activity.

SIGNOR-279149

Q92934

Q13153

0

phosphorylation

down-regulates

0.335

Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau.

SIGNOR-73533

P49427

Q15418

0

phosphorylation

down-regulates quantity by destabilization

0.335

RSK1 phosphorylated Thr162 on UBE2R1.RSK1 induced self-ubiquitination and destabilisation of UBE2R1 by phosphorylation.

SIGNOR-277330

P55283

P07737

0

null

up-regulates activity

0.335

Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation.

SIGNOR-253111

P60484

Q9H4B4

0

phosphorylation

down-regulates activity

0.335

Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis

SIGNOR-168473

Q00613

Q9H422

0

phosphorylation

up-regulates activity

0.335

We show that Yak1 directly phosphorylates Hsf1 in vitro, leading to the increase in DNA binding activity of Hsf1.

SIGNOR-279054

O43639

Q16620

0

binding

up-regulates

0.335

We identified the nck2 adaptor protein as a novel interaction partner of the active form of trkb. Additionally, we identified three tyrosines in icd-trkb (y694, y695, and y771) that are crucial for this interaction.

SIGNOR-89764

P09917

P17612

0

phosphorylation

down-regulates activity

0.335

These results indicate that PKA phosphorylates 5-LO on Ser-523, which inhibits the catalytic activity of 5-LO and reduces cellular LT generation.

SIGNOR-264410

Q08345

P02452

0

binding

up-regulates activity

0.335

The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.

SIGNOR-272340

Q9UBP6

P31749

0

phosphorylation

down-regulates

0.335

The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells

SIGNOR-24994

P04637

Q92481

0

binding

up-regulates quantity by stabilization

0.335

These data suggest that AP-2Œ≤ enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2Œ≤ interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2Œ≤ up-regulates the transcription of the CRYAB gene through stabilizing p53.

SIGNOR-255422

P17844

P17252

0

phosphorylation

down-regulates activity

0.335

We report that p68 is phosphorylated by protein kinase C in vitro and binds calmodulin in a Ca(2+)-dependent manner. Both phosphorylation and calmodulin binding inhibited p68 ATPase activity | In addition, a 20-amino acid peptide corresponding to residues 549-568 of p68 was phosphorylated in a Ca- and phospholipid-dependent manner hy PKC

SIGNOR-248896

P19086

P30542

0

binding

up-regulates activity

0.335

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

SIGNOR-257092

Q9UGP5

P24941

0

phosphorylation

up-regulates quantity by stabilization

0.335

Phosphorylation of DNA polymerase λ is required to maintain its stability. Recently, we identified Pol lambda as an interaction partner of cyclin-dependent kinase 2 (CDK2) that is central to the cell cycle G1/S transition and S-phase progression. Experiments with phosphorylation-defective mutants suggest that phosphorylation of Thr 553 is important for maintaining Pol lambda stability, as it is targeted to the proteasomal degradation pathway through ubiquitination unless this residue is phosphorylated.

SIGNOR-276169

P51813

Q06187

0

phosphorylation

up-regulates

0.335

Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism.

SIGNOR-98028

P30519

P68400

0

phosphorylation

up-regulates activity

0.335

Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. | CK2 activation is abolished by the S79A mutation but preserved in S179A and T248A mutations, indicating that S79 is the target of CK2-dependent activation of HO2

SIGNOR-250895

Q14938

P55317

0

binding

up-regulates

0.335

Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex.

SIGNOR-205082

O15126

P00533

0

phosphorylation

up-regulates activity

0.335

In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation

SIGNOR-262857

P33993

P60228

0

binding

up-regulates quantity by stabilization

0.335

Our data show that INT6 interacts with a C-terminal domain of MCM7. Collectively, our observations suggest that INT6 restrains the increased degradation of MCM7 occurring during DNA replication by protecting its polyubiquitylated derivatives from the proteasome activity.

SIGNOR-259154

Q9UQ13

P27361

0

phosphorylation

down-regulates quantity by destabilization

0.335

Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation.

SIGNOR-277443

P06493

P22674

0

binding

up-regulates activity

0.335

CDK2 is the predominant activating complex form of CCNO, but CCNO can bind to CDK1 to form an activating complex in the absence of CDK2.

