GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q96KB5	O75385	1	phosphorylation	down-regulates activity	0.2	We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.	SIGNOR-277473
P12931	Q7Z3C6	1	phosphorylation	up-regulates activity	0.342	Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation.	SIGNOR-266367
P04818	P01106	0	transcriptional regulation	up-regulates quantity by expression	0.337	Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.	SIGNOR-267374
P28482	Q14005	1	phosphorylation	up-regulates	0.265	The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response.	SIGNOR-121852
P30086	Q00535	0	phosphorylation	down-regulates quantity by destabilization	0.337	Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif "KLYEQ" in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA).	SIGNOR-276672
P35222	O95996	0	relocalization	down-regulates quantity by destabilization	0.79	The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation.	SIGNOR-81545
P84243	Q9C0A6	0	methylation	up-regulates activity	0.2	SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription.	SIGNOR-264622
O75674	P06241	0	phosphorylation	up-regulates activity	0.434	Tyr-457, located in the presumed Src SH2 binding site, is the predominant tyrosine residue that is phosphorylated by Fyn.Fyn can phosphorylate Srcasm, and association of these molecules relies on cooperative binding between the SH2 and SH3 domains of Fyn and corresponding canonical binding sites in Srcasm. Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner. The evidence suggests that Srcasm may help promote Src family kinase signaling in cells.	SIGNOR-251185
Q96RG2	P13807	1	phosphorylation	down-regulates activity	0.508	Recombinant human PASK (hPASK) phosphorylates purified muscle glycogen synthase, causing robust inactivation. Furthermore, hPASK interacts directly with glycogen synthase when expressed in cultured cells and this interaction and the phosphorylation of glycogen synthase by human PASK (hPASK) are inhibited by glycogen.	SIGNOR-245866
Q00341	P07333	1	transcriptional regulation	down-regulates quantity by repression	0.342	Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer.	SIGNOR-266696
P31749	Q969H0	1	phosphorylation	up-regulates activity	0.41	A reciprocal immunoprecipiation with anti-phospho-Akt substrate antibody followed by immunoblotting with anti-FLAG antibodies confirmed these findings (Fig. 1C). We concluded that Fbw7 is phosphorylated at S227 in vivo. Phosphorylation of Fbw7 is required for its biological activity.	SIGNOR-276328
P53350	Q2M2Z5	1	phosphorylation	up-regulates	0.519	Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz.	SIGNOR-149630
P50613	Q9H0D6	1	phosphorylation	up-regulates activity	0.247	CDKs and Xrn2 phosphorylation promote transcription termination. \| Cdk7 phosphorylated Xrn2-Thr439 but was less efficient than Cdk9. \|	SIGNOR-259851
Q01082	P36897	0	phosphorylation	up-regulates	0.522	This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead.	SIGNOR-97626
Q9UHD2	Q96AQ6	1	phosphorylation	down-regulates quantity by destabilization	0.29	Phosphorylation of HPIP on serine 147 by TBK1 promotes E2-mediated GREB1 expression. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.	SIGNOR-273643
P31749	Q01813	1	phosphorylation	up-regulates quantity	0.564	A reduction in AKT expression as a result of AKT1 shRNA expression or MK-2206 treatment decreased the half-life of endogenous PFKP, while the expression of active Myr-AKT1 prolonged the half-life of PFKP.\|In addition, depletion of endogenous PFKP and reconstitution of RNAi resistant WT Flag-rPFKP or Flag-rPFKP S386A expression in U251 or U87 and EGFRvIII cells revealed that the S386A mutation abolished PFKP phosphorylation induced by EGF, constitutively active Myr-AKT1, and EGFRvIII.	SIGNOR-279788
P51617	P40763	1	phosphorylation	up-regulates	0.55	Irak1 can directly use stat3 as a substrate and cause stat3 serine 727 phosphorylation.	SIGNOR-129685
P46934	O15399	1	ubiquitination	down-regulates activity	0.328	Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses.\|This suggests that Nedd4 association reduces GluN2D function, mostly likely by promoting GluN2D ubiquitination and internalization.	SIGNOR-278636
Q14164	O43524	1	phosphorylation	down-regulates	0.407	Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation.	SIGNOR-202054
Q08050	P24941	0	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
Q9UHD2	Q14980	1	phosphorylation	up-regulates activity	0.2	Our studies now reveal TBK1 as another kinase that phosphorylates NuMA and that is required for its association with dynein and for localization of NuMA to the centrosomes in mitotic cells.	SIGNOR-278432
Q16695	Q92831	0	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269621
P04637	Q9BY41	0	deacetylation	down-regulates activity	0.456	HDAC8 mediates CM-induced deacetylation of p53.Collectively, these results indicate that although binding to p53 and HDAC8 occurs through distinct regions of the CM protein, simultaneous interaction with HDAC8 and p53 is required for aberrant deacetylation and inactivation of p53.	SIGNOR-255738
P23396	P28482	0	phosphorylation	up-regulates	0.2	Erk phosphorylates threonine 42 residue of ribosomal protein s3.	SIGNOR-137955
