GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
O75874	P98177	0	transcriptional regulation	up-regulates quantity by expression	0.264	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260102
Q8N884	Q8WV44	0	ubiquitination	up-regulates activity	0.2	Our finding that RINCK positively regulates cGAS activation by mediating the monoubiquitination of cGAS uncovers the function of RINCK in cGAS mediated innate immunity.\|Together, these data suggest that RINCK mediates cGAS monoubiquitination.	SIGNOR-278794
P40763	P45983	0	phosphorylation	up-regulates activity	0.567	Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3,	SIGNOR-235704
P51608	P08581	1	post transcriptional regulation	down-regulates quantity by repression	0.27	MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2	SIGNOR-264683
P07332	P16284	1	phosphorylation	up-regulates activity	0.276	PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.	SIGNOR-262868
P98161	P51817	0	phosphorylation	up-regulates	0.257	The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd.	SIGNOR-158852
Q9BZS1	Q9NZQ7	1	transcriptional regulation	up-regulates quantity by expression	0.468	FOXP3 expression additionally increased programmed death ligand 1 (PD-L1) expression, which, when inhibited with CCL5, decreased the tumor burden and Treg infiltration in orthotopic murine, Pan-02 PDAC tumors	SIGNOR-277728
P51812	P32314	1	phosphorylation	down-regulates quantity by destabilization	0.2	Importantly, we identified RSK2 kinase as the upstream kinase for the FOXN2 phosphodegron. The Ser365 and Ser369 sites in a conserved DSGYAS motif are responsible for the ubiquitination of FOXN2 by β-Trcp.	SIGNOR-273841
Q92934	Q9Y243	0	phosphorylation	down-regulates	0.542	Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155.	SIGNOR-81122
Q9UQL6	O94806	0	phosphorylation	up-regulates activity	0.265	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275926
Q13362	O96017	0	phosphorylation	up-regulates	0.322	Found that chk2 associated with the b' regulatory subunit of protein phosphatase pp2a. In vitro kinase assays showed that b'gamma3 was a potent chk2 substrate. This phosphorylation increased the catalytic phosphatase activity of pp2a.	SIGNOR-129255
O14976	Q00610	1	phosphorylation	up-regulates activity	0.857	Clathrin heavy chain (CHC) was phosphorylated at T606 by its association partner cyclin G-associated kinase (GAK). This phosphorylation was required for proper cell proliferation and tumor growth of cells implanted into nude mice.	SIGNOR-275448
P30304	Q12778	1	dephosphorylation	up-regulates activity	0.313	In this study, we revealed that Cdc25A enhances Foxo1 stability by dephosphorylating Cdk2, and Foxo1 was shown to directly regulate transcription of the metastatic factor MMP1.	SIGNOR-277139
Q9UHC7	P60484	1	ubiquitination	down-regulates quantity by destabilization	0.43	EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase.\|In fact, epidermal growth factor-stimulated pAKT phosphorylates and subsequently stabilizes MKRN1, which then ubiquitinates and induces the degradation of PTEN.	SIGNOR-278830
Q9NYA1	P27361	0	phosphorylation	up-regulates	0.601	Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.	SIGNOR-118550
Q9NZQ7	P51955	0	phosphorylation	up-regulates quantity by stabilization	0.2	NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen.	SIGNOR-277314
P40763	P07948	0	phosphorylation	up-regulates activity	0.659	An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3.	SIGNOR-279062
P24941	P05067	1	phosphorylation	down-regulates quantity by destabilization	0.267	These include a significant increase in APP phosphorylation at Thr 668 by cdk2, cdk4, and cdk5, which increases its beta-amyloid production and APP proteolysis by the activated caspases during cell cycle ( xref ; xref ; xref ; xref ).	SIGNOR-280210
Q05655	P52757	1	phosphorylation	down-regulates	0.269	A novel cross-talk in diacylglycerol signaling: the rac-gap beta2-chimaerin is negatively regulated by protein kinase cdelta-mediated phosphorylation. phosphorylation of beta2-chimaerin on ser(169) located in the sh2-c1 domain linker region via protein kinase cdelta, which retained beta2-chimaerin in the cytosol and prevented its c1 domain-mediated translocation to membranes	SIGNOR-164687
P24941	P30307	1	phosphorylation	up-regulates	0.754	The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry.	SIGNOR-165872
P81274	Q96KB5	0	phosphorylation	up-regulates	0.27	We found that the 450th threonine (thr450) of lgn/gpsm2 was phosphorylated by the serine/threonine kinase pbk/topk during mitosis. Western blot analysis indicated the highest expression and the phosphorylated form of lgn/gpsm2 protein in g2/m phase.	SIGNOR-166461
P03372	P78527	0	phosphorylation	up-regulates quantity by stabilization	0.386	DNA-PK phosphorylates ERalpha at Ser-118.\|Phosphorylation resulted in stabilization of ERalpha protein as inhibition of DNA-PK resulted in its proteasomal degradation.	SIGNOR-279561