SIGNOR-275617

Q9H2D6

P53350

0

phosphorylation

up-regulates

0.335

Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1

SIGNOR-198353

Q12800

P28482

0

phosphorylation

down-regulates

0.335

We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309.

SIGNOR-184168

O75955

P12931

0

phosphorylation

up-regulates activity

0.335

Taken together, we conclude that mitochondrial c-Src phosphorylates flotillin-1 at Tyr56 and Tyr149, and that these phosphorylations are required for its interaction with CxII and the prevention of ROS production.

SIGNOR-273805

P21127

P50613

0

phosphorylation

up-regulates activity

0.335

We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase

SIGNOR-245871

P08908

Q5T0F9

0

transcriptional regulation

down-regulates quantity by repression

0.335

Human Freud-2/CC2D1B: a novel repressor of postsynaptic serotonin-1A receptor expression|Human Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter in human HEK-293 5-HT1A-negative cells and neuronal SK-N-SH cells, a model of postsynaptic 5-HT1A receptor-positive cells.

SIGNOR-268298

O60763

P67870

0

phosphorylation

up-regulates activity

0.335

Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. | Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae

SIGNOR-251082

Q02750

Q16584

0

phosphorylation

up-regulates activity

0.335

Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells.

SIGNOR-280019

Q13887

Q05655

0

phosphorylation

up-regulates activity

0.335

Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the CBP interaction region enhances its transactivation function. | Inhibition of protein kinase activity by H7 or calphostin C blocked both full-length and N-terminal fragment (amino acids 1-238) KLF5 activities. Mutation at a potential protein kinase C phosphorylation site within the CBP interaction domain of KLF5 reduces its transactivation function. Furthermore, using the GST pull-down approach, we showed that phosphorylation of KLF5 enhances its interaction with CBP. The results of the present study provide a mechanism for KLF5 transactivation function. | We found that KLF5s activity was reduced to half when the serine in the potential PKC phosphorylation site was mutated to alanine (Fig. 6B, S153A) Nonetheless, the S153A mutant still retains significant transactivation activity.

SIGNOR-249206

P14672

P04637

0

transcriptional regulation

down-regulates quantity by repression

0.335

P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.

SIGNOR-267465

P49675

P49715

0

transcriptional regulation

up-regulates quantity by expression

0.335

Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.

SIGNOR-254043

P05106

Q99704

0

binding

down-regulates activity

0.334

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

SIGNOR-257687

Q8NHW3

P28482

0

phosphorylation

up-regulates activity

0.334

These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription.

SIGNOR-108564

Q01082

P68400

0

phosphorylation

down-regulates

0.334

We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment.

SIGNOR-150471

P40189

Q05655

0

phosphorylation

up-regulates activity

0.334

Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling.

SIGNOR-249177

P08151

Q13131

0

phosphorylation

down-regulates activity

0.334

AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.

SIGNOR-259862

O43665

P17612

0

phosphorylation

down-regulates activity

0.334

We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel.

SIGNOR-109173

Q15554

P31943

0

post transcriptional regulation

down-regulates quantity

0.334

During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels.

SIGNOR-266807

P10415

Q16539

0

phosphorylation

down-regulates activity

0.334

Bcl-2 phosphorylation by p38 mapkin this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, ser(87) and thr(56) as the bcl-2 residues phosphorylated by p38 mapk and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of bcl-2 protein.

SIGNOR-146786

P28356

P09429

0

binding

up-regulates activity

0.334

We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.

SIGNOR-236956

O15392

Q16254

0

transcriptional regulation

down-regulates quantity by repression

0.334

This TGF-beta response is triggered through a Smad2/3-dependent hypophosphorylation of Rb and the subsequent association of the Rb/E2F4 repressive complex to CDE/CHR elements in the proximal region of the survivin promoter.

SIGNOR-271678

O00418

Q16539

0

phosphorylation

down-regulates activity

0.334

Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%.

SIGNOR-249707

P54253

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.334

NICD and MDM2 ubiquitinate and degrade ATXN1.|These results suggest that NICD and MDM2 synergistically reduce ATXN1 expression at the posttranscriptional level.