P05231	Q12968	0	transcriptional regulation	up-regulates quantity by expression	0.283	The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. \|Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.	SIGNOR-251732
Q15025	Q86VP1	1	relocalization	up-regulates activity	0.45	ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi.	SIGNOR-275735
P49841	Q13976	0	phosphorylation	down-regulates activity	0.26	Moreover, PrkG1 inhibits GSK3\u03b2 by binding and directly phosphorylating GSK3\u03b2 at its serine-9 residue (Zhao et al., xref ).\|Moreover, PrkG1 inhibits GSK3beta by binding and directly phosphorylating GSK3beta at its serine 9 residue.	SIGNOR-280094
Q92911	P15056	0	transcriptional regulation	down-regulates quantity by repression	0.2	The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression.	SIGNOR-251989
P10586	Q13136	0	relocalization	up-regulates activity	0.8	We have identified a novel cytoplasmic 160 kDa phosphoserine protein termed LAR-interacting protein 1 (LIP.1), which binds to the LAR membrane-distal D2 protein tyrosine phosphatase domain and appears to localize LAR to focal adhesions.	SIGNOR-264141
P33151	P12931	0	phosphorylation	down-regulates activity	0.567	cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity.	SIGNOR-246462
Q16690	P28482	1	dephosphorylation	down-regulates	0.781	Here we demonstrate that dusp5, an inducible nuclear phosphatase, interacts specifically with erk2 via a kinase interaction motif (kim) within its amino-terminal noncatalytic domain. This binding determines the substrate specificity of dusp5 in vivo, as it inactivates erk2 but not jun n-terminal protein kinase or p38 map kinase.	SIGNOR-134049
P27695	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.416	Once the reaction proceeds beyond the monoubiquitination stage, MDM2 polyubiquitinates APE1 for degradation.	SIGNOR-278555
P62714	P05771	1	dephosphorylation	down-regulates activity	0.469	Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.	SIGNOR-248585
Q9Y243	O43524	1	phosphorylation	down-regulates quantity by destabilization	0.708	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249644
P51681	P35626	0	phosphorylation	down-regulates activity	0.2	Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism	SIGNOR-251463
Q03393	Q13237	0	phosphorylation	up-regulates	0.53	Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps	SIGNOR-71751
Q05397	P63000	1	phosphorylation	up-regulates activity	0.574	Both Src and FAK phosphorylate Rac1 at tyrosine 64.\|Our investigations of direct interactions between Rac1, Src, and FAK were motivated by our previous insights into FAK augmentation of Rac1 activation during cell spreading, and the Cerione lab 's work on the interactions between Src and Cdc42 , .	SIGNOR-279652
Q9UP95	Q9BYP7	0	phosphorylation	down-regulates activity	0.464	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities\|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264627
P06493	P31948	1	phosphorylation	down-regulates activity	0.264	Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions.	SIGNOR-262729
P11309	P01106	1	phosphorylation	up-regulates activity	0.697	FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells	SIGNOR-261557
P51397	P42345	0	phosphorylation	down-regulates activity	0.395	A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51.	SIGNOR-259812
Q8IYW5	Q12888	1	ubiquitination	up-regulates quantity	0.822	E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR\|We further found that overexpression of RNF168 enhanced 53BP1 ubiquitination inhibited by G0S2 overexpression in U87 and LN229 cells in response to IR (Fig. xref f).	SIGNOR-278777
Q05397	O43707	1	phosphorylation	down-regulates	0.558	Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin	SIGNOR-192195
P01100	O75534	0	post transcriptional regulation	down-regulates quantity	0.295	By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv	SIGNOR-261145
Q9UMX1	Q8TBB1	0	ubiquitination	down-regulates quantity	0.2	Indeed, they target different lysine residues in the SuFu protein, as LNX1 ubiquitinates SuFu at K59 and K470, and SCF Fbxl17 acts at K257, while Itch ubiquitinates at K321 and K457.\|XREF_FIG, ectopic LNX1 expression reduced SuFu protein levels in HEK-293T cells, while shRNA mediated knockdown of LNX1 increased these levels.	SIGNOR-278626
Q04759	Q9UHD2	1	phosphorylation	up-regulates activity	0.2	TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation	SIGNOR-272472
Q14938	A6NFN3	1	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268913
Q13315	Q99708	1	phosphorylation	down-regulates	0.828	Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45	SIGNOR-79872
O94907	P50553	0	transcriptional regulation	down-regulates quantity by repression	0.306	We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1.	SIGNOR-245885
Q9P275	Q15910	1	deubiquitination	up-regulates quantity by stabilization	0.2	We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme that deubiquitinates EZH2 at K222.	SIGNOR-277481
P05412	P27361	0	phosphorylation	up-regulates	0.781	Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein.	SIGNOR-91379