P24723	Q9BZL6	1	phosphorylation	up-regulates	0.2	Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs.	SIGNOR-89431
P17612	Q13131	1	phosphorylation	down-regulates activity	0.423	These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine.	SIGNOR-256112
P14780	P10915	1	cleavage	down-regulates quantity by destabilization	0.341	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256328
Q16763	P31749	0	phosphorylation	up-regulates quantity by stabilization	0.437	Mechanistically, Akt1 physically interacted with and phosphorylated UBE2S at Thr 152, enhancing its stability by inhibiting proteasomal degradation.	SIGNOR-265078
P05412	P45985	0	phosphorylation	up-regulates activity	0.537	SEK1 phosphorylates and activates both p38 and c-Jun NH(2)-terminal kinase (JNK), whereas MKK3 and MKK6 selectively phosphorylate and activate p38.	SIGNOR-279063
O75385	Q8TDY2	1	phosphorylation	up-regulates	0.913	Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks.	SIGNOR-186992
P49841	Q15797	1	phosphorylation	down-regulates	0.504	Phosphorylation at the gsk3 sites represses the transcriptional activity of smad1 by enhancing proteasomal degradation of psmad1cter	SIGNOR-159484
Q01974	Q15750	0	phosphorylation	down-regulates	0.278	Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain	SIGNOR-180566
P60484	P35568	1	dephosphorylation	down-regulates activity	0.576	In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser 307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon HCV infection occurred in a PTEN dependent manner.\|In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser-307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon Hepatitis C virus infection occurred in a PTEN-dependent manner.	SIGNOR-277078
P49674	P55957	1	phosphorylation	up-regulates activity	0.345	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. \| These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250806
Q8TCQ1	P42081	1	ubiquitination	down-regulates quantity by destabilization	0.2	Among nine family members examined, forced expression of MARCH1, -2, and -8 induced a significant reduction of surface CD86 in several cell lines.\|CD86 is ubiquitinated by MARCH1.	SIGNOR-278628
O43791	O75496	1	ubiquitination	down-regulates activity	0.2	SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication.	SIGNOR-268926
P60953	Q9C0H5	0	gtpase-activating protein	down-regulates activity	0.577	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-260495
P62136	P04637	1	dephosphorylation	down-regulates activity	0.314	Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities\|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248557
Q96F24	P42345	0	phosphorylation	up-regulates activity	0.2	Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association.	SIGNOR-265875
P49840	Q13554	0	phosphorylation	down-regulates	0.291	Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival.	SIGNOR-167962
Q92949	Q71U36	1	transcriptional regulation	up-regulates quantity by expression	0.298	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266938
Q02078	Q13164	0	phosphorylation	up-regulates	0.711	We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.	SIGNOR-236579
O60825	P17612	0	phosphorylation	up-regulates activity	0.444	PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚	SIGNOR-250025
Q86UR5	P20336	1	relocalization	up-regulates activity	0.805	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264381
P83916	Q5XPI4	0	polyubiquitination	down-regulates quantity by destabilization	0.2	In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation.	SIGNOR-272034
Q05639	P04049	0	phosphorylation	down-regulates quantity by destabilization	0.2	Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.	SIGNOR-276407
P42345	O75385	1	phosphorylation	down-regulates activity	0.849	mTORC1, which is often referred to as the gatekeeper to autophagy, is a key regulator of the Ulk1-Atg13-FIP200 kinase complex.11,14,25 Under nutrient-rich conditions, active mTORC1 associates with and inactivates the Ulk1-Atg13-FIP200 complex by phosphorylating Ulk1 and Atg13.	SIGNOR-183903
Q16875	Q9P1W9	0	phosphorylation	up-regulates quantity by stabilization	0.2	We used biochemical methods to determine that PIM2 can directly bind and change the phosphorylation of PFKFB3 at Ser478 to enhance PFKFB3 protein stability through the ubiquitin-proteasome pathway.	SIGNOR-277554
Q15262	O43490	1	dephosphorylation	down-regulates activity	0.2	PTPRK dephosphorylates CD133, which is a stem cell marker; phosphorylated CD133 accelerates xenograft tumor growth of colon cancer cells through the activation of AKT, but the functional significance of this has remained elusive.\|Together, these observations suggest that PTPRK suppresses CD133\u2010mediated colon cancer growth both in\u00a0vitro and in\u00a0vivo.	SIGNOR-277133