SIGNOR-278823

P01106

Q8TEK3

0

binding

up-regulates activity

0.334

Our data suggest that the c-Myc-dependent transcriptional switch is modulated by DOT1L, as in the presence of DOT1L c-Myc preferentially forms an active complex with p300 rather than a repressive complex containing HDAC1 and DNMT1

SIGNOR-239362

Q9GZR7

Q00987

0

polyubiquitination

up-regulates activity

0.334

MDM2 mediates nonproteolytic polyubiquitylation of the DEAD-Box RNA helicase DDX24. Unexpectedly, however, the polyubiquitylation of DDX24 did not elicit its proteasomal degradation but rather promoted its association with preribosomal ribonucleoprotein (pre-rRNP) processing complexes that are required for the early steps of pre-rRNA processing.

SIGNOR-272845

Q9UM73

P23467

0

dephosphorylation

down-regulates

0.334

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

SIGNOR-157175

P19086

P55085

0

binding

up-regulates activity

0.334

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

SIGNOR-257232

P23760

P49841

0

phosphorylation

up-regulates quantity

0.334

The ubiquitously expressed CK2 often provides the priming phosphorylation for GSK-3, however, we found that GSK-3beta alone was sufficient to phosphorylate PAX3 at both Ser205 and Ser197 and Ser201 in-vitro.

SIGNOR-278482

Q9Y385

P49137

0

phosphorylation

down-regulates quantity by destabilization

0.334

Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production. These findings strongly suggest that MK2 directly phosphorylates Ube2j1 at Ser(184) upon p38-activating stress in vivo.

SIGNOR-263091

Q15858

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.334

The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).

SIGNOR-253458

P49757

Q14012

0

phosphorylation

down-regulates

0.334

Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2.

SIGNOR-149993

P00533

Q15759

0

phosphorylation

down-regulates

0.334

P38 map kinase mediates stress-induced internalization of egfrthe underlying mechanism entails phosphorylation of egfr at a short segment (amino acids 1002-1022) containing multiple serines and threonines, as well as phosphorylation of two rab5 effectors, eea1 and gdi.

SIGNOR-149086

Q8TDI8

O75838

0

binding

up-regulates activity

0.334

Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia.

SIGNOR-269664

P17600

O75914

0

phosphorylation

up-regulates activity

0.334

Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release

SIGNOR-250246

O75475

O00311

0

phosphorylation

up-regulates

0.334

We now report identification of the cdc7-activator of s-phase kinase (ask) heterodimer as a novel interactor of ledgf. the kinase phosphorylated ledgf in vitro, with ser-206 being the major target, and ledgf phosphorylated at this residue could be detected during s phase of the cell cycle. Ledgf potently stimulated the enzymatic activity of cdc7-ask, increasing phosphorylation of mcm2 in vitro by more than 10-fold.

SIGNOR-25763

O43255

P12931

0

phosphorylation

up-regulates activity

0.334

In human breast cancer cell lines, the protein kinase Src has been shown to activate Siah2 by phosphorylation of tyrosines 86, 140, and 263.|This function is promoted by Src phosphorylation of Siah2, which increases C/EBPdelta binding, ubiquitination, and degradation.

SIGNOR-279555

P47712

Q8IW41

0

phosphorylation

up-regulates activity

0.334

The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells.

SIGNOR-250162

O14921

P17612

0

phosphorylation

up-regulates quantity by stabilization

0.334

Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry.

SIGNOR-259835

O75807

P07948

0

phosphorylation

up-regulates

0.334

Gadd34 was tyrosine-phosphorylated in vivo in a lyn-dependent manner.

SIGNOR-109934

P51813

Q08881

0

phosphorylation

up-regulates activity

0.334

Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.

SIGNOR-251331

O15304

P42684

0

phosphorylation

up-regulates

0.334

Our results also demonstrate that mutation of the siva-1 tyr48 site abrogates the apoptotic function of siva-1 and that apoptosis induced by siva-1 is dependent on expression of kinase-active arg.

