GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P34947	Q9UQL6	1	phosphorylation	down-regulates activity	0.356	GRK5 phosphorylates and promotes the nuclear export of the histone deacetylase, HDAC5.	SIGNOR-279045
Q9UHD2	Q12834	1	phosphorylation	down-regulates activity	0.2	It was found that TBK1 phosphorylates both Cdc20 as well as Cdh1 (Figure 2F).	SIGNOR-279766
Q8WY54	Q13153	1	dephosphorylation	down-regulates activity	0.303	The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family\|POPX Can Dephosphorylate and Downregulate PAK\| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX.	SIGNOR-248761
P00519	P19174	1	phosphorylation	down-regulates activity	0.59	C-Abl induces Tyr phosphorylation of PLC-γ1 in vivo. These findings demonstrate that c-Abl phosphorylates PLC-γ1 in vivo predominantly at Tyr 771 and Tyr 1003.c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity.	SIGNOR-276001
Q03164	P17947	1	methylation	up-regulates quantity by expression	0.441	Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression.	SIGNOR-255874
Q01860	Q9Y243	0	phosphorylation	up-regulates quantity by stabilization	0.257	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-242107
Q15154	O00444	0	phosphorylation	up-regulates activity	0.573	Plk4‚Äêmediated phosphorylation of PCM1 at S372 is critical for the proper localisation of centriolar satellites, its dimer formation and interaction with other satellite components\|Therefore, Plk4 is responsible for PCM1 phosphorylation at S372.	SIGNOR-279556
P17612	Q9UNF0	1	phosphorylation	down-regulates activity	0.2	PKCα phosphorylates PACSIN2 at serine 313 in the linker region and decreases its membrane binding and tubulation activities. Phosphorylation of PACSIN2 at S313 negatively regulated protein interaction between NS5A and core, which affected viral assembly	SIGNOR-273799
P17612	Q9H2S1	1	phosphorylation	down-regulates	0.2	Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization	SIGNOR-145040
P45983	Q96J02	1	phosphorylation	up-regulates activity	0.654	Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222	SIGNOR-245323
P36507	P41279	0	phosphorylation	up-regulates	0.436	Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases.	SIGNOR-129694
P12931	Q13009	1	phosphorylation	up-regulates	0.657	Tiam1 cooperated with src to induce activation of rac1 in vivo and the formation of membrane ruffles.	SIGNOR-102354
P08575	P07948	1	dephosphorylation	down-regulates activity	0.666	CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.\| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)	SIGNOR-248354
Q14247	Q15139	0	phosphorylation	down-regulates	0.421	Pkd phosphorylates cortactin in vitro and in vivo at serine 298 thereby generating a 14-3-3 binding motif. In vitro, a phosphorylation-deficient cortactin-s298a protein accelerated vca-arp-cortactin-mediated synergistic actin polymerization and showed reduced f-actin binding	SIGNOR-164756
Q15652	P68431	1	demethylation	down-regulates activity	0.2	We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.	SIGNOR-265171
Q9Y4K3	O43318	1	ubiquitination	up-regulates activity	0.893	Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.	SIGNOR-236071
Q14738	Q13315	0	phosphorylation	up-regulates activity	0.297	In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth.	SIGNOR-276319
Q00535	P06400	1	phosphorylation	down-regulates	0.336	Phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a cdk5 inhibitor, roscovitine, which does not inhibit the usual rb cyclin-d kinases cdk4 and cdk6. Furthermore, analyses of levels and subcellular localization of cdk-related cyclins did not reveal any change following cdk5 activation, arguing for a direct effect of cdk5 activity on rb protein. Rb phosphorylation was visualized using phosphorylation-dependent antibodies (p-rbser795 and p-rbser807/811).	SIGNOR-134468
P31749	Q53EL6	1	phosphorylation	down-regulates	0.435	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-252505
Q9BXM7	P60484	1	phosphorylation	down-regulates activity	0.47	PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import.	SIGNOR-277915
Q12972	P07948	0	phosphorylation	down-regulates activity	0.312	Tyrosine phosphorylation of NIPP1 by Lyn was abolished by the Tyr-264 to Asp mutation.	SIGNOR-251405
Q92915	P19784	0	phosphorylation	up-regulates activity	0.307	Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275741
P54577	P18848	0	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269431
P21127	O00303	1	phosphorylation	up-regulates activity	0.515	EIF3f is phosphorylated by CDK11p46 at Ser46 during apoptosis.\|Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis.	SIGNOR-273133
P61073	Q05655	0	phosphorylation	down-regulates activity	0.2	Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C \| However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization.	SIGNOR-260898
Q676U5	Q9H2C0	0	ubiquitination	down-regulates quantity	0.2	Here we identify Gigaxonin24, an E3 ligase mutated in a fatal neurodegenerative disease called giant axonal neuropathy (GAN)25, as the first regulator of ATG16L1. Gigaxonin poly-ubiquitinates and controls the degradation of ATG16L1, and is essential to activate autophagy.	SIGNOR-268948
P36956	P23443	0	phosphorylation	up-regulates activity	0.424	Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation.\|Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element-binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation ( xref ).	SIGNOR-280120