Q15772	Q92736	1	phosphorylation	down-regulates activity	0.248	Conclusions : Unlike other kinases (PKA, CaMKII) that increase RyR2 activity, SPEG phosphorylation reduces RyR2 mediated SR Ca 2+ -release.\|Further, we show that SPEG phosphorylates RyR2 at a previously uncharacterized serine (S2367) located in the central domain of the channel. xref Importantly, in contrast to previously studied phosphorylation sites that activate RyR2 (e.g. S2808, S2814), we show that SPEG mediated RyR2-S2367 phosphorylation suppresses pathogenic diastolic SR Ca 2+ -leak.	SIGNOR-279114
Q9UGL1	P84243	1	demethylation	up-regulates activity	0.2	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264304
Q9H1B7	P01148	1	transcriptional regulation	up-regulates quantity by expression	0.416	EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.	SIGNOR-267154
Q96HP0	P67775	0	phosphorylation	down-regulates activity	0.2	Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons\|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). \| In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching	SIGNOR-275669
Q99814	P11309	0	phosphorylation	up-regulates quantity by stabilization	0.2	PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits.	SIGNOR-277310
P15036	P09486	1	transcriptional regulation	up-regulates quantity by expression	0.305	Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin	SIGNOR-259874
P53350	Q53GL7	1	phosphorylation	up-regulates activity	0.2	PLK1, an important regulator for cell mitosis, directly interacts with and phosphorylates PARP10 at T601. PARP10 phosphorylation at T601 significantly decreases its binding to NEMO and disrupts its inhibition to NEMO ubiquitination, thereby enhancing the transcription activity of NF-κB toward multiple target genes and promoting HCC development.	SIGNOR-273728
P29372	P78318	1	monoubiquitination	down-regulates quantity by destabilization	0.2	We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. MID1 serves as the E3 ligase for α4 (2B), leading to a conformational change in α4 whereby the UIM of α4 binds in cis to the covalently attached ubiquitin (Ub; 3). This structural rearrangement then leads to calpain-mediated cleavage of the C terminus of α4 (4), allowing for polyubiquitination of PP2Ac by a currently unknown E3 ligase (5) and subsequent degradation by the proteasome.	SIGNOR-272040
P49711	O14746	1	transcriptional regulation	down-regulates quantity by repression	0.328	CTCF binds the proximal exonic region of hTERT and inhibits its transcription	SIGNOR-253832
P29353	P36897	0	phosphorylation	up-regulates	0.548	We now report that upon TGF-_ stimulation, T_RI phosphorylates ShcA on serine and, to a lesser degree, on tyrosine to activate Erk MAP kinases.	SIGNOR-227503
Q13464	P35241	1	phosphorylation	up-regulates activity	0.68	A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kcphosphorylated C-rad as T564-phosphorylated C-rad. \| In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active.	SIGNOR-248994
P51692	P00533	0	phosphorylation	up-regulates	0.829	Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor.	SIGNOR-113393
P49768	P46531	1	cleavage	up-regulates	0.797	Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains.	SIGNOR-72886
Q9NVI1	O94782	0	deubiquitination	down-regulates activity	0.666	Phosphorylation of FANCI may also turn the ubiquitinated ID complex into a poor substrate for deubiquitination by the USP1–UAF1 complex, resulting in increased levels of monoubiquitinated FANCD2.	SIGNOR-263272
P53350	Q13485	1	phosphorylation	down-regulates quantity by destabilization	0.254	We observed that PLK1 could significantly promote the ubiquitination and degradation of Smad4 wild type, Smad4 S171A, Smad4 S187A, Smad4 S191A, respectively, but PLK1-induced the ubiquitination and degradation of Smad4 T197A were obviously inhibited (Fig. 1M).	SIGNOR-277591
Q14469	P37231	1	transcriptional regulation	down-regulates quantity by repression	0.248	CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo	SIGNOR-253584
P54646	Q9BZL4	1	phosphorylation	down-regulates	0.259	Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo.	SIGNOR-195148
Q96EQ8	Q9BYX4	1	polyubiquitination	down-regulates quantity by destabilization	0.657	Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.	SIGNOR-271646
P43405	P19174	1	phosphorylation	up-regulates activity	0.775	Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771.	SIGNOR-246576
Q92793	Q9H2X6	0	phosphorylation	up-regulates activity	0.424	Moreover, we show that HIPK2 strongly potentiates the transcriptional activity of CREB-binding protein.\|We show that HIPK2 interacts with and phosphorylates several regions of CBP.	SIGNOR-279191
P23528	P53667	0	phosphorylation	down-regulates	0.814	Our results suggest that limk1-mediated cofilin phosphorylation is required for accurate spindle orientation by stabilizing cortical actin networks during mitosis	SIGNOR-159885
P02818	P07858	0	cleavage	down-regulates quantity by destabilization	0.33	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42.	SIGNOR-256318
P17612	Q14103	1	phosphorylation	up-regulates	0.349	Protein kinase a enhances, whereas glycogen synthase kinase-3 beta inhibits, the activity of the exon 2-encoded transactivator domain of heterogeneous nuclear ribonucleoprotein d in a hierarchical fashion.	SIGNOR-116144