SIGNOR-104992

P32942

Q04759

0

phosphorylation

up-regulates activity

0.334

Ser489 was a phosphorylation site in vitro for recombinant protein kinase Ctheta. Finally, treatment of Jurkat cells with chelerythrine chloride, a protein kinase C inhibitor, prevented ICAM-3-triggered spreading.

SIGNOR-248979

P10276

Q8IZD2

0

binding

up-regulates activity

0.334

MLL5 binds to retinoic acid receptor α (RARα) and induces transcriptional activation of RARα target genes by methylation of lysine residues of histone H3.

SIGNOR-260041

Q13501

Q12981

0

binding

up-regulates activity

0.334

RNF185 functions as a ubiquitin E3 ligase, enabling BNIP1-p62 interaction. BNIP1 is polyubiquitinated by RNF185 and associates with autophagy receptor p62. In addition, we checked the endogenous localization of BNIP1 and p62 in HeLa cells (Fig. 7F). Alexa Fluor 488 conjugated endogenous BNIP1 and TRITIC conjugated endogenous p62 overlapped well in the cytoplasm, further providing the locational evidence for the recruitment of p62 by BNIP1.

SIGNOR-271932

P31749

P41134

0

binding

up-regulates

0.334

We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation;

SIGNOR-255658

O43918

Q9UER7

0

binding

down-regulates activity

0.334

The interaction between AIRE and DAXX has been validated by in vivo coimmunoprecipitation analysis and colocalization study in mammalian cells. The interaction has been further confirmed by showing in transactivation assays that DAXX exerts a strong repressive role on the transcriptional activity of AIRE.

SIGNOR-239287

Q12778

O15021

0

phosphorylation

down-regulates activity

0.334

MAST4 phosphorylation of FOXO1 regulates RTKN2 expression.

SIGNOR-279079

Q04912

P00533

0

phosphorylation

up-regulates activity

0.334

This showed that EGFR activation transphosphorylated Ron.|Together, these data suggested that (1) Ron activation transphosphorylated EGFR and vice versa and (2) activated Ron biochemically interacted with EGFR.

SIGNOR-280000

Q9UEY8

P17252

0

phosphorylation

down-regulates quantity by destabilization

0.334

Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. | Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. | The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin

SIGNOR-249143

P23528

Q15139

0

phosphorylation

down-regulates activity

0.334

PKD1 regulates cofilin S3-phosphorylation|Both, oxidative stress as well as RhoA activation enhanced cofilin phosphorylation at S3, implicating an increased inhibition due to PKD1-mediated signalling events

SIGNOR-275944

P06744

P68400

0

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

P30304

P48729

0

phosphorylation

down-regulates

0.333

Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a

SIGNOR-164734

P12004

P00519

0

phosphorylation

up-regulates activity

0.333

In the current study, we are able to establish a new pathway in which the Ron receptor tyrosine kinase activates c-Abl which in turn catalyzes Y211 phosphorylation of PCNA.|We previously showed that Y211 phosphorylation stabilized chromatin bound PCNA, which in turn promoted cell proliferation, and that c-Abl functioned to enhance chromatin association of PCNA in cancer cells.

SIGNOR-279389

O14640

P46937

0

binding

down-regulates

0.333

Yap restricts elevated wnt independently of the axinapcgsk-3beta complex partly by limiting the activity of dishevelled (dvl).

SIGNOR-199806

Q13315

P67775

0

dephosphorylation

down-regulates activity

0.333

Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro.

SIGNOR-248644

Q8IWB6

P06493

0

phosphorylation

down-regulates quantity by destabilization

0.333

Cdk1 phosphorylation of Tex14 is required for the Tex14-Plk1 interaction

SIGNOR-273524

Q15417

P06241

0

phosphorylation

down-regulates activity

0.333

We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin

SIGNOR-251159

P53041

P48730

0

phosphorylation

up-regulates activity

0.333

Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90.

SIGNOR-277373

O15169

P62136

0

dephosphorylation

down-regulates activity

0.333

The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated

SIGNOR-248551

Q9UJA2

Q8NCQ5

0

binding

down-regulates quantity by destabilization

0.333

Fbxo15 Targets CLS1 Protein for Ubiquitination and Degradation to Disrupt Mitochondrial Function. S. aureus infection induces expression of a kinase, PINK1, that phosphorylates an indispensable protein CLS1, which in turn triggers CLS1 ubiquitination and degradation by the F box protein (SCFFbxo15).