Q16539	O75928	1	phosphorylation	up-regulates activity	0.316	The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles	SIGNOR-262949
P08559	P24752	0	acetylation	down-regulates activity	0.393	We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)	SIGNOR-267633
Q14249	Q13490	0	ubiquitination	up-regulates activity	0.468	Alternatively, cIAP1 may mediate a vital function of EndoG other than cell death.\|Cellular inhibitor of apoptosis protein 1 ubiquitinates endonuclease G but does not affect endonuclease G-mediated cell death.	SIGNOR-278605
P28329	Q05513	0	phosphorylation	up-regulates	0.288	Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity.	SIGNOR-129340
P68400	P11388	1	phosphorylation	down-regulates quantity by destabilization	0.595	This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361.	SIGNOR-276300
Q13131	Q09472	1	phosphorylation	down-regulates	0.376	The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity.	SIGNOR-176637
P31152	P31749	1	phosphorylation	up-regulates activity	0.271	Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308.	SIGNOR-275450
P24941	Q08050	1	phosphorylation	up-regulates activity	0.75	We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins.	SIGNOR-250731
P37840	Q9H4B4	0	phosphorylation	down-regulates activity	0.319	Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.	SIGNOR-189053
Q01860	Q13049	0	ubiquitination	down-regulates quantity by destabilization	0.268	This further supports that TRIM32 and Oct4 do physically interact, so that TRIM32 can specifically ubiquitinate Oct4 and thereby target it for degradation.	SIGNOR-278620
P56915	O00308	0	ubiquitination	up-regulates activity	0.31	These results indicated that Wwp2 augments the transcription activity of Gsc.\|We confirmed that Gsc was being mono-ubiquitinated by Wwp2 via in vitro ubiquitination assays that utilized purified Gsc, recombinant Wwp2 and ubiquitin-K0 proteins that resulted in a pattern of Gsc ubiquitination similar to WT ubiquitin (XREF_FIG).	SIGNOR-278797
O14757	Q13315	0	phosphorylation	up-regulates	0.845	Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation.	SIGNOR-163106
Q9UKV8	P48729	0	phosphorylation	down-regulates activity	0.369	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276510
P17655	P49840	1	cleavage	up-regulates activity	0.2	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251612
Q7Z6Z7	Q07820	1	ubiquitination	down-regulates quantity by destabilization	0.502	Mule was identified as Mcl-1 ubiquitin ligase E3 to promote Mcl-1 degradation via the proteasomal pathway [46]. We found that knockdown of Mule (Fig. 4C) but not β-TRCP or FBXW7 (data not shown) prevented Mcl-1 downregulation caused by PKCη depletion.	SIGNOR-261909
Q01130	Q13627	0	phosphorylation	down-regulates activity	0.408	Dyrk1A inhibits SC35\u2032s activity to promote tau exon 10 inclusion.\|Dyrk1A interacts with and phosphorylates SC35 and inhibits its activity to promote tau exon 10 inclusion.	SIGNOR-278307
O43559	Q16620	0	phosphorylation	up-regulates activity	0.602	The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type	SIGNOR-250202
Q9NWT6	P46531	1	hydroxylation	down-regulates	0.55	We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation.	SIGNOR-161057
Q01484	Q15172	1	relocalization	up-regulates quantity	0.282	Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins.	SIGNOR-266729
Q05655	P78357	1	phosphorylation	down-regulates activity	0.2	Inhibition of PKCdelta increased p190 activity, while PKCdelta overexpression diminished p190 activity.\|We further show that PKC\u03b4 was able to phosphorylate and bind distinct domains of p190.	SIGNOR-279260
Q15717	Q8TD08	0	phosphorylation	down-regulates activity	0.346	ERK8 phosphorylates HuR to prevent its binding to PDCD4 mRNA A. ERK8 or control siRNA was transfected into HeLa cells for 48 h followed by treatment of cells with 0.5 mM H2O2 or PBS for 1 h. Cells were fixed and immunofluorescence was performed to monitor HuR localization.	SIGNOR-278314
P02545	P17252	0	phosphorylation	up-regulates activity	0.362	Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence.	SIGNOR-248904
Q6PHR2	P08151	1	phosphorylation	up-regulates activity	0.673	We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro. \| Our data suggest that serine/threonine kinase ULK3 is involved in the SHH pathway as a positive regulator of GLI proteins.	SIGNOR-260797
Q13557	P56524	1	phosphorylation	up-regulates	0.358	These results demonstrate that camkiideltab preferentially targets hdac4, and this involves serine 210overexpression of camkiideltab in primary neonatal cardiomyocytes increases the activity of the mef2 transcription factor and completely rescues hdac4-mediated repression of mef2	SIGNOR-151418
