GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P16615	P45984	0	phosphorylation	up-regulates activity	0.2	JNK2 Enhances SERCA2 Function in a CaMKII-Independent Manner..\|We found that JNK2 and SERCA2 proteins are physically associated with each other, and that JNK2 directly elevates the maximal rate of the SERCA2 activity by phosphorylating SERCA2.	SIGNOR-279540
P28482	Q9BYB0	1	phosphorylation	down-regulates activity	0.2	Interestingly, we discovered that several kinases in the MEK and ERK2 pathway destabilize Shank3 and that genetic deletion and pharmacological inhibition of ERK2 increases Shank3 abundance in vivo.\|We also determined that phosphorylation of Shank3 by ERK2 at selective residues promotes its ubiquitination and degradation.	SIGNOR-279538
P46459	Q00536	0	phosphorylation	down-regulates activity	0.439	Moreover, inhibition of Pctaire1 activity by transfecting its kinase-dead (KD) mutant into COS-7 cells enhances the self association of NSF.\|We demonstrate that the D2 domain of NSF, which is required for the oligomerization of NSF subunits, binds directly to and is phosphorylated by Pctaire1 on serine 569.	SIGNOR-279511
P31749	O60285	1	phosphorylation	up-regulates	0.262	Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity.	SIGNOR-252591
Q05513	P31751	1	phosphorylation	up-regulates activity	0.498	The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells.	SIGNOR-248997
O75822	P68400	0	phosphorylation	up-regulates activity	0.326	CK2 phosphorylates the eIF3j subunit at Ser127. CK2-phosphorylation of eIF3j triggers its association with the eIF3 complex.	SIGNOR-266402
P68431	O14965	0	phosphorylation	up-regulates activity	0.2	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-98289
P17612	Q13972	1	phosphorylation	up-regulates	0.519	Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors.	SIGNOR-73202
P04049	P67775	0	dephosphorylation	up-regulates	0.592	Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1.	SIGNOR-141170
P67775	P28482	1	dephosphorylation	down-regulates activity	0.621	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).Mapk activity is tightly regulated by phosphorylation and dephosphorylation. The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase	SIGNOR-103159
P25963	O15111	0	phosphorylation	down-regulates quantity by destabilization	0.896	We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation	SIGNOR-52875
P14373	A8K0Z3	1	ubiquitination	up-regulates activity	0.2	Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport.	SIGNOR-253514
P51451	Q8N884	1	phosphorylation	down-regulates activity	0.2	DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS.	SIGNOR-275844
P63000	Q8IVF5	0	guanine nucleotide exchange factor	up-regulates activity	0.589	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-260578
P35241	P61586	0	phosphorylation	up-regulates activity	0.47	Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies.	SIGNOR-268430
P41162	P28482	0	phosphorylation	down-regulates activity	0.403	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. Among the ERK2 substrates, we identified the E-twenty six (ETS) domain-containing protein ETV3. We determined that phosphorylation of this protein by ERK2 was functionally relevant, abrogating the DNA-binding activity of ETV3 at thousands of targets across the genome, thereby providing an additional mechanism for transcriptional regulation downstream of ERK2 activation.	SIGNOR-262758
P45985	O15264	1	phosphorylation	up-regulates activity	0.459	p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273956
P04275	O00327	0	transcriptional regulation	down-regulates quantity by repression	0.324	We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype.	SIGNOR-253704
Q86VW2	P63000	1	guanine nucleotide exchange factor	up-regulates	0.622	Exogenous expression of geft promotes myogenesis ofc2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process.	SIGNOR-236882
Q9BWT1	P31749	0	phosphorylation	down-regulates	0.338	The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus.	SIGNOR-252533
P49841	P17947	1	phosphorylation	down-regulates quantity by destabilization	0.2	We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7.	SIGNOR-277541
Q9Y243	P49841	1	phosphorylation	down-regulates activity	0.736	Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1	SIGNOR-245424
Q9UNE7	Q8IVS8	1	ubiquitination	down-regulates quantity by destabilization	0.2	Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. ERK1 phosphorylates GLYCTK2 at S220 to promotes its stability	SIGNOR-280258
P11940	Q13064	0	ubiquitination	down-regulates activity	0.2	MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA\|Altogether, it is thus clear that the ubiquitination of PABPC1 or PABPC4 by MKRN3 negatively regulates the formation of translation initiation complex (TIC), attenuates their binding to poly (A)-tail contained mRNAs, and leads to the shortened poly (A) tail-length of GNRH1 mRNA.	SIGNOR-278764
Q9BTC0	P08648	1	transcriptional regulation	up-regulates quantity by expression	0.2	Dido1 upregulates the expression of Integrin αV, thereby influencing the attachment, apoptosis and migration of melanoma cells.	SIGNOR-261580