O43609	Q06124	0	dephosphorylation	down-regulates	0.409	These results identify sprouty proteins as in vivo targets of corkscrew/shp-2 tyrosine phosphatases and show how corkscrew/shp-2 proteins can promote rtk signaling by inactivating a feedback inhibitor.	SIGNOR-144547
P43243	P35637	0	relocalization	up-regulates activity	0.486	Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates.	SIGNOR-262822
Q99717	Q13464	0	phosphorylation	up-regulates activity	0.306	The results showed that SMAD5 was directly phosphorylated at Ser463/465 by ROCK1 (Fig.\u00a04g).\|These data indicated that the activation of SMAD5 induced by TEM8 was mediated directly by the RhoC/ROCK1 pathway.To evaluate the effect of SMAD5 on the cellular functions of TEM8, SMAD5 was knockdown in TEM8-overexpressing cells.	SIGNOR-280107
P28482	P31749	0	phosphorylation	up-regulates activity	0.533	AKT1 stimulated PLD activity via activation of ERK.\|AKT1 actually phosphorylated ERK2 as a substrate (K(m) 1 \u03bcm).	SIGNOR-279136
P36894	Q9HCE7	0	ubiquitination	down-regulates	0.66	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-153399
O60502	Q01813	1	deglycosylation	up-regulates activity	0.2	Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity\|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively.	SIGNOR-267606
P19784	Q8N163	1	phosphorylation	up-regulates activity	0.2	CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. \|In our results, CK2alpha affected the\|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1	SIGNOR-267667
Q9BST9	Q15139	0	phosphorylation	up-regulates activity	0.355	Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane.	SIGNOR-275511
O43150	P84085	1	gtpase-activating protein	up-regulates activity	0.497	Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6. Pap protein exhibits Arf GAP activity in vitro.	SIGNOR-269707
P35790	Q8TB45	1	phosphorylation	down-regulates quantity by destabilization	0.2	These data suggests that CKI overexpression may overcome a requirement for phosphorylation at the major mTOR sites in DEPTOR for formation of the degron and are consistent with our finding that CKI can phosphorylate S286 and S287 in DEPTOR in vitro in the absence of mTOR.	SIGNOR-279605
Q2KJY2	P46934	0	ubiquitination	down-regulates quantity by destabilization	0.316	Nedd4 polyubiquitinates Kif26b and thus targets it for degradation via the ubiquitin-proteasome pathway.	SIGNOR-278767
Q9UL54	Q13188	1	phosphorylation	up-regulates	0.274	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-201327
P15259	Q13153	0	phosphorylation	down-regulates quantity by destabilization	0.2	The ability of Pak1 to phosphorylate wild-type PGAM2 was increased after exposure of the cells to etoposide (XREF_FIG).\|Bar, 20 \u00b5m. (E) Primary mouse embryonic fibroblasts at early passages were treated with 20 \u00b5M etoposide in the presence of 20 \u00b5M MG132, and cell lysates were immunoblotted with antibodies against Pak1 and phospho-Ser118 in phosphoglycerate mutase as indicated. (F) Pak1 kinase phosphorylates PGAM2 at Ser118 in vitro.	SIGNOR-280237
P00519	P03372	1	phosphorylation	up-regulates	0.446	Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes.	SIGNOR-163562
O75925	O75626	1	sumoylation	up-regulates	0.324	Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor.	SIGNOR-197265
Q96FE7	P39880	0	transcriptional regulation	down-regulates quantity by repression	0.368	We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition.	SIGNOR-260072
P35568	P42345	0	phosphorylation	down-regulates activity	0.766	Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten	SIGNOR-106590
P19883	Q9UJU2	0	transcriptional regulation	up-regulates quantity by expression	0.28	We further demonstrate that Fst is a direct target of the WNT/β-catenin pathway. Activation and inactivation of β-catenin induced and inhibited Fst expression, respectively, in both C2C12 cells and mouse embryos. Specific TCF/LEF1 binding sites within the promoter and intron 1 region of the Fst gene were required for RSPO2 and WNT/β-catenin-induced Fst expression.	SIGNOR-251722
Q15172	Q01484	0	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
Q16539	Q14765	1	phosphorylation	up-regulates	0.599	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154787
Q06124	P17612	0	phosphorylation	down-regulates activity	0.451	We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.	SIGNOR-276891
P13497	P05997	1	cleavage	up-regulates activity	0.607	BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro. BMP-1 efficiently cleaves pro-α2(V) C-propeptides at a single site between residues 1250 (Glu) and 1251 (Asp).	SIGNOR-256343
P11021	O95260	0	post transcriptional regulation	down-regulates quantity by destabilization	0.295	We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway.	SIGNOR-261345
P12931	O14920	1	phosphorylation	up-regulates	0.362	These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation.	SIGNOR-99318
Q15582	Q13118	0	transcriptional regulation	up-regulates quantity by expression	0.242	Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia.	SIGNOR-253212
Q9Y2I6	Q96GD4	0	phosphorylation	up-regulates	0.252	Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability.	SIGNOR-168053