Q93009	P68400	0	phosphorylation	up-regulates quantity by stabilization	0.372	We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53.	SIGNOR-276530
P26678	Q13976	0	phosphorylation	up-regulates activity	0.409	Phosphorylation of PLB by PKA or cGKI at Ser 16 relieves the inhibition of SERCA2a and results in increased contractility through enhanced Ca 2+ i reuptake into the SR.	SIGNOR-279269
P04049	P98170	1	phosphorylation	up-regulates activity	0.504	Interaction and stabilization of X-linked inhibitor of apoptosis by Raf-1 protein kinase.\|We also demonstrate that Raf-1 phosphorylates XIAP in vitro and in vivo.	SIGNOR-279105
P53671	P23528	1	phosphorylation	down-regulates activity	0.766	We report here that limk1 and limk2 phosphorylate both cofilin and actin-depolymerizing factor (adf) specifically at ser-3 and exhibit partially distinct substrate specificity when tested using site-directed cofilin mutants as substrates	SIGNOR-105098
Q9Y478	P29474	1	phosphorylation	up-regulates	0.2	Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.	SIGNOR-112367
Q9UQM7	Q9UQD0	1	phosphorylation	up-regulates activity	0.279	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability\|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275785
P46736	P0C0S8	1	deubiquitination	down-regulates	0.2	Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a	SIGNOR-167142
Q16665	Q96A26	1	transcriptional regulation	up-regulates quantity by expression	0.282	In this work, we report the identification of an HIF-1 alpha-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1 alpha through a hypoxia-responsive element on the HGTD-P promoter region.	SIGNOR-260292
P53350	Q9HAW4	1	phosphorylation	down-regulates	0.773	We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase	SIGNOR-148442
Q07352	P49137	0	phosphorylation	down-regulates	0.62	Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation.	SIGNOR-161274
P49841	P46821	1	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
Q15796	O96013	0	phosphorylation	down-regulates quantity by destabilization	0.339	In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation.	SIGNOR-279084
Q9BY11	O96013	0	phosphorylation	up-regulates activity	0.295	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.	SIGNOR-263023
P49841	O00213	1	phosphorylation	up-regulates quantity	0.293	In this regards, GSK3beta may promote amyloidogenic processing of APP by regulating the cellular level of monomeric FE65 for the formation of LRP1, FE65, and APP complex.\|In this study, we showed that FE65 is phosphorylated at T579 by GSK3beta.	SIGNOR-278359
P22607	Q04760	1	phosphorylation	up-regulates activity	0.2	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276181
P20248	P30304	0	dephosphorylation	up-regulates activity	0.692	Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1 [4,5] .	SIGNOR-277136
Q12888	Q96GD4	0	phosphorylation	up-regulates activity	0.409	Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores.	SIGNOR-264411
P17612	P19793	1	phosphorylation	down-regulates	0.2	Serine 27, a human retinoid x receptor alpha residue, phosphorylated by protein kinase a is essential for cyclicamp-mediated downregulation of rxralpha function.	SIGNOR-104954
P62714	O96017	1	dephosphorylation	up-regulates activity	0.309	Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells\|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation.	SIGNOR-248582
Q9Y2U5	Q13163	1	phosphorylation	up-regulates	0.762	Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.	SIGNOR-104634
Q9BXH1	Q07812	1	relocalization	up-regulates	0.49	Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.	SIGNOR-185671
O14647	P84243	1	relocalization	up-regulates quantity	0.2	Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage.	SIGNOR-264527
P61586	Q9P2N2	0	gtpase-activating protein	down-regulates activity	0.504	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-260483
P17252	Q9BZL6	1	phosphorylation	up-regulates activity	0.393	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.\|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275955
P53667	P49137	0	phosphorylation	up-regulates	0.36	Mk2 activated limk1 by phosphorylation at ser-323.	SIGNOR-144333
P13569	Q13131	0	phosphorylation	down-regulates activity	0.493	AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.\|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type\|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions	SIGNOR-259858
P07948	Q9Y6M4	0	phosphorylation	up-regulates quantity by stabilization	0.2	Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane.	SIGNOR-275395
Q4FZB7	P62805	1	methylation	down-regulates activity	0.2	SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation.	SIGNOR-266651
Q9Y463	P46527	1	phosphorylation	up-regulates	0.355	Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation	SIGNOR-235805