Q14847	P12931	0	phosphorylation	up-regulates activity	0.253	Integrin-dependent translocation of LASP-1 to the cytoskeleton of activated platelets correlates with LASP-1 phosphorylation at tyrosine 171 by Src-kinase	SIGNOR-271706
Q9BYB0	P28482	0	phosphorylation	down-regulates activity	0.2	Interestingly, we discovered that several kinases in the MEK and ERK2 pathway destabilize Shank3 and that genetic deletion and pharmacological inhibition of ERK2 increases Shank3 abundance in vivo.\|We also determined that phosphorylation of Shank3 by ERK2 at selective residues promotes its ubiquitination and degradation.	SIGNOR-279538
O14936	Q00535	0	phosphorylation	up-regulates activity	0.288	Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK.\|We found that Cdk5 phosphorylates and regulates CASK distribution to membranes.	SIGNOR-280216
P06127	P17252	0	phosphorylation	up-regulates	0.339	Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation.	SIGNOR-85179
Q5S007	P10415	1	phosphorylation	up-regulates activity	0.329	Thus, we propose that Thr56 phosphorylation of Bcl-2 by LRRK2 G2019S might be a crucial step of mitochondrial disorder, which initiates the subsequent cellular damage in the context of PD relevant to G2019S.\|We found that LRRK2 G2019S induced loss of the MMP was recovered in both GFP-Bcl-2 and GFP-M-Bcl-2 stable cells (XREF_FIG -lower panel).	SIGNOR-279531
Q15418	O94822	0	ubiquitination	down-regulates activity	0.2	Ltn1 ubiquitylation of RSK1, RSK2, and TWY3 could either result in degradation or impart a regulatory function on target proteins distinct from degradation.	SIGNOR-278757
Q9H6Z9	P14618	1	hydroxylation	up-regulates activity	0.436	Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.	SIGNOR-267476
P53350	Q9Y2I6	1	phosphorylation	down-regulates activity	0.7	Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction	SIGNOR-103356
P48730	P10636	1	phosphorylation	down-regulates	0.374	Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells.	SIGNOR-121717
P28482	Q86U44	1	phosphorylation	up-regulates quantity by stabilization	0.273	Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265948
P46821	P49841	0	phosphorylation	down-regulates activity	0.527	GSK-3beta phosphorylates MAP1B and the adenomatous polyposis coil gene product (APC; Grimes and Jope 2001; Frame and Cohen 2001). The phosphorylation of MAP1B by GSK-3beta suppresses detyrosination of microtubules and decreases the numbers of stable microtubules	SIGNOR-264843
Q12933	P67775	0	dephosphorylation	down-regulates activity	0.2	We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity.	SIGNOR-248640
P03951	P14210	1	cleavage	up-regulates activity	0.313	the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain.	SIGNOR-256515
P56178	P31749	0	phosphorylation	up-regulates	0.264	Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5.	SIGNOR-252513
O75807	P07948	0	phosphorylation	up-regulates	0.334	Gadd34 was tyrosine-phosphorylated in vivo in a lyn-dependent manner.	SIGNOR-109934
P11309	P36888	1	phosphorylation	up-regulates quantity	0.42	Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway.	SIGNOR-259927
O14965	Q96CX2	1	phosphorylation	up-regulates activity	0.272	In addition, Aurora A phosphorylated KCTD12 at serine 243, thereby initiating a positive feedback loop necessary for KCTD12 to exert its cancer-promoting effects.	SIGNOR-273544
P49841	P35568	1	phosphorylation	down-regulates quantity by destabilization	0.454	HG activates GSK3beta, which phosphorylates IRS1 at serine 332, leading to the ubiquitination and proteasome mediated degradation of IRS1.	SIGNOR-279183
Q08999	P67775	0	dephosphorylation	up-regulates	0.581	Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation.	SIGNOR-129752
P78527	P31749	1	phosphorylation	up-regulates activity	0.754	DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform	SIGNOR-252431
Q92834	P61006	1	guanine nucleotide exchange factor	up-regulates activity	0.427	PGR interacts with the small GTPase RAB8A, which participates in cilia biogenesis and maintenance. We show that RPGR primarily associates with the GDP-bound form of RAB8A and stimulates GDP/GTP nucleotide exchange. RPGR functions as a GEF for RAB8A and RPGR–RAB8A association may facilitate ciliary trafficking.	SIGNOR-253030
Q92769	Q96KB5	0	phosphorylation	up-regulates activity	0.2	The results of in vitro studies further confirmed the effect of TOPK on HDAC activity by showing that TOPK overexpression significantly up-regulated p-HDAC1 and p-HDAC2, resulting in an increase in the acetylation of histones H3 and H4 in BV2 cells.\|These results indicated that TOPK overexpression resulted in the phosphorylation of HDAC1 and HDAC2, which might inactivate them and promote the acetylation of Histone 3 and Histone 4.	SIGNOR-279087
Q13882	P78357	1	phosphorylation	up-regulates activity	0.2	As a consequence, Brk stimulates p190 and attenuates p120 functions, leading to RhoA inactivation and Ras activation, respectively.\|Brk phosphorylates p190 at the Y (1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120RasGAP (p120).	SIGNOR-279274