Q07817	P42229	0	transcriptional regulation	up-regulates quantity by expression	0.653	FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells	SIGNOR-261551
P52952	P68400	0	phosphorylation	up-regulates activity	0.332	Mutational analysis and in vitro kinase assays suggested that this 40-kDa Csx/Nkx2.5 kinase is a catalytic subunit of casein kinase II (CKII) that phosphorylates the serine residue between the first and second helix of the homeodomain. This CKII site is phosphorylated in vivo. CKII-dependent phosphorylation of the homeodomain increased Csx/Nkx2. 5 DNA binding. Serine-to-alanine mutation at the CKII phosphorylation site reduced transcriptional activity when the carboxyl-terminal repressor domain was deleted.	SIGNOR-250924
O60674	P22681	0	ubiquitination	down-regulates quantity by destabilization	0.587	K63 linked poly-ubiquitination on K970 of JAK2 kinase domain is promoted by Cbl.	SIGNOR-278538
P49840	Q969R2	1	phosphorylation	up-regulates activity	0.2	CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.\|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.	SIGNOR-264875
Q8IWQ3	Q15831	0	phosphorylation	up-regulates	0.503	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122485
P11717	Q8IWJ2	0	relocalization	up-regulates activity	0.529	Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector	SIGNOR-253085
P22888	P10589	0	transcriptional regulation	down-regulates quantity by repression	0.275	Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.	SIGNOR-266218
Q13164	P14921	1	phosphorylation	up-regulates	0.42	9-cis retinoid x receptor alpha (rxr alpha) interacted with erk2 but not erk5 in intact cells, whereas ets-1 interacted preferentially with erk5. Increased phosphorylation of rxr alpha and ets-1 was detected in response to 1,25d. Activated erk2 and erk5 specifically phosphorylated rxr alpha and ets-1, respectively.Mutagenesis of ets-1 (t38a) reduced cyp24 promoter activity to levels observed with the dominant-negative mek5(a) and inhibited erk5-directed phosphorylation. Mutated rxr alpha (s260a) inhibited 1,25d-induced cyp24 promoter activity and abolished phosphorylation by activated erk2.	SIGNOR-88666
Q9BZB8	P06493	0	phosphorylation	up-regulates activity	0.581	Combined, our results suggest that XGef is involved in XRINGO and CDK1 mediated activation of CPEB and that an XGef, XRINGO, ERK2, and CPEB complex forms in ovo to facilitate this process.\|Notably, specific inhibition of XRINGO and CDK1 activity in CPEB phosphorylation-competent extracts completely blocks phosphorylation of CPEB, which suggests that XRINGO and CDK1 directly phosphorylates CPEB.	SIGNOR-280205
Q16512	P04049	1	phosphorylation	up-regulates	0.2	Interaction between active pak1 and raf-1 is necessary for phosphorylation and activation of raf-1.	SIGNOR-112549
P06239	Q9NP31	1	phosphorylation	up-regulates activity	0.578	Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition.	SIGNOR-262888
O15530	Q05655	1	phosphorylation	up-regulates activity	0.577	PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. PKCδ was also phosphorylated in the activation loop site (T505)	SIGNOR-250269
P46934	P55036	1	polyubiquitination	down-regulates quantity by destabilization	0.451	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-272753
P09619	Q13237	0	phosphorylation	down-regulates activity	0.272	Secretory PKG II inhibited PDGF‐BB ‐induced PDGFRβ activation via phosphorylating its Ser254.	SIGNOR-277577
O14757	Q04206	1	phosphorylation	up-regulates activity	0.454	Here we demonstrate that ARF induces the ATR- and Chk1-dependent phosphorylation of the RelA transactivation domain at threonine 505, a site required for ARF-dependent repression of RelA transcriptional activity.	SIGNOR-280225
P36896	Q13705	0	phosphorylation	up-regulates activity	0.691	Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.	SIGNOR-235146
P12931	P22001	1	phosphorylation	up-regulates	0.31	The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties.	SIGNOR-114641
Q9HAU4	O15198	1	ubiquitination	down-regulates	0.644	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-193390
P28482	Q13153	1	phosphorylation	down-regulates activity	0.402	We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal	SIGNOR-249432
Q9NTG7	P05108	1	deacetylation	up-regulates quantity by stabilization	0.2	Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.\|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis.	SIGNOR-268718
P17252	P04004	1	phosphorylation	up-regulates quantity by stabilization	0.318	Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.	SIGNOR-248962
Q86YF9	P49841	0	phosphorylation	up-regulates activity	0.39	Phosphorylation of Dzip1 by GSK3\u03b2 Promotes the Release of Rab8 GDP from GDI2.	SIGNOR-278251
P16298	Q13469	1	dephosphorylation	up-regulates	0.614	Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.	SIGNOR-233438
P17096	Q05655	0	phosphorylation	down-regulates	0.263	In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64	SIGNOR-73610
P42226	Q13191	0	ubiquitination	down-regulates quantity	0.2	Having shown that Cbl-b negatively regulates Stat6, we further investigated the mechanism of this regulation by determining whether Cbl-b associates with Stat6.\|Our data demonstrate that Stat6 is ubiquitinated at K108 and K398 by Cbl-b, and that Stat6 ubiquitination is a critical post-translational regulatory mechanism for Stat6.	SIGNOR-278806