Q96KB5

O75385

1

phosphorylation

down-regulates activity

0.2

We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.

SIGNOR-277473

P12931

Q7Z3C6

1

phosphorylation

up-regulates activity

0.342

Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation.

SIGNOR-266367

P04818

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.337

Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.

SIGNOR-267374

P28482

Q14005

1

phosphorylation

up-regulates

0.265

The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response.

SIGNOR-121852

P30086

Q00535

0

phosphorylation

down-regulates quantity by destabilization

0.337

Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif "KLYEQ" in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA).

SIGNOR-276672

P35222

O95996

0

relocalization

down-regulates quantity by destabilization

0.79

The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation.

SIGNOR-81545

P84243

Q9C0A6

0

methylation

up-regulates activity

0.2

SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription.

SIGNOR-264622

O75674

P06241

0

phosphorylation

up-regulates activity

0.434

Tyr-457, located in the presumed Src SH2 binding site, is the predominant tyrosine residue that is phosphorylated by Fyn.Fyn can phosphorylate Srcasm, and association of these molecules relies on cooperative binding between the SH2 and SH3 domains of Fyn and corresponding canonical binding sites in Srcasm. Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner. The evidence suggests that Srcasm may help promote Src family kinase signaling in cells.

SIGNOR-251185

Q96RG2

P13807

1

phosphorylation

down-regulates activity

0.508

Recombinant human PASK (hPASK) phosphorylates purified muscle glycogen synthase, causing robust inactivation. Furthermore, hPASK interacts directly with glycogen synthase when expressed in cultured cells and this interaction and the phosphorylation of glycogen synthase by human PASK (hPASK) are inhibited by glycogen.

SIGNOR-245866

Q00341

P07333

1

transcriptional regulation

down-regulates quantity by repression

0.342

Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer.

SIGNOR-266696

P31749

Q969H0

1

phosphorylation

up-regulates activity

0.41

A reciprocal immunoprecipiation with anti-phospho-Akt substrate antibody followed by immunoblotting with anti-FLAG antibodies confirmed these findings (Fig. 1C). We concluded that Fbw7 is phosphorylated at S227 in vivo. Phosphorylation of Fbw7 is required for its biological activity.

SIGNOR-276328

P53350

Q2M2Z5

1

phosphorylation

up-regulates

0.519

Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz.

SIGNOR-149630

P50613

Q9H0D6

1

phosphorylation

up-regulates activity

0.247

CDKs and Xrn2 phosphorylation promote transcription termination. | Cdk7 phosphorylated Xrn2-Thr439 but was less efficient than Cdk9. |

SIGNOR-259851

Q01082

P36897

0

phosphorylation

up-regulates

0.522

This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead.

SIGNOR-97626

Q9UHD2

Q96AQ6

1

phosphorylation

down-regulates quantity by destabilization

0.29

Phosphorylation of HPIP on serine 147 by TBK1 promotes E2-mediated GREB1 expression. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.

SIGNOR-273643

P31749

Q01813

1

phosphorylation

up-regulates quantity

0.564

A reduction in AKT expression as a result of AKT1 shRNA expression or MK-2206 treatment decreased the half-life of endogenous PFKP, while the expression of active Myr-AKT1 prolonged the half-life of PFKP.|In addition, depletion of endogenous PFKP and reconstitution of RNAi resistant WT Flag-rPFKP or Flag-rPFKP S386A expression in U251 or U87 and EGFRvIII cells revealed that the S386A mutation abolished PFKP phosphorylation induced by EGF, constitutively active Myr-AKT1, and EGFRvIII.

SIGNOR-279788

P51617

P40763

1

phosphorylation

up-regulates

0.55

Irak1 can directly use stat3 as a substrate and cause stat3 serine 727 phosphorylation.

SIGNOR-129685

P46934

O15399

1

ubiquitination

down-regulates activity

0.328

Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses.|This suggests that Nedd4 association reduces GluN2D function, mostly likely by promoting GluN2D ubiquitination and internalization.

SIGNOR-278636

Q14164

O43524

1

phosphorylation

down-regulates

0.407

Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation.

SIGNOR-202054

Q08050

P24941

0

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

Q9UHD2

Q14980

1

phosphorylation

up-regulates activity

0.2

Our studies now reveal TBK1 as another kinase that phosphorylates NuMA and that is required for its association with dynein and for localization of NuMA to the centrosomes in mitotic cells.

SIGNOR-278432

Q16695

Q92831

0

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269621

P04637

Q9BY41

0

deacetylation

down-regulates activity

0.456

HDAC8 mediates CM-induced deacetylation of p53.Collectively, these results indicate that although binding to p53 and HDAC8 occurs through distinct regions of the CM protein, simultaneous interaction with HDAC8 and p53 is required for aberrant deacetylation and inactivation of p53.

SIGNOR-255738

P23396

P28482

0

phosphorylation

up-regulates

0.2

Erk phosphorylates threonine 42 residue of ribosomal protein s3.