P24941	Q8IXJ6	1	phosphorylation	down-regulates	0.395	We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2.	SIGNOR-177972
Q8N0W4	P78352	1	relocalization	up-regulates activity	0.754	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264192
Q12857	Q14393	1	transcriptional regulation	down-regulates quantity	0.2	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268876
O96006	P62753	1	transcriptional regulation	up-regulates quantity by expression	0.2	HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. \| Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid.	SIGNOR-266082
Q13261	P23458	1	null	up-regulates	0.462	Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256227
Q9HBH9	Q16539	0	phosphorylation	up-regulates	0.415	Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity	SIGNOR-48349
P29692	Q13683	1	transcriptional regulation	down-regulates quantity by repression	0.2	alpha7 Integrin Expression Is Negatively Regulated by deltaEF1 during Skeletal Myogenesis	SIGNOR-241773
P33981	Q13257	1	phosphorylation	up-regulates activity	0.713	Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.\|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2.	SIGNOR-252036
Q99814	P27361	0	phosphorylation	up-regulates quantity by stabilization	0.26	The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells.	SIGNOR-277584
Q9BRP0	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.2	In breast cancer cells, MDM2 overexpression or p53 KD reduced OVOL2 protein expression, and the proteasome inhibitor MG132 blocked the MDM2 overexpression\u2010 or p53 KD\u2010mediated reduction in OVOL2 expression (Figure\u00a06B,C).\|The E3 ubiquitin ligase MDM2 ubiquitinates and degrades the OVOL2 protein.	SIGNOR-278826
P60953	Q15811	0	guanine nucleotide exchange factor	up-regulates activity	0.848	Significantly, here we identify the long isoform of ITSN-1, which has Cdc42 GEF activity\| We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A).	SIGNOR-260612
Q9H334	P07333	1	transcriptional regulation	down-regulates quantity by repression	0.296	Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation.	SIGNOR-269048
Q01538	Q02750	0	phosphorylation	down-regulates activity	0.261	Altogether our findings reveal that Myt1 is inactivated by MEK1 mediated phosphorylation to fragment the Golgi complex in G2 and for the entry of cells into mitosis.\|MEK1 inactivates Myt1 to regulate Golgi membrane fragmentation and mitotic entry in mammalian cells.	SIGNOR-279052
P00533	Q9ULV8	0	polyubiquitination	down-regulates quantity by destabilization	0.761	In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.	SIGNOR-272605
O43255	P55036	1	polyubiquitination	down-regulates quantity by destabilization	0.432	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s.	SIGNOR-272748
Q14680	Q15831	0	phosphorylation	up-regulates	0.2	Site-directed mutagenesis indicated that thr167 and ser171, located between the dfg and ape motifs in the activation loop or t-loop, need to be autophosphorylated for melk to be active as a protein kinase (fig. 5). These sites are conserved in all other ampk-related protein kinases (fig. 4a), and the site corresponding to thr167 has been shown to be phosphorylated by protein kinase lkb1 (5).	SIGNOR-141038
P24928	P27361	0	phosphorylation	down-regulates	0.316	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120176
Q05209	Q05397	1	dephosphorylation	down-regulates activity	0.538	We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.\| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis.	SIGNOR-248661
P11309	P39019	1	phosphorylation	up-regulates	0.438	The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay.	SIGNOR-141411
P62136	P24941	0	phosphorylation	down-regulates activity	0.377	Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity	SIGNOR-92265
Q15382	Q8IW41	0	phosphorylation	down-regulates activity	0.401	Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation.	SIGNOR-276313
P18031	Q05397	1	dephosphorylation	down-regulates activity	0.346	The focal adhesion kinase (FAK) is a key regulator of cell migration. Phosphorylation at Tyr-397 activates FAK \|The dephosphorylation at Tyr-397 in FAK triggered by wild-type alpha-actinin and PTP 1B caused a significant increase in cell migration.	SIGNOR-248431
Q9H4P4	O60260	1	polyubiquitination	down-regulates quantity by destabilization	0.2	Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner. More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate.	SIGNOR-272639
P35575	P16220	0	transcriptional regulation	up-regulates quantity	0.2	Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-256105
P12931	Q68CZ2	1	phosphorylation	up-regulates	0.408	Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate	SIGNOR-187843
P17252	Q92793	1	phosphorylation	down-regulates	0.261	The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex,	SIGNOR-166368
O15111	Q9Y261	1	phosphorylation	down-regulates	0.2	Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression	SIGNOR-195316