P31749	Q9P0U3	0	desumoylation	down-regulates quantity by destabilization	0.28	Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity.	SIGNOR-252736
Q96KG9	P31749	0	phosphorylation	up-regulates activity	0.255	In previous work, we demonstrated that TEIF (transcriptional element-interacting factor) distributes in the centrosomes and regulates centrosome status under both physiologic and pathologic conditions.\|A consensus motif for Akt phosphorylation (RHRVLT) proved to be involved in centrosomal TEIF localization, and the 469-threonine of this motif may be phosphorylated by Akt both in vitro and in vivo. Elimination of this phosphorylated site on TEIF caused reduced centrosome distribution and centrosome splitting or amplification.	SIGNOR-265496
P04637	P17252	0	phosphorylation	up-regulates activity	0.437	Here, we demonstrate that cotransfection of p53 with either PKC alpha or PKC zeta increases p53's transcriptional activity. Mutagenesis of p53 indicates that serine 371 is the major site for phosphorylation by PKC alpha in vitro.	SIGNOR-248999
P52333	Q13261	0	null	up-regulates	0.501	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-256226
P32298	P30411	1	phosphorylation	down-regulates activity	0.288	Expression of GRK4α drastically increased the basal level of32P incorporation into B2R. GRK4α elevated the basal phosphorylation of Ser339 and Ser346/Ser348. phosphorylation of specific residues was correlated with the initiation of receptor internalization and the regulation of its desensitization.	SIGNOR-251193
P0CG47	Q96BN8	0	cleavage	up-regulates quantity	0.671	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270819
Q92918	Q13200	1	phosphorylation	up-regulates activity	0.2	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).	SIGNOR-273899
Q15262	P40763	1	dephosphorylation	down-regulates activity	0.374	In this study, we investigated whether receptor-type tyrosine protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3 specifying motif, negatively regulates STAT3 activation in NKTCL.\|Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705).	SIGNOR-277060
P05771	P48736	1	phosphorylation	up-regulates activity	0.501	Remarkably we find that PKCβ phosphorylates Ser582 in the helical domain of the PI3Kγ catalytic subunit p110γ in response to clustering of the high-affinity IgE receptor (FcεRI) and/or store-operated Ca²⁺- influx in mast cells. Phosphorylation of p110γ correlates with the release of the p84 PI3Kγ adapter subunit from the p84-p110γ complex.As functional p84-p110γ is key to GPCR-mediated p110γ signaling, this suggests that PKCβ-mediated p110γ phosphorylation disconnects PI3Kγ from its canonical inputs from trimeric G proteins, and enables p110γ to operate downstream of Ca²⁺ and PKCβ.	SIGNOR-276496
P49841	P35222	1	phosphorylation	down-regulates activity	0.86	Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).	SIGNOR-116528
P28482	Q14674	1	phosphorylation	down-regulates	0.277	Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro	SIGNOR-113130
P06493	Q9NTG7	1	phosphorylation	up-regulates activity	0.315	Both SIRT3 T150 and S159 phosphorylated by CDK1 indicates that CDK1-SIRT3 pathway may play a role in the overall mitochondrial protein acetylation involved in mitochondrial homeostasis and apoptosis.	SIGNOR-279395
Q9H000	Q04206	1	ubiquitination	down-regulates quantity by destabilization	0.341	MKRN2 promotes p65 ubiquitination and degradation through RING finger domain.	SIGNOR-278591
P35613	Q8NEZ5	0	ubiquitination	down-regulates quantity by destabilization	0.427	F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells	SIGNOR-273452
P18031	P05787	1	dephosphorylation	down-regulates activity	0.2	Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine.	SIGNOR-265495
O15350	O14757	0	phosphorylation	up-regulates	0.536	We found that endogenous p73alpha is serine phosphorylated by endogenous chk1 upon dna damage, which is a mechanism required for the apoptotic-inducing function of p73alpha.	SIGNOR-118913
P16104	Q13043	0	phosphorylation	up-regulates activity	0.2	Western blot and kinase assay results with a mutant S139A H2AX confirmed that MST1 phosphorylates H2AX at Ser-139.	SIGNOR-278457
Q8IWU2	Q00535	0	phosphorylation	up-regulates	0.497	Here, we demonstrate that lmtk2 is phosphorylated on serine-1418 (lmtk2ser ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate pp1cthr __	SIGNOR-195329
Q92519	P14618	1	phosphorylation	up-regulates activity	0.2	This study demonstrated that TRIB2, not a "pseudokinase", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells.	SIGNOR-275431
O95149	Q6ZN04	0	polyubiquitination	down-regulates quantity by destabilization	0.556	HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation.	SIGNOR-272079
P17612	P42261	1	phosphorylation	up-regulates activity	0.494	Phosphorylation of Ser-845 on GluR1 by PKA potentiates its response to glutamate.	SIGNOR-249987
P49757	Q8IUQ4	0	ubiquitination	down-regulates	0.4	We report that siah-1 interacts directly with and promotes the degradation of the cell fate regulator numb.	SIGNOR-113469
Q16659	P06493	0	phosphorylation	up-regulates	0.484	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.	SIGNOR-164499
Q13315	Q8IW19	1	phosphorylation	up-regulates activity	0.4	We show that APLF undergoes ATM dependent hyperphosphorylation following IR and that APLF is directly phosphorylated by ATM in vitro.	SIGNOR-279492