O75874

P98177

0

transcriptional regulation

up-regulates quantity by expression

0.264

We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.

SIGNOR-260102

Q8N884

Q8WV44

0

ubiquitination

up-regulates activity

0.2

Our finding that RINCK positively regulates cGAS activation by mediating the monoubiquitination of cGAS uncovers the function of RINCK in cGAS mediated innate immunity.|Together, these data suggest that RINCK mediates cGAS monoubiquitination.

SIGNOR-278794

P40763

P45983

0

phosphorylation

up-regulates activity

0.567

Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3,

SIGNOR-235704

P51608

P08581

1

post transcriptional regulation

down-regulates quantity by repression

0.27

MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2

SIGNOR-264683

P07332

P16284

1

phosphorylation

up-regulates activity

0.276

PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.

SIGNOR-262868

P98161

P51817

0

phosphorylation

up-regulates

0.257

The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd.

SIGNOR-158852

Q9BZS1

Q9NZQ7

1

transcriptional regulation

up-regulates quantity by expression

0.468

FOXP3 expression additionally increased programmed death ligand 1 (PD-L1) expression, which, when inhibited with CCL5, decreased the tumor burden and Treg infiltration in orthotopic murine, Pan-02 PDAC tumors

SIGNOR-277728

P51812

P32314

1

phosphorylation

down-regulates quantity by destabilization

0.2

Importantly, we identified RSK2 kinase as the upstream kinase for the FOXN2 phosphodegron. The Ser365 and Ser369 sites in a conserved DSGYAS motif are responsible for the ubiquitination of FOXN2 by β-Trcp.

SIGNOR-273841

Q92934

Q9Y243

0

phosphorylation

down-regulates

0.542

Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155.

SIGNOR-81122

Q9UQL6

O94806

0

phosphorylation

up-regulates activity

0.265

Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].

SIGNOR-275926

Q13362

O96017

0

phosphorylation

up-regulates

0.322

Found that chk2 associated with the b' regulatory subunit of protein phosphatase pp2a. In vitro kinase assays showed that b'gamma3 was a potent chk2 substrate. This phosphorylation increased the catalytic phosphatase activity of pp2a.

SIGNOR-129255

O14976

Q00610

1

phosphorylation

up-regulates activity

0.857

Clathrin heavy chain (CHC) was phosphorylated at T606 by its association partner cyclin G-associated kinase (GAK). This phosphorylation was required for proper cell proliferation and tumor growth of cells implanted into nude mice.

SIGNOR-275448

P30304

Q12778

1

dephosphorylation

up-regulates activity

0.313

In this study, we revealed that Cdc25A enhances Foxo1 stability by dephosphorylating Cdk2, and Foxo1 was shown to directly regulate transcription of the metastatic factor MMP1.

SIGNOR-277139

Q9UHC7

P60484

1

ubiquitination

down-regulates quantity by destabilization

0.43

EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase.|In fact, epidermal growth factor-stimulated pAKT phosphorylates and subsequently stabilizes MKRN1, which then ubiquitinates and induces the degradation of PTEN.

SIGNOR-278830

Q9NYA1

P27361

0

phosphorylation

up-regulates

0.601

Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.

SIGNOR-118550

Q9NZQ7

P51955

0

phosphorylation

up-regulates quantity by stabilization

0.2

NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen.

SIGNOR-277314

P40763

P07948

0

phosphorylation

up-regulates activity

0.659

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

SIGNOR-279062

P24941

P05067

1

phosphorylation

down-regulates quantity by destabilization

0.267

These include a significant increase in APP phosphorylation at Thr 668 by cdk2, cdk4, and cdk5, which increases its beta-amyloid production and APP proteolysis by the activated caspases during cell cycle ( xref ; xref ; xref ; xref ).

SIGNOR-280210

Q05655

P52757

1

phosphorylation

down-regulates

0.269

A novel cross-talk in diacylglycerol signaling: the rac-gap beta2-chimaerin is negatively regulated by protein kinase cdelta-mediated phosphorylation. phosphorylation of beta2-chimaerin on ser(169) located in the sh2-c1 domain linker region via protein kinase cdelta, which retained beta2-chimaerin in the cytosol and prevented its c1 domain-mediated translocation to membranes

SIGNOR-164687

P24941

P30307

1

phosphorylation

up-regulates

0.754

The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry.

SIGNOR-165872

P81274

Q96KB5

0

phosphorylation

up-regulates

0.27

We found that the 450th threonine (thr450) of lgn/gpsm2 was phosphorylated by the serine/threonine kinase pbk/topk during mitosis. Western blot analysis indicated the highest expression and the phosphorylated form of lgn/gpsm2 protein in g2/m phase.