Q9UPG8	Q09472	0	acetylation	up-regulates	0.2	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140947
P29350	P00533	1	dephosphorylation	down-regulates	0.415	The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation.	SIGNOR-59965
O14965	Q9UNN5	1	phosphorylation	down-regulates activity	0.2	This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1	SIGNOR-180891
Q13426	O14647	0	relocalization	up-regulates quantity	0.2	CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs.	SIGNOR-264528
P06239	P10586	0	dephosphorylation	up-regulates	0.364	We confirmed that lar dephosphorylated the phosphorylated tyrosine residues of lck..Activation Of lck and fyn involves tyrosine dephosphorylation of the cooh-terminal regulatory domain of kinases, followed by autophosphorylation of the kinase domain.	SIGNOR-96771
P10415	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.2	A previous study has demonstrated that GSK3B triggers the degradation of BCL2 by inducing phosphorylation of BCL2 at Ser70, which induced autophagy by interrupting the interaction between BECN1 and BCL2 [32].	SIGNOR-279784
Q16552	P51449	0	transcriptional regulation	up-regulates	0.54	We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells	SIGNOR-255029
Q5T0T0	P13762	1	polyubiquitination	down-regulates quantity by destabilization	0.2	Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.	SIGNOR-271407
P40763	Q07912	0	phosphorylation	up-regulates activity	0.286	Since STAT1 and STAT3 are structurally related [3], we also assessed if ACK1 could induce the phosphorylation of STAT3 at residue Y705 (p-STAT3).\|Our work demonstrates that catalytically active ACK1 can promote the activation of STAT1 and STAT3.\|Here we demonstrate that catalytically active ACK1 induces the tyrosine phosphorylation of STAT1 and STAT3.	SIGNOR-279312
Q9Y618	P37231	1	transcriptional regulation	down-regulates quantity by repression	0.745	In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.	SIGNOR-253508
Q86YC2	Q13535	0	phosphorylation	up-regulates activity	0.307	ATR promotes PALB2 accumulation at DNA damage sites.\|In the context of PALB2 regulation, the phosphorylation of PALB2 by ATR plays a positive role in PALB2 recruitment.	SIGNOR-279588
P27361	O95817	1	phosphorylation	down-regulates quantity by destabilization	0.312	We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377.	SIGNOR-277318
Q9Y4C1	Q71DI3	1	demethylation	up-regulates activity	0.2	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.	SIGNOR-276844
P62834	P17612	0	phosphorylation	down-regulates activity	0.521	Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells.	SIGNOR-250042
P22455	Q13043	1	phosphorylation	down-regulates activity	0.2	FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2 dependent apoptosis.\|We provide evidence suggesting that by Y433-MST1 phosphorylation , FGFR4 inhibits MST1 / 2 activation .	SIGNOR-279714
P07737	P55283	1	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
P27361	P10415	1	phosphorylation	up-regulates	0.56	Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association.	SIGNOR-74935
Q06124	Q13480	1	dephosphorylation	down-regulates activity	0.952	These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.\|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro.	SIGNOR-248674
P09619	Q05397	1	phosphorylation	up-regulates	0.553	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.	SIGNOR-167658
Q00613	P17612	0	phosphorylation	up-regulates	0.314	Protein kinase a binds and activates heat shock factor 1hsf1 binds avidly to the catalytic subunit of pka, (pkac_) and becomes phosphorylated on a novel serine phosphorylation site within its central regulatory domain (serine 320 or s320), both in vitro and in vivo. Intracellular pkac_ levels and phosphorylation of hsf1 at s320 were both required for hsf1 to be localized to the nucleus, bind to response elements in the promoter of an hsf1 target gene	SIGNOR-169853
Q05086	P00519	0	phosphorylation	down-regulates activity	0.273	Our results suggest that c-Abl protects p53 from HPV-E6-E6AP complex-mediated degradation by phosphorylating E6AP and impairing its E3 ligase activity	SIGNOR-260930
Q92686	P17252	0	phosphorylation	up-regulates activity	0.394	Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM.	SIGNOR-248913
P04637	O15297	0	dephosphorylation	down-regulates activity	0.558	PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair.	SIGNOR-248319
O75469	Q00535	0	phosphorylation	down-regulates activity	0.345	In vitro kinase assays showed that Cdk5 directly phosphorylates PXR.\|Taken together, these data indicate that Cdk5 negatively regulates PXR activity, and that inhibition of Cdk5 is at least partially responsible for flavonoids induced activation of PXR.	SIGNOR-279402
Q15831	P46937	1	phosphorylation	down-regulates activity	0.305	LKB1 induces phosphorylation of Yap, leading to Yap nuclear exclusion and ultimately its degradation.\|These data indicated that LKB1 expression inhibits Yes-associated protein transcriptional function.	SIGNOR-280139