Q9UBP0	P53990	0	relocalization	up-regulates activity	0.519	Our results suggest that inclusion of IST1 into the ESCRT complex allows recruitment of spastin to promote fission of recycling tubules from the endosome. Thus, we reveal a novel cellular role for MT severing and identify a mechanism by which endosomal recycling can be coordinated with the degradative machinery.	SIGNOR-269047
Q2M2I8	P49757	1	phosphorylation	up-regulates	0.459	Collectively, these observations demonstrate that numb endocytic activity is regulated by aak1 and that phosphorylation may be a critical step in promoting coated pit maturation.	SIGNOR-179606
P05231	Q14653	0	transcriptional regulation	up-regulates quantity by expression	0.406	Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation	SIGNOR-251721
Q12778	P31751	0	phosphorylation	down-regulates activity	0.658	Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus.	SIGNOR-68652
P05771	P14598	1	phosphorylation	up-regulates	0.565	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89197
P13726	P17252	0	phosphorylation	up-regulates	0.2	We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. The phosphorylation of ser253 is known to be mediated by protein kinase c_	SIGNOR-199872
Q9H093	O95835	1	phosphorylation	down-regulates	0.307	Phosphorylation at ser-464 by nuak1 and nuak2 leads to decreased protein level and is required to regulate cellular senescence and cellular ploidy	SIGNOR-161796
P43405	Q8TB45	1	phosphorylation	down-regulates activity	0.2	We found that tyrosine (Tyr) 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (spleen tyrosine kinase) as a kinase involved in DEPTOR Tyr 289 phosphorylation in an ephrin (erythropoietin-producing hepatocellular carcinoma) receptor-dependent manner.	SIGNOR-277572
O15379	Q9BXM7	0	phosphorylation	up-regulates activity	0.2	PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death.\|PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c.	SIGNOR-279093
P06493	Q9BYG3	1	phosphorylation	up-regulates activity	0.28	The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1.	SIGNOR-262696
O15119	P38936	1	transcriptional regulation	down-regulates quantity by repression	0.304	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249602
P30411	P25098	0	phosphorylation	down-regulates activity	0.2	Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251445
P30304	Q9P1W9	0	phosphorylation	down-regulates quantity by destabilization	0.361	The proteasome-dependent degradation of CDC25A, seen in this study upon PIM-2 over-expression, suggests that PIM-2 promotes CDC25A phosphorylation that triggers its ubiquitylation.	SIGNOR-279750
Q9UI08	Q13976	0	phosphorylation	down-regulates activity	0.2	Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts	SIGNOR-268290
Q99720	Q9NZQ7	1	stabilization	up-regulates quantity by stabilization	0.2	We propose that Sigma1 is a ligand-operated scaffolding protein that promotes the stability, processing, assembly, and trafficking of specific proteins in the secretory pathway of cancer cells. In support of this hypothesis, we found that siRNA-mediated knockdown of Sigma1 resulted in a significant decrease in PD-L1 protein levels in triple-negative MDA-MB-231 breast cancer and androgen-independent PC3 prostate cancer cells	SIGNOR-274974
P43629	P48730	0	phosphorylation	up-regulates	0.2	In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.	SIGNOR-158125
P31751	O60858	0	polyubiquitination	down-regulates quantity by destabilization	0.2	Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.	SIGNOR-271853
O15266	P68400	0	phosphorylation	up-regulates	0.338	We show also that casein kinase ii phosphorylates shox on serine 106 efficiently in vitro. S106a shox mutant, defective in phosphorylation, does not activate transcription and fails to induce cell-cycle arrest and apoptosis	SIGNOR-142875
Q9UKE5	Q15797	1	phosphorylation	down-regulates activity	0.2	Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.	SIGNOR-276334
Q15139	Q96A00	1	phosphorylation	up-regulates activity	0.2	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.	SIGNOR-249260
Q14680	Q13501	1	phosphorylation	up-regulates activity	0.2	Consistent with our SILAC experiments, MELK directly phosphorylated SQSTM1 (XREF_FIG).\|Furthermore, we show that MELK promotes melanoma growth by activating NF-kappaB pathway activity via Sequestosome 1 (SQSTM1 and p62).	SIGNOR-279544
P12931	P51812	1	phosphorylation	up-regulates	0.355	Together, our findings suggest that src-dependent phosphorylation at tyr-529 facilitates inactive erk binding to rsk2, which might be a general requirement for rsk2 activation by egf through the mek/erk pathway.	SIGNOR-160052
P19784	Q15022	1	phosphorylation	up-regulates activity	0.2	CK2 is the kinase for the phosphorylation of S583 of SUZ12.	SIGNOR-277797
P10275	Q86UZ6	1	transcriptional regulation	down-regulates quantity by repression	0.2	Our study confirmed a novel positive association between ZBTB46 activity and LIF levels in prostate cancer tissues and cells. Under androgen regulation, low levels of ZBTB46 are an essential transcriptional factor for maintaining LIF-STAT3 signaling, while the loss of androgen signaling or inhibition of AR signaling causes LIF-enhanced therapeutic resistance and CRPC characteristics through the upregulation of ZBTB46. We also found that LIF activation drives malignant progression and NE-like reprogramming in prostate cancer by activating STAT3 signaling.	SIGNOR-277989