SIGNOR-272170

Q9NRF2

P48357

0

binding

up-regulates activity

0.333

The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex

SIGNOR-253077

P57078

P98170

0

polyubiquitination

up-regulates activity

0.333

In this study, we report that in addition to RIP1 and RIP2, also RIP3 and RIP4 directly interact with XIAP, cIAP1 and cIAP2. When comparing the ability of these IAPs to directly conjugate RIP1–RIP4 with ubiquitin chains, we found that cIAP1 was the most effective E3 and was capable of ubiquitinating all four RIPs in the presence of the E2 component UbcH5a. On the contrary, XIAP was only capable of inducing weak ubiquitination of RIP4.

SIGNOR-272716

Q13562

Q02779

0

binding

up-regulates activity

0.333

we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2

SIGNOR-234599

O00429

Q14012

0

phosphorylation

up-regulates activity

0.333

For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission

SIGNOR-262552

Q00839

Q9UHD9

0

binding

up-regulates quantity by stabilization

0.333

Confirmation of binding of recombinant full-length hnRNPA1 and hnRNPU proteins with ubiquilin-2 by GST-pull-down assays|Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein

SIGNOR-262271

P10070

Q8N752

0

phosphorylation

up-regulates

0.333

Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed

SIGNOR-179972

P10071

Q8N752

0

phosphorylation

up-regulates

0.333

Ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed

SIGNOR-144554

O75581

O94921

0

phosphorylation

up-regulates

0.333

Low-density lipoprotein receptor related proteins 5 and 6 (lrp5/6) are transmembrane receptors that initiate wnt/beta-catenin signaling. Phosphorylation of pppsp motifs in the lrp6 cytoplasmic domain is crucial for signal transduction. Using a kinome-wide rnai screen, we show that pppsp phosphorylation requires the drosophila cyclin-dependent kinase (cdk) l63. L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6.

SIGNOR-162924

Q13541

P19784

0

phosphorylation

down-regulates activity

0.333

The kinase is quite distinct from casein kinase 2, which also phosphorylates Ser-111 of 4E-BP1. The possible importance of these kinases in the phosphorylation of 4E-BP1 in fat cells is discussed. It is suggested that the phosphorylation of Ser-111 might be a priming event that facilitates the subsequent phosphorylation of Thr-36, Thr-45, Ser-64 and Thr69 by a rapamycin-sensitive process that initiates the dissociation of 4E-BP1 from eIF4E and hence the formation of the eIF4F complex.

SIGNOR-249334

P08247

Q05193

0

binding

up-regulates activity

0.333

The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling.

SIGNOR-264119

P51532

Q96EP1

0

polyubiquitination

down-regulates quantity by destabilization

0.333

Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination.

SIGNOR-271457

P08238

P68400

0

phosphorylation

down-regulates

0.333

Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation.

SIGNOR-179264

P46527

Q00536

0

phosphorylation

down-regulates quantity by destabilization

0.333

In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells.|Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target.

SIGNOR-273016

P10636

P07384

0

cleavage

down-regulates activity

0.333

Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains

SIGNOR-251584

P78527

P09629

0

binding

up-regulates activity

0.333

Ku70 and Ku80 associated with HOXB7 in vivo. Ku70/Ku80 heterodimer formation is a prerequisite for HOXB7 binding. interaction between Ku70/80 and HOXB7 may affect the catalytic activity of DNA-PK. HOXB7 stimulates DNA-PK activity

SIGNOR-226063

P06493

Q9Y5B0

0

dephosphorylation

down-regulates activity

0.333

Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.|We can not exclude that, in addition to S90 and S453, other Cdk1 phosphorylation sites in Gwl are dephosphorylated by Fcp1; nevertheless, assaying S67-Ensa kinase activity of V5-GwlS90A and V5-GwlS453A mutant proteins, isolated from transfected and prometaphase arrested HeLa cells, revealed that both mutants had significantly reduced S67-Ensa kinase activity compared to V5-GwlWT (XREF_FIG).|We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells.

SIGNOR-277141