P16615

P45984

0

phosphorylation

up-regulates activity

0.2

JNK2 Enhances SERCA2 Function in a CaMKII-Independent Manner..|We found that JNK2 and SERCA2 proteins are physically associated with each other, and that JNK2 directly elevates the maximal rate of the SERCA2 activity by phosphorylating SERCA2.

SIGNOR-279540

P28482

Q9BYB0

1

phosphorylation

down-regulates activity

0.2

Interestingly, we discovered that several kinases in the MEK and ERK2 pathway destabilize Shank3 and that genetic deletion and pharmacological inhibition of ERK2 increases Shank3 abundance in vivo.|We also determined that phosphorylation of Shank3 by ERK2 at selective residues promotes its ubiquitination and degradation.

SIGNOR-279538

P46459

Q00536

0

phosphorylation

down-regulates activity

0.439

Moreover, inhibition of Pctaire1 activity by transfecting its kinase-dead (KD) mutant into COS-7 cells enhances the self association of NSF.|We demonstrate that the D2 domain of NSF, which is required for the oligomerization of NSF subunits, binds directly to and is phosphorylated by Pctaire1 on serine 569.

SIGNOR-279511

P31749

O60285

1

phosphorylation

up-regulates

0.262

Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity.

SIGNOR-252591

Q05513

P31751

1

phosphorylation

up-regulates activity

0.498

The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells.

SIGNOR-248997

O75822

P68400

0

phosphorylation

up-regulates activity

0.326

CK2 phosphorylates the eIF3j subunit at Ser127. CK2-phosphorylation of eIF3j triggers its association with the eIF3 complex.

SIGNOR-266402

P68431

O14965

0

phosphorylation

up-regulates activity

0.2

Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.

SIGNOR-98289

P17612

Q13972

1

phosphorylation

up-regulates

0.519

Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors.

SIGNOR-73202

P04049

P67775

0

dephosphorylation

up-regulates

0.592

Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1.

SIGNOR-141170

P67775

P28482

1

dephosphorylation

down-regulates activity

0.621

P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).Mapk activity is tightly regulated by phosphorylation and dephosphorylation. The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase

SIGNOR-103159

P25963

O15111

0

phosphorylation

down-regulates quantity by destabilization

0.896

We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation

SIGNOR-52875

P14373

A8K0Z3

1

ubiquitination

up-regulates activity

0.2

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

SIGNOR-253514

P51451

Q8N884

1

phosphorylation

down-regulates activity

0.2

DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS.

SIGNOR-275844

P63000

Q8IVF5

0

guanine nucleotide exchange factor

up-regulates activity

0.589

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-260578

P35241

P61586

0

phosphorylation

up-regulates activity

0.47

Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies.

SIGNOR-268430

P41162

P28482

0

phosphorylation

down-regulates activity

0.403

We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. Among the ERK2 substrates, we identified the E-twenty six (ETS) domain-containing protein ETV3. We determined that phosphorylation of this protein by ERK2 was functionally relevant, abrogating the DNA-binding activity of ETV3 at thousands of targets across the genome, thereby providing an additional mechanism for transcriptional regulation downstream of ERK2 activation.

SIGNOR-262758

P45985

O15264

1

phosphorylation

up-regulates activity

0.459

p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.

SIGNOR-273956

P04275

O00327

0

transcriptional regulation

down-regulates quantity by repression

0.324

We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype.

SIGNOR-253704

Q86VW2

P63000

1

guanine nucleotide exchange factor

up-regulates

0.622

Exogenous expression of geft promotes myogenesis ofc2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process.

SIGNOR-236882

Q9BWT1

P31749

0

phosphorylation

down-regulates

0.338

The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus.

SIGNOR-252533

P49841

P17947

1

phosphorylation

down-regulates quantity by destabilization

0.2

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

SIGNOR-277541

Q9Y243

P49841

1

phosphorylation

down-regulates activity

0.736

Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1

SIGNOR-245424

Q9UNE7

Q8IVS8

1

ubiquitination

down-regulates quantity by destabilization

0.2

Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. ERK1 phosphorylates GLYCTK2 at S220 to promotes its stability

SIGNOR-280258

P11940

Q13064

0

ubiquitination

down-regulates activity

0.2

MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA|Altogether, it is thus clear that the ubiquitination of PABPC1 or PABPC4 by MKRN3 negatively regulates the formation of translation initiation complex (TIC), attenuates their binding to poly (A)-tail contained mRNAs, and leads to the shortened poly (A) tail-length of GNRH1 mRNA.

SIGNOR-278764

Q9BTC0

P08648

1

transcriptional regulation

up-regulates quantity by expression

0.2

Dido1 upregulates the expression of Integrin αV, thereby influencing the attachment, apoptosis and migration of melanoma cells.