SIGNOR-166461

P03372

P78527

0

phosphorylation

up-regulates quantity by stabilization

0.386

DNA-PK phosphorylates ERalpha at Ser-118.|Phosphorylation resulted in stabilization of ERalpha protein as inhibition of DNA-PK resulted in its proteasomal degradation.

SIGNOR-279561

P24723

Q9BZL6

1

phosphorylation

up-regulates

0.2

Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs.

SIGNOR-89431

P17612

Q13131

1

phosphorylation

down-regulates activity

0.423

These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine.

SIGNOR-256112

P14780

P10915

1

cleavage

down-regulates quantity by destabilization

0.341

Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.

SIGNOR-256328

Q16763

P31749

0

phosphorylation

up-regulates quantity by stabilization

0.437

Mechanistically, Akt1 physically interacted with and phosphorylated UBE2S at Thr 152, enhancing its stability by inhibiting proteasomal degradation.

SIGNOR-265078

P05412

P45985

0

phosphorylation

up-regulates activity

0.537

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

SIGNOR-279063

O75385

Q8TDY2

1

phosphorylation

up-regulates

0.913

Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks.

SIGNOR-186992

P49841

Q15797

1

phosphorylation

down-regulates

0.504

Phosphorylation at the gsk3 sites represses the transcriptional activity of smad1 by enhancing proteasomal degradation of psmad1cter

SIGNOR-159484

Q01974

Q15750

0

phosphorylation

down-regulates

0.278

Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain

SIGNOR-180566

P60484

P35568

1

dephosphorylation

down-regulates activity

0.576

In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser 307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon HCV infection occurred in a PTEN dependent manner.|In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser-307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon Hepatitis C virus infection occurred in a PTEN-dependent manner.

SIGNOR-277078

P49674

P55957

1

phosphorylation

up-regulates activity

0.345

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

SIGNOR-250806

Q8TCQ1

P42081

1

ubiquitination

down-regulates quantity by destabilization

0.2

Among nine family members examined, forced expression of MARCH1, -2, and -8 induced a significant reduction of surface CD86 in several cell lines.|CD86 is ubiquitinated by MARCH1.

SIGNOR-278628

O43791

O75496

1

ubiquitination

down-regulates activity

0.2

SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication.

SIGNOR-268926

P60953

Q9C0H5

0

gtpase-activating protein

down-regulates activity

0.577

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-260495

P62136

P04637

1

dephosphorylation

down-regulates activity

0.314

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

SIGNOR-248557

Q96F24

P42345

0

phosphorylation

up-regulates activity

0.2

Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association.

SIGNOR-265875

P49840

Q13554

0

phosphorylation

down-regulates

0.291

Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival.

SIGNOR-167962

Q92949

Q71U36

1

transcriptional regulation

up-regulates quantity by expression

0.298

FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).

SIGNOR-266938

Q02078

Q13164

0

phosphorylation

up-regulates

0.711

We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.

SIGNOR-236579

O60825

P17612

0

phosphorylation

up-regulates activity

0.444

PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚

SIGNOR-250025

Q86UR5

P20336

1

relocalization

up-regulates activity

0.805

N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle

SIGNOR-264381

P83916

Q5XPI4

0

polyubiquitination

down-regulates quantity by destabilization

0.2

In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation.

SIGNOR-272034

Q05639

P04049

0

phosphorylation

down-regulates quantity by destabilization

0.2

Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.

SIGNOR-276407

P42345

O75385

1

phosphorylation

down-regulates activity

0.849

mTORC1, which is often referred to as the gatekeeper to autophagy, is a key regulator of the Ulk1-Atg13-FIP200 kinase complex.11,14,25 Under nutrient-rich conditions, active mTORC1 associates with and inactivates the Ulk1-Atg13-FIP200 complex by phosphorylating Ulk1 and Atg13.

SIGNOR-183903

Q16875

Q9P1W9

0

phosphorylation

up-regulates quantity by stabilization

0.2

We used biochemical methods to determine that PIM2 can directly bind and change the phosphorylation of PFKFB3 at Ser478 to enhance PFKFB3 protein stability through the ubiquitin-proteasome pathway.

SIGNOR-277554

Q15262

O43490

1

dephosphorylation

down-regulates activity

0.2

PTPRK dephosphorylates CD133, which is a stem cell marker; phosphorylated CD133 accelerates xenograft tumor growth of colon cancer cells through the activation of AKT, but the functional significance of this has remained elusive.|Together, these observations suggest that PTPRK suppresses CD133\u2010mediated colon cancer growth both in\u00a0vitro and in\u00a0vivo.