P34947

Q9UQL6

1

phosphorylation

down-regulates activity

0.356

GRK5 phosphorylates and promotes the nuclear export of the histone deacetylase, HDAC5.

SIGNOR-279045

Q9UHD2

Q12834

1

phosphorylation

down-regulates activity

0.2

It was found that TBK1 phosphorylates both Cdc20 as well as Cdh1 (Figure 2F).

SIGNOR-279766

Q8WY54

Q13153

1

dephosphorylation

down-regulates activity

0.303

The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX.

SIGNOR-248761

P00519

P19174

1

phosphorylation

down-regulates activity

0.59

C-Abl induces Tyr phosphorylation of PLC-γ1 in vivo. These findings demonstrate that c-Abl phosphorylates PLC-γ1 in vivo predominantly at Tyr 771 and Tyr 1003.c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity.

SIGNOR-276001

Q03164

P17947

1

methylation

up-regulates quantity by expression

0.441

Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression.

SIGNOR-255874

Q01860

Q9Y243

0

phosphorylation

up-regulates quantity by stabilization

0.257

Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.

SIGNOR-242107

Q15154

O00444

0

phosphorylation

up-regulates activity

0.573

Plk4‚Äêmediated phosphorylation of PCM1 at S372 is critical for the proper localisation of centriolar satellites, its dimer formation and interaction with other satellite components|Therefore, Plk4 is responsible for PCM1 phosphorylation at S372.

SIGNOR-279556

P17612

Q9UNF0

1

phosphorylation

down-regulates activity

0.2

PKCα phosphorylates PACSIN2 at serine 313 in the linker region and decreases its membrane binding and tubulation activities. Phosphorylation of PACSIN2 at S313 negatively regulated protein interaction between NS5A and core, which affected viral assembly

SIGNOR-273799

P17612

Q9H2S1

1

phosphorylation

down-regulates

0.2

Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization

SIGNOR-145040

P45983

Q96J02

1

phosphorylation

up-regulates activity

0.654

Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222

SIGNOR-245323

P36507

P41279

0

phosphorylation

up-regulates

0.436

Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases.

SIGNOR-129694

P12931

Q13009

1

phosphorylation

up-regulates

0.657

Tiam1 cooperated with src to induce activation of rac1 in vivo and the formation of membrane ruffles.

SIGNOR-102354

P08575

P07948

1

dephosphorylation

down-regulates activity

0.666

CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)

SIGNOR-248354

Q14247

Q15139

0

phosphorylation

down-regulates

0.421

Pkd phosphorylates cortactin in vitro and in vivo at serine 298 thereby generating a 14-3-3 binding motif. In vitro, a phosphorylation-deficient cortactin-s298a protein accelerated vca-arp-cortactin-mediated synergistic actin polymerization and showed reduced f-actin binding

SIGNOR-164756

Q15652

P68431

1

demethylation

down-regulates activity

0.2

We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.

SIGNOR-265171

Q9Y4K3

O43318

1

ubiquitination

up-regulates activity

0.893

Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.

SIGNOR-236071

Q14738

Q13315

0

phosphorylation

up-regulates activity

0.297

In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth.

SIGNOR-276319

Q00535

P06400

1

phosphorylation

down-regulates

0.336

Phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a cdk5 inhibitor, roscovitine, which does not inhibit the usual rb cyclin-d kinases cdk4 and cdk6. Furthermore, analyses of levels and subcellular localization of cdk-related cyclins did not reveal any change following cdk5 activation, arguing for a direct effect of cdk5 activity on rb protein. Rb phosphorylation was visualized using phosphorylation-dependent antibodies (p-rbser795 and p-rbser807/811).

SIGNOR-134468

P31749

Q53EL6

1

phosphorylation

down-regulates

0.435

Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.

SIGNOR-252505

Q9BXM7

P60484

1

phosphorylation

down-regulates activity

0.47

PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import.

SIGNOR-277915

Q12972

P07948

0

phosphorylation

down-regulates activity

0.312

Tyrosine phosphorylation of NIPP1 by Lyn was abolished by the Tyr-264 to Asp mutation.

SIGNOR-251405

Q92915

P19784

0

phosphorylation

up-regulates activity

0.307

Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.

SIGNOR-275741

P54577

P18848

0

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269431

P21127

O00303

1

phosphorylation

up-regulates activity

0.515

EIF3f is phosphorylated by CDK11p46 at Ser46 during apoptosis.|Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis.

SIGNOR-273133

P61073

Q05655

0

phosphorylation

down-regulates activity

0.2

Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization.

SIGNOR-260898

Q676U5

Q9H2C0

0

ubiquitination

down-regulates quantity

0.2

Here we identify Gigaxonin24, an E3 ligase mutated in a fatal neurodegenerative disease called giant axonal neuropathy (GAN)25, as the first regulator of ATG16L1. Gigaxonin poly-ubiquitinates and controls the degradation of ATG16L1, and is essential to activate autophagy.

SIGNOR-268948

P36956

P23443

0

phosphorylation

up-regulates activity

0.424

Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation.|Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element-binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation ( xref ).