SIGNOR-261580

Q14847

P12931

0

phosphorylation

up-regulates activity

0.253

Integrin-dependent translocation of LASP-1 to the cytoskeleton of activated platelets correlates with LASP-1 phosphorylation at tyrosine 171 by Src-kinase

SIGNOR-271706

Q9BYB0

P28482

0

phosphorylation

down-regulates activity

0.2

Interestingly, we discovered that several kinases in the MEK and ERK2 pathway destabilize Shank3 and that genetic deletion and pharmacological inhibition of ERK2 increases Shank3 abundance in vivo.|We also determined that phosphorylation of Shank3 by ERK2 at selective residues promotes its ubiquitination and degradation.

SIGNOR-279538

O14936

Q00535

0

phosphorylation

up-regulates activity

0.288

Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK.|We found that Cdk5 phosphorylates and regulates CASK distribution to membranes.

SIGNOR-280216

P06127

P17252

0

phosphorylation

up-regulates

0.339

Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation.

SIGNOR-85179

Q5S007

P10415

1

phosphorylation

up-regulates activity

0.329

Thus, we propose that Thr56 phosphorylation of Bcl-2 by LRRK2 G2019S might be a crucial step of mitochondrial disorder, which initiates the subsequent cellular damage in the context of PD relevant to G2019S.|We found that LRRK2 G2019S induced loss of the MMP was recovered in both GFP-Bcl-2 and GFP-M-Bcl-2 stable cells (XREF_FIG -lower panel).

SIGNOR-279531

Q15418

O94822

0

ubiquitination

down-regulates activity

0.2

Ltn1 ubiquitylation of RSK1, RSK2, and TWY3 could either result in degradation or impart a regulatory function on target proteins distinct from degradation.

SIGNOR-278757

Q9H6Z9

P14618

1

hydroxylation

up-regulates activity

0.436

Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.

SIGNOR-267476

P53350

Q9Y2I6

1

phosphorylation

down-regulates activity

0.7

Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction

SIGNOR-103356

P48730

P10636

1

phosphorylation

down-regulates

0.374

Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells.

SIGNOR-121717

P28482

Q86U44

1

phosphorylation

up-regulates quantity by stabilization

0.273

Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.

SIGNOR-265948

P46821

P49841

0

phosphorylation

down-regulates activity

0.527

GSK-3beta phosphorylates MAP1B and the adenomatous polyposis coil gene product (APC; Grimes and Jope 2001; Frame and Cohen 2001). The phosphorylation of MAP1B by GSK-3beta suppresses detyrosination of microtubules and decreases the numbers of stable microtubules

SIGNOR-264843

Q12933

P67775

0

dephosphorylation

down-regulates activity

0.2

We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity.

SIGNOR-248640

P03951

P14210

1

cleavage

up-regulates activity

0.313

the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain.

SIGNOR-256515

P56178

P31749

0

phosphorylation

up-regulates

0.264

Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5.

SIGNOR-252513

O75807

P07948

0

phosphorylation

up-regulates

0.334

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

SIGNOR-109934

P11309

P36888

1

phosphorylation

up-regulates quantity

0.42

Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway.

SIGNOR-259927

O14965

Q96CX2

1

phosphorylation

up-regulates activity

0.272

In addition, Aurora A phosphorylated KCTD12 at serine 243, thereby initiating a positive feedback loop necessary for KCTD12 to exert its cancer-promoting effects.

SIGNOR-273544

P49841

P35568

1

phosphorylation

down-regulates quantity by destabilization

0.454

HG activates GSK3beta, which phosphorylates IRS1 at serine 332, leading to the ubiquitination and proteasome mediated degradation of IRS1.

SIGNOR-279183

Q08999

P67775

0

dephosphorylation

up-regulates

0.581

Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation.

SIGNOR-129752

P78527

P31749

1

phosphorylation

up-regulates activity

0.754

DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform

SIGNOR-252431

Q92834

P61006

1

guanine nucleotide exchange factor

up-regulates activity

0.427

PGR interacts with the small GTPase RAB8A, which participates in cilia biogenesis and maintenance. We show that RPGR primarily associates with the GDP-bound form of RAB8A and stimulates GDP/GTP nucleotide exchange. RPGR functions as a GEF for RAB8A and RPGR–RAB8A association may facilitate ciliary trafficking.

SIGNOR-253030

Q92769

Q96KB5

0

phosphorylation

up-regulates activity

0.2

The results of in vitro studies further confirmed the effect of TOPK on HDAC activity by showing that TOPK overexpression significantly up-regulated p-HDAC1 and p-HDAC2, resulting in an increase in the acetylation of histones H3 and H4 in BV2 cells.|These results indicated that TOPK overexpression resulted in the phosphorylation of HDAC1 and HDAC2, which might inactivate them and promote the acetylation of Histone 3 and Histone 4.