SIGNOR-137955

P05231

Q12968

0

transcriptional regulation

up-regulates quantity by expression

0.283

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.

SIGNOR-251732

Q15025

Q86VP1

1

relocalization

up-regulates activity

0.45

ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi.

SIGNOR-275735

P49841

Q13976

0

phosphorylation

down-regulates activity

0.26

Moreover, PrkG1 inhibits GSK3\u03b2 by binding and directly phosphorylating GSK3\u03b2 at its serine-9 residue (Zhao et al., xref ).|Moreover, PrkG1 inhibits GSK3beta by binding and directly phosphorylating GSK3beta at its serine 9 residue.

SIGNOR-280094

Q92911

P15056

0

transcriptional regulation

down-regulates quantity by repression

0.2

The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression.

SIGNOR-251989

P10586

Q13136

0

relocalization

up-regulates activity

0.8

We have identified a novel cytoplasmic 160 kDa phosphoserine protein termed LAR-interacting protein 1 (LIP.1), which binds to the LAR membrane-distal D2 protein tyrosine phosphatase domain and appears to localize LAR to focal adhesions.

SIGNOR-264141

P33151

P12931

0

phosphorylation

down-regulates activity

0.567

cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity.

SIGNOR-246462

Q16690

P28482

1

dephosphorylation

down-regulates

0.781

Here we demonstrate that dusp5, an inducible nuclear phosphatase, interacts specifically with erk2 via a kinase interaction motif (kim) within its amino-terminal noncatalytic domain. This binding determines the substrate specificity of dusp5 in vivo, as it inactivates erk2 but not jun n-terminal protein kinase or p38 map kinase.

SIGNOR-134049

P27695

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.416

Once the reaction proceeds beyond the monoubiquitination stage, MDM2 polyubiquitinates APE1 for degradation.

SIGNOR-278555

P62714

P05771

1

dephosphorylation

down-regulates activity

0.469

Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.

SIGNOR-248585

Q9Y243

O43524

1

phosphorylation

down-regulates quantity by destabilization

0.708

AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.

SIGNOR-249644

P51681

P35626

0

phosphorylation

down-regulates activity

0.2

Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism

SIGNOR-251463

Q03393

Q13237

0

phosphorylation

up-regulates

0.53

Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps

SIGNOR-71751

Q05397

P63000

1

phosphorylation

up-regulates activity

0.574

Both Src and FAK phosphorylate Rac1 at tyrosine 64.|Our investigations of direct interactions between Rac1, Src, and FAK were motivated by our previous insights into FAK augmentation of Rac1 activation during cell spreading, and the Cerione lab 's work on the interactions between Src and Cdc42 , .

SIGNOR-279652

Q9UP95

Q9BYP7

0

phosphorylation

down-regulates activity

0.464

We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs

SIGNOR-264627

P06493

P31948

1

phosphorylation

down-regulates activity

0.264

Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions.

SIGNOR-262729

P11309

P01106

1

phosphorylation

up-regulates activity

0.697

FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells

SIGNOR-261557

P51397

P42345

0

phosphorylation

down-regulates activity

0.395

A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51.

SIGNOR-259812

Q8IYW5

Q12888

1

ubiquitination

up-regulates quantity

0.822

E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR|We further found that overexpression of RNF168 enhanced 53BP1 ubiquitination inhibited by G0S2 overexpression in U87 and LN229 cells in response to IR (Fig. xref f).

SIGNOR-278777

Q05397

O43707

1

phosphorylation

down-regulates

0.558

Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin

SIGNOR-192195

P01100

O75534

0

post transcriptional regulation

down-regulates quantity

0.295

By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv

SIGNOR-261145

Q9UMX1

Q8TBB1

0

ubiquitination

down-regulates quantity

0.2

Indeed, they target different lysine residues in the SuFu protein, as LNX1 ubiquitinates SuFu at K59 and K470, and SCF Fbxl17 acts at K257, while Itch ubiquitinates at K321 and K457.|XREF_FIG, ectopic LNX1 expression reduced SuFu protein levels in HEK-293T cells, while shRNA mediated knockdown of LNX1 increased these levels.

SIGNOR-278626

Q04759

Q9UHD2

1

phosphorylation

up-regulates activity

0.2

TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation

SIGNOR-272472

Q14938

A6NFN3

1

transcriptional regulation

up-regulates quantity

0.2

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268913

Q13315

Q99708

1

phosphorylation

down-regulates

0.828

Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45

SIGNOR-79872

O94907

P50553

0

transcriptional regulation

down-regulates quantity by repression

0.306

We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1.

SIGNOR-245885

Q9P275

Q15910

1

deubiquitination

up-regulates quantity by stabilization

0.2

We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme that deubiquitinates EZH2 at K222.

SIGNOR-277481

P05412

P27361

0

phosphorylation

up-regulates

0.781

Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein.