SIGNOR-280120

Q07817

P42229

0

transcriptional regulation

up-regulates quantity by expression

0.653

FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells

SIGNOR-261551

P52952

P68400

0

phosphorylation

up-regulates activity

0.332

Mutational analysis and in vitro kinase assays suggested that this 40-kDa Csx/Nkx2.5 kinase is a catalytic subunit of casein kinase II (CKII) that phosphorylates the serine residue between the first and second helix of the homeodomain. This CKII site is phosphorylated in vivo. CKII-dependent phosphorylation of the homeodomain increased Csx/Nkx2. 5 DNA binding. Serine-to-alanine mutation at the CKII phosphorylation site reduced transcriptional activity when the carboxyl-terminal repressor domain was deleted.

SIGNOR-250924

O60674

P22681

0

ubiquitination

down-regulates quantity by destabilization

0.587

K63 linked poly-ubiquitination on K970 of JAK2 kinase domain is promoted by Cbl.

SIGNOR-278538

P49840

Q969R2

1

phosphorylation

up-regulates activity

0.2

CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.

SIGNOR-264875

Q8IWQ3

Q15831

0

phosphorylation

up-regulates

0.503

Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold

SIGNOR-122485

P11717

Q8IWJ2

0

relocalization

up-regulates activity

0.529

Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector

SIGNOR-253085

P22888

P10589

0

transcriptional regulation

down-regulates quantity by repression

0.275

Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.

SIGNOR-266218

Q13164

P14921

1

phosphorylation

up-regulates

0.42

9-cis retinoid x receptor alpha (rxr alpha) interacted with erk2 but not erk5 in intact cells, whereas ets-1 interacted preferentially with erk5. Increased phosphorylation of rxr alpha and ets-1 was detected in response to 1,25d. Activated erk2 and erk5 specifically phosphorylated rxr alpha and ets-1, respectively.Mutagenesis of ets-1 (t38a) reduced cyp24 promoter activity to levels observed with the dominant-negative mek5(a) and inhibited erk5-directed phosphorylation. Mutated rxr alpha (s260a) inhibited 1,25d-induced cyp24 promoter activity and abolished phosphorylation by activated erk2.

SIGNOR-88666

Q9BZB8

P06493

0

phosphorylation

up-regulates activity

0.581

Combined, our results suggest that XGef is involved in XRINGO and CDK1 mediated activation of CPEB and that an XGef, XRINGO, ERK2, and CPEB complex forms in ovo to facilitate this process.|Notably, specific inhibition of XRINGO and CDK1 activity in CPEB phosphorylation-competent extracts completely blocks phosphorylation of CPEB, which suggests that XRINGO and CDK1 directly phosphorylates CPEB.

SIGNOR-280205

Q16512

P04049

1

phosphorylation

up-regulates

0.2

Interaction between active pak1 and raf-1 is necessary for phosphorylation and activation of raf-1.

SIGNOR-112549

P06239

Q9NP31

1

phosphorylation

up-regulates activity

0.578

Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition.

SIGNOR-262888

O15530

Q05655

1

phosphorylation

up-regulates activity

0.577

PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. PKCδ was also phosphorylated in the activation loop site (T505)

SIGNOR-250269

P46934

P55036

1

polyubiquitination

down-regulates quantity by destabilization

0.451

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-272753

P09619

Q13237

0

phosphorylation

down-regulates activity

0.272

Secretory PKG II inhibited PDGF‐BB ‐induced PDGFRβ activation via phosphorylating its Ser254.

SIGNOR-277577

O14757

Q04206

1

phosphorylation

up-regulates activity

0.454

Here we demonstrate that ARF induces the ATR- and Chk1-dependent phosphorylation of the RelA transactivation domain at threonine 505, a site required for ARF-dependent repression of RelA transcriptional activity.

SIGNOR-280225

P36896

Q13705

0

phosphorylation

up-regulates activity

0.691

Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.

SIGNOR-235146

P12931

P22001

1

phosphorylation

up-regulates

0.31

The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties.

SIGNOR-114641

Q9HAU4

O15198

1

ubiquitination

down-regulates

0.644

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps

SIGNOR-193390

P28482

Q13153

1

phosphorylation

down-regulates activity

0.402

We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal

SIGNOR-249432

Q9NTG7

P05108

1

deacetylation

up-regulates quantity by stabilization

0.2

Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis.

SIGNOR-268718

P17252

P04004

1

phosphorylation

up-regulates quantity by stabilization

0.318

Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.

SIGNOR-248962

Q86YF9

P49841

0

phosphorylation

up-regulates activity

0.39

Phosphorylation of Dzip1 by GSK3\u03b2 Promotes the Release of Rab8 GDP from GDI2.

SIGNOR-278251

P16298

Q13469

1

dephosphorylation

up-regulates

0.614

Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.

SIGNOR-233438

P17096

Q05655

0

phosphorylation

down-regulates

0.263

In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64

SIGNOR-73610

P42226

Q13191

0

ubiquitination

down-regulates quantity

0.2

Having shown that Cbl-b negatively regulates Stat6, we further investigated the mechanism of this regulation by determining whether Cbl-b associates with Stat6.|Our data demonstrate that Stat6 is ubiquitinated at K108 and K398 by Cbl-b, and that Stat6 ubiquitination is a critical post-translational regulatory mechanism for Stat6.

SIGNOR-278806

P31749

Q9P0U3

0

desumoylation

down-regulates quantity by destabilization

0.28

Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity.