SIGNOR-279087

Q13882

P78357

1

phosphorylation

up-regulates activity

0.2

As a consequence, Brk stimulates p190 and attenuates p120 functions, leading to RhoA inactivation and Ras activation, respectively.|Brk phosphorylates p190 at the Y (1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120RasGAP (p120).

SIGNOR-279274

P24941

Q8IXJ6

1

phosphorylation

down-regulates

0.395

We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2.

SIGNOR-177972

Q8N0W4

P78352

1

relocalization

up-regulates activity

0.754

Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.

SIGNOR-264192

Q12857

Q14393

1

transcriptional regulation

down-regulates quantity

0.2

By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development

SIGNOR-268876

O96006

P62753

1

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-266082

Q13261

P23458

1

null

up-regulates

0.462

Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated

SIGNOR-256227

Q9HBH9

Q16539

0

phosphorylation

up-regulates

0.415

Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity

SIGNOR-48349

P29692

Q13683

1

transcriptional regulation

down-regulates quantity by repression

0.2

alpha7 Integrin Expression Is Negatively Regulated by deltaEF1 during Skeletal Myogenesis

SIGNOR-241773

P33981

Q13257

1

phosphorylation

up-regulates activity

0.713

Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2.

SIGNOR-252036

Q99814

P27361

0

phosphorylation

up-regulates quantity by stabilization

0.26

The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells.

SIGNOR-277584

Q9BRP0

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.2

In breast cancer cells, MDM2 overexpression or p53 KD reduced OVOL2 protein expression, and the proteasome inhibitor MG132 blocked the MDM2 overexpression\u2010 or p53 KD\u2010mediated reduction in OVOL2 expression (Figure\u00a06B,C).|The E3 ubiquitin ligase MDM2 ubiquitinates and degrades the OVOL2 protein.

SIGNOR-278826

P60953

Q15811

0

guanine nucleotide exchange factor

up-regulates activity

0.848

Significantly, here we identify the long isoform of ITSN-1, which has Cdc42 GEF activity| We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A).

SIGNOR-260612

Q9H334

P07333

1

transcriptional regulation

down-regulates quantity by repression

0.296

Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation.

SIGNOR-269048

Q01538

Q02750

0

phosphorylation

down-regulates activity

0.261

Altogether our findings reveal that Myt1 is inactivated by MEK1 mediated phosphorylation to fragment the Golgi complex in G2 and for the entry of cells into mitosis.|MEK1 inactivates Myt1 to regulate Golgi membrane fragmentation and mitotic entry in mammalian cells.

SIGNOR-279052

P00533

Q9ULV8

0

polyubiquitination

down-regulates quantity by destabilization

0.761

In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.

SIGNOR-272605

O43255

P55036

1

polyubiquitination

down-regulates quantity by destabilization

0.432

S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s.

SIGNOR-272748

Q14680

Q15831

0

phosphorylation

up-regulates

0.2

Site-directed mutagenesis indicated that thr167 and ser171, located between the dfg and ape motifs in the activation loop or t-loop, need to be autophosphorylated for melk to be active as a protein kinase (fig. 5). These sites are conserved in all other ampk-related protein kinases (fig. 4a), and the site corresponding to thr167 has been shown to be phosphorylated by protein kinase lkb1 (5).

SIGNOR-141038

P24928

P27361

0

phosphorylation

down-regulates

0.316

Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.

SIGNOR-120176

Q05209

Q05397

1

dephosphorylation

down-regulates activity

0.538

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

SIGNOR-248661

P11309

P39019

1

phosphorylation

up-regulates

0.438

The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay.

SIGNOR-141411

P62136

P24941

0

phosphorylation

down-regulates activity

0.377

Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity

SIGNOR-92265

Q15382

Q8IW41

0

phosphorylation

down-regulates activity

0.401

Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation.

SIGNOR-276313

P18031

Q05397

1

dephosphorylation

down-regulates activity

0.346

The focal adhesion kinase (FAK) is a key regulator of cell migration. Phosphorylation at Tyr-397 activates FAK |The dephosphorylation at Tyr-397 in FAK triggered by wild-type alpha-actinin and PTP 1B caused a significant increase in cell migration.

SIGNOR-248431

Q9H4P4

O60260

1

polyubiquitination

down-regulates quantity by destabilization

0.2

Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner. More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate.

SIGNOR-272639

P35575

P16220

0

transcriptional regulation

up-regulates quantity

0.2

Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB

SIGNOR-256105

P12931

Q68CZ2

1

phosphorylation

up-regulates

0.408

Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate

SIGNOR-187843

P17252

Q92793

1

phosphorylation

down-regulates

0.261

The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex,

SIGNOR-166368

O15111

Q9Y261

1

phosphorylation

down-regulates

0.2

Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression

SIGNOR-195316

Q9UPG8

Q09472

0

acetylation

up-regulates

0.2

Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.