SIGNOR-91379

Q15772

Q92736

1

phosphorylation

down-regulates activity

0.248

Conclusions : Unlike other kinases (PKA, CaMKII) that increase RyR2 activity, SPEG phosphorylation reduces RyR2 mediated SR Ca 2+ -release.|Further, we show that SPEG phosphorylates RyR2 at a previously uncharacterized serine (S2367) located in the central domain of the channel. xref Importantly, in contrast to previously studied phosphorylation sites that activate RyR2 (e.g. S2808, S2814), we show that SPEG mediated RyR2-S2367 phosphorylation suppresses pathogenic diastolic SR Ca 2+ -leak.

SIGNOR-279114

Q9UGL1

P84243

1

demethylation

up-regulates activity

0.2

KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.

SIGNOR-264304

Q9H1B7

P01148

1

transcriptional regulation

up-regulates quantity by expression

0.416

EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.

SIGNOR-267154

Q96HP0

P67775

0

phosphorylation

down-regulates activity

0.2

Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching

SIGNOR-275669

Q99814

P11309

0

phosphorylation

up-regulates quantity by stabilization

0.2

PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits.

SIGNOR-277310

P15036

P09486

1

transcriptional regulation

up-regulates quantity by expression

0.305

Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin

SIGNOR-259874

P53350

Q53GL7

1

phosphorylation

up-regulates activity

0.2

PLK1, an important regulator for cell mitosis, directly interacts with and phosphorylates PARP10 at T601. PARP10 phosphorylation at T601 significantly decreases its binding to NEMO and disrupts its inhibition to NEMO ubiquitination, thereby enhancing the transcription activity of NF-κB toward multiple target genes and promoting HCC development.

SIGNOR-273728

P29372

P78318

1

monoubiquitination

down-regulates quantity by destabilization

0.2

We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. MID1 serves as the E3 ligase for α4 (2B), leading to a conformational change in α4 whereby the UIM of α4 binds in cis to the covalently attached ubiquitin (Ub; 3). This structural rearrangement then leads to calpain-mediated cleavage of the C terminus of α4 (4), allowing for polyubiquitination of PP2Ac by a currently unknown E3 ligase (5) and subsequent degradation by the proteasome.

SIGNOR-272040

P49711

O14746

1

transcriptional regulation

down-regulates quantity by repression

0.328

CTCF binds the proximal exonic region of hTERT and inhibits its transcription

SIGNOR-253832

P29353

P36897

0

phosphorylation

up-regulates

0.548

We now report that upon TGF-_ stimulation, T_RI phosphorylates ShcA on serine and, to a lesser degree, on tyrosine to activate Erk MAP kinases.

SIGNOR-227503

Q13464

P35241

1

phosphorylation

up-regulates activity

0.68

A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kcphosphorylated C-rad as T564-phosphorylated C-rad. | In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active.

SIGNOR-248994

P51692

P00533

0

phosphorylation

up-regulates

0.829

Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor.

SIGNOR-113393

P49768

P46531

1

cleavage

up-regulates

0.797

Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains.

SIGNOR-72886

Q9NVI1

O94782

0

deubiquitination

down-regulates activity

0.666

Phosphorylation of FANCI may also turn the ubiquitinated ID complex into a poor substrate for deubiquitination by the USP1–UAF1 complex, resulting in increased levels of monoubiquitinated FANCD2.

SIGNOR-263272

P53350

Q13485

1

phosphorylation

down-regulates quantity by destabilization

0.254

We observed that PLK1 could significantly promote the ubiquitination and degradation of Smad4 wild type, Smad4 S171A, Smad4 S187A, Smad4 S191A, respectively, but PLK1-induced the ubiquitination and degradation of Smad4 T197A were obviously inhibited (Fig. 1M).

SIGNOR-277591

Q14469

P37231

1

transcriptional regulation

down-regulates quantity by repression

0.248

CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo

SIGNOR-253584

P54646

Q9BZL4

1

phosphorylation

down-regulates

0.259

Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo.

SIGNOR-195148

Q96EQ8

Q9BYX4

1

polyubiquitination

down-regulates quantity by destabilization

0.657

Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.

SIGNOR-271646

P43405

P19174

1

phosphorylation

up-regulates activity

0.775

Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771.

SIGNOR-246576

Q92793

Q9H2X6

0

phosphorylation

up-regulates activity

0.424

Moreover, we show that HIPK2 strongly potentiates the transcriptional activity of CREB-binding protein.|We show that HIPK2 interacts with and phosphorylates several regions of CBP.

SIGNOR-279191

P23528

P53667

0

phosphorylation

down-regulates

0.814

Our results suggest that limk1-mediated cofilin phosphorylation is required for accurate spindle orientation by stabilizing cortical actin networks during mitosis

SIGNOR-159885

P02818

P07858

0

cleavage

down-regulates quantity by destabilization

0.33

This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42.

SIGNOR-256318

P17612

Q14103

1

phosphorylation

up-regulates

0.349

Protein kinase a enhances, whereas glycogen synthase kinase-3 beta inhibits, the activity of the exon 2-encoded transactivator domain of heterogeneous nuclear ribonucleoprotein d in a hierarchical fashion.