SIGNOR-252736

Q96KG9

P31749

0

phosphorylation

up-regulates activity

0.255

In previous work, we demonstrated that TEIF (transcriptional element-interacting factor) distributes in the centrosomes and regulates centrosome status under both physiologic and pathologic conditions.|A consensus motif for Akt phosphorylation (RHRVLT) proved to be involved in centrosomal TEIF localization, and the 469-threonine of this motif may be phosphorylated by Akt both in vitro and in vivo. Elimination of this phosphorylated site on TEIF caused reduced centrosome distribution and centrosome splitting or amplification.

SIGNOR-265496

P04637

P17252

0

phosphorylation

up-regulates activity

0.437

Here, we demonstrate that cotransfection of p53 with either PKC alpha or PKC zeta increases p53's transcriptional activity. Mutagenesis of p53 indicates that serine 371 is the major site for phosphorylation by PKC alpha in vitro.

SIGNOR-248999

P52333

Q13261

0

null

up-regulates

0.501

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-256226

P32298

P30411

1

phosphorylation

down-regulates activity

0.288

Expression of GRK4α drastically increased the basal level of32P incorporation into B2R. GRK4α elevated the basal phosphorylation of Ser339 and Ser346/Ser348. phosphorylation of specific residues was correlated with the initiation of receptor internalization and the regulation of its desensitization.

SIGNOR-251193

P0CG47

Q96BN8

0

cleavage

up-regulates quantity

0.671

Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.

SIGNOR-270819

Q92918

Q13200

1

phosphorylation

up-regulates activity

0.2

Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).

SIGNOR-273899

Q15262

P40763

1

dephosphorylation

down-regulates activity

0.374

In this study, we investigated whether receptor-type tyrosine protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3 specifying motif, negatively regulates STAT3 activation in NKTCL.|Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705).

SIGNOR-277060

P05771

P48736

1

phosphorylation

up-regulates activity

0.501

Remarkably we find that PKCβ phosphorylates Ser582 in the helical domain of the PI3Kγ catalytic subunit p110γ in response to clustering of the high-affinity IgE receptor (FcεRI) and/or store-operated Ca²⁺- influx in mast cells. Phosphorylation of p110γ correlates with the release of the p84 PI3Kγ adapter subunit from the p84-p110γ complex.As functional p84-p110γ is key to GPCR-mediated p110γ signaling, this suggests that PKCβ-mediated p110γ phosphorylation disconnects PI3Kγ from its canonical inputs from trimeric G proteins, and enables p110γ to operate downstream of Ca²⁺ and PKCβ.

SIGNOR-276496

P49841

P35222

1

phosphorylation

down-regulates activity

0.86

Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).

SIGNOR-116528

P28482

Q14674

1

phosphorylation

down-regulates

0.277

Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro

SIGNOR-113130

P06493

Q9NTG7

1

phosphorylation

up-regulates activity

0.315

Both SIRT3 T150 and S159 phosphorylated by CDK1 indicates that CDK1-SIRT3 pathway may play a role in the overall mitochondrial protein acetylation involved in mitochondrial homeostasis and apoptosis.

SIGNOR-279395

Q9H000

Q04206

1

ubiquitination

down-regulates quantity by destabilization

0.341

MKRN2 promotes p65 ubiquitination and degradation through RING finger domain.

SIGNOR-278591

P35613

Q8NEZ5

0

ubiquitination

down-regulates quantity by destabilization

0.427

F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells

SIGNOR-273452

P18031

P05787

1

dephosphorylation

down-regulates activity

0.2

Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine.

SIGNOR-265495

O15350

O14757

0

phosphorylation

up-regulates

0.536

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

SIGNOR-118913

P16104

Q13043

0

phosphorylation

up-regulates activity

0.2

Western blot and kinase assay results with a mutant S139A H2AX confirmed that MST1 phosphorylates H2AX at Ser-139.

SIGNOR-278457

Q8IWU2

Q00535

0

phosphorylation

up-regulates

0.497

Here, we demonstrate that lmtk2 is phosphorylated on serine-1418 (lmtk2ser ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate pp1cthr __

SIGNOR-195329

Q92519

P14618

1

phosphorylation

up-regulates activity

0.2

This study demonstrated that TRIB2, not a "pseudokinase", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells.

SIGNOR-275431

O95149

Q6ZN04

0

polyubiquitination

down-regulates quantity by destabilization

0.556

HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation.

SIGNOR-272079

P17612

P42261

1

phosphorylation

up-regulates activity

0.494

Phosphorylation of Ser-845 on GluR1 by PKA potentiates its response to glutamate.

SIGNOR-249987

P49757

Q8IUQ4

0

ubiquitination

down-regulates

0.4

We report that siah-1 interacts directly with and promotes the degradation of the cell fate regulator numb.

SIGNOR-113469

Q16659

P06493

0

phosphorylation

up-regulates

0.484

Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.

SIGNOR-164499

Q13315

Q8IW19

1

phosphorylation

up-regulates activity

0.4

We show that APLF undergoes ATM dependent hyperphosphorylation following IR and that APLF is directly phosphorylated by ATM in vitro.