SIGNOR-140947

P29350

P00533

1

dephosphorylation

down-regulates

0.415

The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation.

SIGNOR-59965

O14965

Q9UNN5

1

phosphorylation

down-regulates activity

0.2

This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1

SIGNOR-180891

Q13426

O14647

0

relocalization

up-regulates quantity

0.2

CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs.

SIGNOR-264528

P06239

P10586

0

dephosphorylation

up-regulates

0.364

We confirmed that lar dephosphorylated the phosphorylated tyrosine residues of lck..Activation Of lck and fyn involves tyrosine dephosphorylation of the cooh-terminal regulatory domain of kinases, followed by autophosphorylation of the kinase domain.

SIGNOR-96771

P10415

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

A previous study has demonstrated that GSK3B triggers the degradation of BCL2 by inducing phosphorylation of BCL2 at Ser70, which induced autophagy by interrupting the interaction between BECN1 and BCL2 [32].

SIGNOR-279784

Q16552

P51449

0

transcriptional regulation

up-regulates

0.54

We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells

SIGNOR-255029

Q5T0T0

P13762

1

polyubiquitination

down-regulates quantity by destabilization

0.2

Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.

SIGNOR-271407

P40763

Q07912

0

phosphorylation

up-regulates activity

0.286

Since STAT1 and STAT3 are structurally related [3], we also assessed if ACK1 could induce the phosphorylation of STAT3 at residue Y705 (p-STAT3).|Our work demonstrates that catalytically active ACK1 can promote the activation of STAT1 and STAT3.|Here we demonstrate that catalytically active ACK1 induces the tyrosine phosphorylation of STAT1 and STAT3.

SIGNOR-279312

Q9Y618

P37231

1

transcriptional regulation

down-regulates quantity by repression

0.745

In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.

SIGNOR-253508

Q86YC2

Q13535

0

phosphorylation

up-regulates activity

0.307

ATR promotes PALB2 accumulation at DNA damage sites.|In the context of PALB2 regulation, the phosphorylation of PALB2 by ATR plays a positive role in PALB2 recruitment.

SIGNOR-279588

P27361

O95817

1

phosphorylation

down-regulates quantity by destabilization

0.312

We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377.

SIGNOR-277318

Q9Y4C1

Q71DI3

1

demethylation

up-regulates activity

0.2

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

SIGNOR-276844

P62834

P17612

0

phosphorylation

down-regulates activity

0.521

Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells.

SIGNOR-250042

P22455

Q13043

1

phosphorylation

down-regulates activity

0.2

FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2 dependent apoptosis.|We provide evidence suggesting that by Y433-MST1 phosphorylation , FGFR4 inhibits MST1 / 2 activation .

SIGNOR-279714

P07737

P55283

1

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

P27361

P10415

1

phosphorylation

up-regulates

0.56

Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association.

SIGNOR-74935

Q06124

Q13480

1

dephosphorylation

down-regulates activity

0.952

These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro.

SIGNOR-248674

P09619

Q05397

1

phosphorylation

up-regulates

0.553

In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.

SIGNOR-167658

Q00613

P17612

0

phosphorylation

up-regulates

0.314

Protein kinase a binds and activates heat shock factor 1hsf1 binds avidly to the catalytic subunit of pka, (pkac_) and becomes phosphorylated on a novel serine phosphorylation site within its central regulatory domain (serine 320 or s320), both in vitro and in vivo. Intracellular pkac_ levels and phosphorylation of hsf1 at s320 were both required for hsf1 to be localized to the nucleus, bind to response elements in the promoter of an hsf1 target gene

SIGNOR-169853

Q05086

P00519

0

phosphorylation

down-regulates activity

0.273

Our results suggest that c-Abl protects p53 from HPV-E6-E6AP complex-mediated degradation by phosphorylating E6AP and impairing its E3 ligase activity

SIGNOR-260930

Q92686

P17252

0

phosphorylation

up-regulates activity

0.394

Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM.

SIGNOR-248913

P04637

O15297

0

dephosphorylation

down-regulates activity

0.558

PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair.

SIGNOR-248319

O75469

Q00535

0

phosphorylation

down-regulates activity

0.345

In vitro kinase assays showed that Cdk5 directly phosphorylates PXR.|Taken together, these data indicate that Cdk5 negatively regulates PXR activity, and that inhibition of Cdk5 is at least partially responsible for flavonoids induced activation of PXR.

SIGNOR-279402

Q15831

P46937

1

phosphorylation

down-regulates activity

0.305

LKB1 induces phosphorylation of Yap, leading to Yap nuclear exclusion and ultimately its degradation.|These data indicated that LKB1 expression inhibits Yes-associated protein transcriptional function.

SIGNOR-280139