SIGNOR-116144

O43609

Q06124

0

dephosphorylation

down-regulates

0.409

These results identify sprouty proteins as in vivo targets of corkscrew/shp-2 tyrosine phosphatases and show how corkscrew/shp-2 proteins can promote rtk signaling by inactivating a feedback inhibitor.

SIGNOR-144547

P43243

P35637

0

relocalization

up-regulates activity

0.486

Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates.

SIGNOR-262822

Q99717

Q13464

0

phosphorylation

up-regulates activity

0.306

The results showed that SMAD5 was directly phosphorylated at Ser463/465 by ROCK1 (Fig.\u00a04g).|These data indicated that the activation of SMAD5 induced by TEM8 was mediated directly by the RhoC/ROCK1 pathway.To evaluate the effect of SMAD5 on the cellular functions of TEM8, SMAD5 was knockdown in TEM8-overexpressing cells.

SIGNOR-280107

P28482

P31749

0

phosphorylation

up-regulates activity

0.533

AKT1 stimulated PLD activity via activation of ERK.|AKT1 actually phosphorylated ERK2 as a substrate (K(m) 1 \u03bcm).

SIGNOR-279136

P36894

Q9HCE7

0

ubiquitination

down-regulates

0.66

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

SIGNOR-153399

O60502

Q01813

1

deglycosylation

up-regulates activity

0.2

Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively.

SIGNOR-267606

P19784

Q8N163

1

phosphorylation

up-regulates activity

0.2

CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1

SIGNOR-267667

Q9BST9

Q15139

0

phosphorylation

up-regulates activity

0.355

Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane.

SIGNOR-275511

O43150

P84085

1

gtpase-activating protein

up-regulates activity

0.497

Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6. Pap protein exhibits Arf GAP activity in vitro.

SIGNOR-269707

P35790

Q8TB45

1

phosphorylation

down-regulates quantity by destabilization

0.2

These data suggests that CKI overexpression may overcome a requirement for phosphorylation at the major mTOR sites in DEPTOR for formation of the degron and are consistent with our finding that CKI can phosphorylate S286 and S287 in DEPTOR in vitro in the absence of mTOR.

SIGNOR-279605

Q2KJY2

P46934

0

ubiquitination

down-regulates quantity by destabilization

0.316

Nedd4 polyubiquitinates Kif26b and thus targets it for degradation via the ubiquitin-proteasome pathway.

SIGNOR-278767

Q9UL54

Q13188

1

phosphorylation

up-regulates

0.274

In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.

SIGNOR-201327

P15259

Q13153

0

phosphorylation

down-regulates quantity by destabilization

0.2

The ability of Pak1 to phosphorylate wild-type PGAM2 was increased after exposure of the cells to etoposide (XREF_FIG).|Bar, 20 \u00b5m. (E) Primary mouse embryonic fibroblasts at early passages were treated with 20 \u00b5M etoposide in the presence of 20 \u00b5M MG132, and cell lysates were immunoblotted with antibodies against Pak1 and phospho-Ser118 in phosphoglycerate mutase as indicated. (F) Pak1 kinase phosphorylates PGAM2 at Ser118 in vitro.

SIGNOR-280237

P00519

P03372

1

phosphorylation

up-regulates

0.446

Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes.

SIGNOR-163562

O75925

O75626

1

sumoylation

up-regulates

0.324

Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor.

SIGNOR-197265

Q96FE7

P39880

0

transcriptional regulation

down-regulates quantity by repression

0.368

We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition.

SIGNOR-260072

P35568

P42345

0

phosphorylation

down-regulates activity

0.766

Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten

SIGNOR-106590

P19883

Q9UJU2

0

transcriptional regulation

up-regulates quantity by expression

0.28

We further demonstrate that Fst is a direct target of the WNT/β-catenin pathway. Activation and inactivation of β-catenin induced and inhibited Fst expression, respectively, in both C2C12 cells and mouse embryos. Specific TCF/LEF1 binding sites within the promoter and intron 1 region of the Fst gene were required for RSPO2 and WNT/β-catenin-induced Fst expression.

SIGNOR-251722

Q15172

Q01484

0

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

Q16539

Q14765

1

phosphorylation

up-regulates

0.599

All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).

SIGNOR-154787

Q06124

P17612

0

phosphorylation

down-regulates activity

0.451

We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.

SIGNOR-276891

P13497

P05997

1

cleavage

up-regulates activity

0.607

BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro. BMP-1 efficiently cleaves pro-α2(V) C-propeptides at a single site between residues 1250 (Glu) and 1251 (Asp).

SIGNOR-256343

P11021

O95260

0

post transcriptional regulation

down-regulates quantity by destabilization

0.295

We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway.

SIGNOR-261345

P12931

O14920

1

phosphorylation

up-regulates

0.362

These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation.

SIGNOR-99318

Q15582

Q13118

0

transcriptional regulation

up-regulates quantity by expression

0.242

Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia.

SIGNOR-253212

Q9Y2I6

Q96GD4

0

phosphorylation

up-regulates

0.252

Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability.

SIGNOR-168053