SIGNOR-279492

Q9UBP0

P53990

0

relocalization

up-regulates activity

0.519

Our results suggest that inclusion of IST1 into the ESCRT complex allows recruitment of spastin to promote fission of recycling tubules from the endosome. Thus, we reveal a novel cellular role for MT severing and identify a mechanism by which endosomal recycling can be coordinated with the degradative machinery.

SIGNOR-269047

Q2M2I8

P49757

1

phosphorylation

up-regulates

0.459

Collectively, these observations demonstrate that numb endocytic activity is regulated by aak1 and that phosphorylation may be a critical step in promoting coated pit maturation.

SIGNOR-179606

P05231

Q14653

0

transcriptional regulation

up-regulates quantity by expression

0.406

Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation

SIGNOR-251721

Q12778

P31751

0

phosphorylation

down-regulates activity

0.658

Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus.

SIGNOR-68652

P05771

P14598

1

phosphorylation

up-regulates

0.565

Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.

SIGNOR-89197

P13726

P17252

0

phosphorylation

up-regulates

0.2

We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. The phosphorylation of ser253 is known to be mediated by protein kinase c_

SIGNOR-199872

Q9H093

O95835

1

phosphorylation

down-regulates

0.307

Phosphorylation at ser-464 by nuak1 and nuak2 leads to decreased protein level and is required to regulate cellular senescence and cellular ploidy

SIGNOR-161796

P43405

Q8TB45

1

phosphorylation

down-regulates activity

0.2

We found that tyrosine (Tyr) 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (spleen tyrosine kinase) as a kinase involved in DEPTOR Tyr 289 phosphorylation in an ephrin (erythropoietin-producing hepatocellular carcinoma) receptor-dependent manner.

SIGNOR-277572

O15379

Q9BXM7

0

phosphorylation

up-regulates activity

0.2

PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death.|PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c.

SIGNOR-279093

P06493

Q9BYG3

1

phosphorylation

up-regulates activity

0.28

The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1.

SIGNOR-262696

O15119

P38936

1

transcriptional regulation

down-regulates quantity by repression

0.304

TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS

SIGNOR-249602

P30411

P25098

0

phosphorylation

down-regulates activity

0.2

Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.

SIGNOR-251445

P30304

Q9P1W9

0

phosphorylation

down-regulates quantity by destabilization

0.361

The proteasome-dependent degradation of CDC25A, seen in this study upon PIM-2 over-expression, suggests that PIM-2 promotes CDC25A phosphorylation that triggers its ubiquitylation.

SIGNOR-279750

Q9UI08

Q13976

0

phosphorylation

down-regulates activity

0.2

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

SIGNOR-268290

Q99720

Q9NZQ7

1

stabilization

up-regulates quantity by stabilization

0.2

We propose that Sigma1 is a ligand-operated scaffolding protein that promotes the stability, processing, assembly, and trafficking of specific proteins in the secretory pathway of cancer cells. In support of this hypothesis, we found that siRNA-mediated knockdown of Sigma1 resulted in a significant decrease in PD-L1 protein levels in triple-negative MDA-MB-231 breast cancer and androgen-independent PC3 prostate cancer cells

SIGNOR-274974

P43629

P48730

0

phosphorylation

up-regulates

0.2

In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.

SIGNOR-158125

P31751

O60858

0

polyubiquitination

down-regulates quantity by destabilization

0.2

Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.

SIGNOR-271853

O15266

P68400

0

phosphorylation

up-regulates

0.338

We show also that casein kinase ii phosphorylates shox on serine 106 efficiently in vitro. S106a shox mutant, defective in phosphorylation, does not activate transcription and fails to induce cell-cycle arrest and apoptosis

SIGNOR-142875

Q9UKE5

Q15797

1

phosphorylation

down-regulates activity

0.2

Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.

SIGNOR-276334

Q15139

Q96A00

1

phosphorylation

up-regulates activity

0.2

A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.

SIGNOR-249260

Q14680

Q13501

1

phosphorylation

up-regulates activity

0.2

Consistent with our SILAC experiments, MELK directly phosphorylated SQSTM1 (XREF_FIG).|Furthermore, we show that MELK promotes melanoma growth by activating NF-kappaB pathway activity via Sequestosome 1 (SQSTM1 and p62).

SIGNOR-279544

P12931

P51812

1

phosphorylation

up-regulates

0.355

Together, our findings suggest that src-dependent phosphorylation at tyr-529 facilitates inactive erk binding to rsk2, which might be a general requirement for rsk2 activation by egf through the mek/erk pathway.

SIGNOR-160052

P19784

Q15022

1

phosphorylation

up-regulates activity

0.2

CK2 is the kinase for the phosphorylation of S583 of SUZ12.

SIGNOR-277797

P10275

Q86UZ6

1

transcriptional regulation

down-regulates quantity by repression

0.2

Our study confirmed a novel positive association between ZBTB46 activity and LIF levels in prostate cancer tissues and cells. Under androgen regulation, low levels of ZBTB46 are an essential transcriptional factor for maintaining LIF-STAT3 signaling, while the loss of androgen signaling or inhibition of AR signaling causes LIF-enhanced therapeutic resistance and CRPC characteristics through the upregulation of ZBTB46. We also found that LIF activation drives malignant progression and NE-like reprogramming in prostate cancer by activating STAT3 signaling.

SIGNOR-277989