SIGNOR-277133

Q16539

O75928

1

phosphorylation

up-regulates activity

0.316

The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles

SIGNOR-262949

P08559

P24752

0

acetylation

down-regulates activity

0.393

We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)

SIGNOR-267633

Q14249

Q13490

0

ubiquitination

up-regulates activity

0.468

Alternatively, cIAP1 may mediate a vital function of EndoG other than cell death.|Cellular inhibitor of apoptosis protein 1 ubiquitinates endonuclease G but does not affect endonuclease G-mediated cell death.

SIGNOR-278605

P28329

Q05513

0

phosphorylation

up-regulates

0.288

Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity.

SIGNOR-129340

P68400

P11388

1

phosphorylation

down-regulates quantity by destabilization

0.595

This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361.

SIGNOR-276300

Q13131

Q09472

1

phosphorylation

down-regulates

0.376

The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity.

SIGNOR-176637

P31152

P31749

1

phosphorylation

up-regulates activity

0.271

Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308.

SIGNOR-275450

P24941

Q08050

1

phosphorylation

up-regulates activity

0.75

We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins.

SIGNOR-250731

P37840

Q9H4B4

0

phosphorylation

down-regulates activity

0.319

Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.

SIGNOR-189053

Q01860

Q13049

0

ubiquitination

down-regulates quantity by destabilization

0.268

This further supports that TRIM32 and Oct4 do physically interact, so that TRIM32 can specifically ubiquitinate Oct4 and thereby target it for degradation.

SIGNOR-278620

P56915

O00308

0

ubiquitination

up-regulates activity

0.31

These results indicated that Wwp2 augments the transcription activity of Gsc.|We confirmed that Gsc was being mono-ubiquitinated by Wwp2 via in vitro ubiquitination assays that utilized purified Gsc, recombinant Wwp2 and ubiquitin-K0 proteins that resulted in a pattern of Gsc ubiquitination similar to WT ubiquitin (XREF_FIG).

SIGNOR-278797

O14757

Q13315

0

phosphorylation

up-regulates

0.845

Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation.

SIGNOR-163106

Q9UKV8

P48729

0

phosphorylation

down-regulates activity

0.369

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

SIGNOR-276510

P17655

P49840

1

cleavage

up-regulates activity

0.2

Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase

SIGNOR-251612

Q7Z6Z7

Q07820

1

ubiquitination

down-regulates quantity by destabilization

0.502

Mule was identified as Mcl-1 ubiquitin ligase E3 to promote Mcl-1 degradation via the proteasomal pathway [46]. We found that knockdown of Mule (Fig. 4C) but not β-TRCP or FBXW7 (data not shown) prevented Mcl-1 downregulation caused by PKCη depletion.

SIGNOR-261909

Q01130

Q13627

0

phosphorylation

down-regulates activity

0.408

Dyrk1A inhibits SC35\u2032s activity to promote tau exon 10 inclusion.|Dyrk1A interacts with and phosphorylates SC35 and inhibits its activity to promote tau exon 10 inclusion.

SIGNOR-278307

O43559

Q16620

0

phosphorylation

up-regulates activity

0.602

The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type

SIGNOR-250202

Q9NWT6

P46531

1

hydroxylation

down-regulates

0.55

We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation.

SIGNOR-161057

Q01484

Q15172

1

relocalization

up-regulates quantity

0.282

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

SIGNOR-266729

Q05655

P78357

1

phosphorylation

down-regulates activity

0.2

Inhibition of PKCdelta increased p190 activity, while PKCdelta overexpression diminished p190 activity.|We further show that PKC\u03b4 was able to phosphorylate and bind distinct domains of p190.

SIGNOR-279260

Q15717

Q8TD08

0

phosphorylation

down-regulates activity

0.346

ERK8 phosphorylates HuR to prevent its binding to PDCD4 mRNA A. ERK8 or control siRNA was transfected into HeLa cells for 48 h followed by treatment of cells with 0.5 mM H2O2 or PBS for 1 h. Cells were fixed and immunofluorescence was performed to monitor HuR localization.

SIGNOR-278314

P02545

P17252

0

phosphorylation

up-regulates activity

0.362

Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence.

SIGNOR-248904

Q6PHR2

P08151

1

phosphorylation

up-regulates activity

0.673

We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro. | Our data suggest that serine/threonine kinase ULK3 is involved in the SHH pathway as a positive regulator of GLI proteins.

SIGNOR-260797

Q13557

P56524

1

phosphorylation

up-regulates

0.358

These results demonstrate that camkiideltab preferentially targets hdac4, and this involves serine 210overexpression of camkiideltab in primary neonatal cardiomyocytes increases the activity of the mef2 transcription factor and completely rescues hdac4-mediated repression of mef2

SIGNOR-151418

Q93009

P68400

0

phosphorylation

up-regulates quantity by stabilization

0.372

We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53.

SIGNOR-276530

P26678

Q13976

0

phosphorylation

up-regulates activity

0.409

Phosphorylation of PLB by PKA or cGKI at Ser 16 relieves the inhibition of SERCA2a and results in increased contractility through enhanced Ca 2+ i reuptake into the SR.

SIGNOR-279269

P04049

P98170

1

phosphorylation

up-regulates activity

0.504

Interaction and stabilization of X-linked inhibitor of apoptosis by Raf-1 protein kinase.|We also demonstrate that Raf-1 phosphorylates XIAP in vitro and in vivo.

SIGNOR-279105

P53671

P23528

1

phosphorylation

down-regulates activity

0.766

We report here that limk1 and limk2 phosphorylate both cofilin and actin-depolymerizing factor (adf) specifically at ser-3 and exhibit partially distinct substrate specificity when tested using site-directed cofilin mutants as substrates

SIGNOR-105098

Q9Y478

P29474

1

phosphorylation

up-regulates

0.2

Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.

SIGNOR-112367

Q9UQM7

Q9UQD0

1

phosphorylation

up-regulates activity

0.279

CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.

SIGNOR-275785

P46736

P0C0S8

1

deubiquitination

down-regulates

0.2

Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a

SIGNOR-167142

Q16665

Q96A26

1

transcriptional regulation

up-regulates quantity by expression

0.282

In this work, we report the identification of an HIF-1 alpha-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1 alpha through a hypoxia-responsive element on the HGTD-P promoter region.

SIGNOR-260292

P53350

Q9HAW4

1

phosphorylation

down-regulates

0.773

We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase

SIGNOR-148442

Q07352

P49137

0

phosphorylation

down-regulates

0.62

Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation.

SIGNOR-161274

P49841

P46821

1

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

Q15796

O96013

0

phosphorylation

down-regulates quantity by destabilization

0.339

In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation.

SIGNOR-279084

Q9BY11

O96013

0

phosphorylation

up-regulates activity

0.295

We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.

SIGNOR-263023

P49841

O00213

1

phosphorylation

up-regulates quantity

0.293

In this regards, GSK3beta may promote amyloidogenic processing of APP by regulating the cellular level of monomeric FE65 for the formation of LRP1, FE65, and APP complex.|In this study, we showed that FE65 is phosphorylated at T579 by GSK3beta.

SIGNOR-278359

P22607

Q04760

1

phosphorylation

up-regulates activity

0.2

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).

SIGNOR-276181

P20248

P30304

0

dephosphorylation

up-regulates activity

0.692

Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1 [4,5] .

SIGNOR-277136

Q12888

Q96GD4

0

phosphorylation

up-regulates activity

0.409

Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores.

SIGNOR-264411

P17612

P19793

1

phosphorylation

down-regulates

0.2

Serine 27, a human retinoid x receptor alpha residue, phosphorylated by protein kinase a is essential for cyclicamp-mediated downregulation of rxralpha function.

SIGNOR-104954

P62714

O96017

1

dephosphorylation

up-regulates activity

0.309

Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation.

SIGNOR-248582

Q9Y2U5

Q13163

1

phosphorylation

up-regulates

0.762

Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.

SIGNOR-104634

Q9BXH1

Q07812

1

relocalization

up-regulates

0.49

Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.

SIGNOR-185671

O14647

P84243

1

relocalization

up-regulates quantity

0.2

Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage.

SIGNOR-264527

P61586

Q9P2N2

0

gtpase-activating protein

down-regulates activity

0.504

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-260483

P17252

Q9BZL6

1

phosphorylation

up-regulates activity

0.393

Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.

SIGNOR-275955

P53667

P49137

0

phosphorylation

up-regulates

0.36

Mk2 activated limk1 by phosphorylation at ser-323.

SIGNOR-144333

P13569

Q13131

0

phosphorylation

down-regulates activity

0.493

AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions

SIGNOR-259858

P07948

Q9Y6M4

0

phosphorylation

up-regulates quantity by stabilization

0.2

Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane.

SIGNOR-275395

Q4FZB7

P62805

1

methylation

down-regulates activity

0.2

SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation.

SIGNOR-266651

Q9Y463

P46527

1

phosphorylation

up-regulates

0.355

Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation

SIGNOR-235805