GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P63092	P43116	2	binding	up-regulates activity	0.435	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256756
P62330	Q5JU85	0	guanine nucleotide exchange factor	up-regulates activity	0.457	Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6.	SIGNOR-264906
P43405	Q06124	0	dephosphorylation	down-regulates activity	0.545	Another SHP isoform, SHP-2, has been linked to negative regulation of Syk.\|Syk and LAT are differentially dephosphorylated by SHP-2 and SHP-1, respectively.	SIGNOR-277085
O75151	Q14865	2	binding	up-regulates activity	0.56	We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.	SIGNOR-264514
O75626	P13500	1	transcriptional regulation	down-regulates quantity by repression	0.2	Blimp-1 binds to the proinflammatory cytokine/chemokine genes, Il-6 and Ccl2, and negatively regulates their expression.	SIGNOR-271679
Q16659	O60229	1	phosphorylation	up-regulates activity	0.406	The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements.	SIGNOR-263094
P17252	P49768	1	phosphorylation	up-regulates activity	0.264	A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis.	SIGNOR-249236
O00198	Q07817	2	binding	down-regulates	0.603	Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1.	SIGNOR-47797
Q8IVT5	Q7KZI7	0	phosphorylation	down-regulates activity	0.315	In vivo, MARK2 appears to negatively regulate KSR1 in insulin sensitivity.\|These data suggest that MARK2 phosphorylates KSR1 on Ser392, which has been shown previously to function as a negative regulatory site xref .	SIGNOR-279343
Q00535	P08908	1	phosphorylation	down-regulates quantity by destabilization	0.27	Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT 1A receptor via phosphorylation\|5-HT1AR was phosphorylated by the Cdk5-p35 complex at Thr314 in the third cytoplasmic loop.	SIGNOR-264406
P06493	P15531	1	phosphorylation	up-regulates	0.266	Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates.	SIGNOR-160493
Q9Y2H1	O75385	1	phosphorylation	down-regulates quantity	0.2	STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination	SIGNOR-270348
Q9HCM9	Q96BY2	2	binding	up-regulates quantity by stabilization	0.483	TRIM39 stabilizes MOAP-1 by inhibiting the poly-ubiquitination process of MOAP-1.In this study, we report the identification and characterization of TRIM39 as a binding partner of MOAP-1. TRIM39 is the first regulator of MOAP-1 protein stability identified.	SIGNOR-272911
Q9Y253	Q96PM5	0	monoubiquitination	down-regulates activity	0.581	Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709).	SIGNOR-272733
P63000	Q3KR16	0	guanine nucleotide exchange factor	up-regulates activity	0.297	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260568
Q99942	O43511	1	ubiquitination	down-regulates quantity by destabilization	0.2	E3 ubiquitin ligase Rma1 is involved in Pendrin degradation	SIGNOR-271497
P24723	P49840	1	phosphorylation	down-regulates	0.321	Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9	SIGNOR-115730
Q5T447	Q9H2D6	1	polyubiquitination	down-regulates quantity by destabilization	0.438	Here, we identify a novel Tara-binding protein HECTD3, a putative member of HECT E3 ubiquitin ligases. HECTD3 directly binds Tara in vitro and forms a complex with Tara in vivo. Overexpression of HECTD3 enhances the ubiquitination of Tara in vivo and promotes the turnover of Tara, whereas depletion of HECTD3 by small interfering RNA decreases Tara degradation.	SIGNOR-271770
Q15418	Q16821	1	phosphorylation	up-regulates activity	0.43	The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates.	SIGNOR-249036
P17676	P06702	1	transcriptional regulation	up-regulates quantity by expression	0.2	Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.\|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells.	SIGNOR-254044
P28702	P48552	2	binding	up-regulates	0.603	Receptor interacting protein 140 (rip140) is a coregulator for a large number of transcription factors. Rip140 interacts with retinoic acid receptor (rar) and retinoid x receptor (rxr) with or without ligands	SIGNOR-95160
Q03112	Q15389	1	transcriptional regulation	up-regulates quantity by expression	0.2	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2	SIGNOR-266059
P14635	A6NLU0	0	ubiquitination	down-regulates quantity by destabilization	0.32	We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis.	SIGNOR-271476
Q9UQM7	Q9Y618	1	phosphorylation	down-regulates	0.2	We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation.	SIGNOR-191773
P60709	Q5T1M5	2	binding	up-regulates activity	0.2	However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin.	SIGNOR-260595
P50570	P15498	2	binding	up-regulates quantity by stabilization	0.488	Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability.	SIGNOR-259080
O95819	Q13233	1	phosphorylation	up-regulates	0.558	Hpk1 binds and phosphorylates mekk1 directly	SIGNOR-44040
Q92765	Q9H1J5	2	binding	down-regulates	0.484	We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos,	SIGNOR-51798
P67775	P10415	1	dephosphorylation	up-regulates activity	0.47	The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A.	SIGNOR-248624
O43353	Q13568	1	phosphorylation	up-regulates	0.304	Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay	SIGNOR-196524
Q13464	P45983	1	phosphorylation	up-regulates activity	0.296	Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter.	SIGNOR-123717
Q01453	P23229	2	binding	up-regulates activity	0.385	PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types.	SIGNOR-251895
P06127	P17252	0	phosphorylation	up-regulates	0.339	Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation.	SIGNOR-85179
P04637	Q6PCD5	0	ubiquitination	up-regulates quantity by stabilization	0.361	RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage.	SIGNOR-271944
P27361	P02686	1	phosphorylation	down-regulates	0.502	Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence.	SIGNOR-143481
P10147	P51681	2	binding	up-regulates activity	0.745	The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days.	SIGNOR-251724
P56545	P12830	1	transcriptional regulation	down-regulates quantity by repression	0.381	Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner	SIGNOR-261578
P19235	P18031	0	dephosphorylation	down-regulates activity	0.459	In vivo interaction between EPO-R and PTP1B suggested that PTP1B dephosphorylates the EPO-R intracellularly.\|Protein tyrosine phosphatase 1B participates in the down-regulation of erythropoietin receptor signalling.	SIGNOR-276994
O94991	Q13635	2	binding	down-regulates activity	0.2	SLITRK5 interacts with SHH and PTCH1. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation.	SIGNOR-268438
P48729	O14503	1	phosphorylation	down-regulates quantity by destabilization	0.2	CK1α-mediated phosphorylation of DEC1 on a conserved degron is required for DEC1 degradation.	SIGNOR-276851
P29375	Q16665	0	transcriptional regulation	up-regulates quantity by expression	0.273	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271565
P42685	P38398	1	phosphorylation	up-regulates quantity by stabilization	0.2	Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. Rak-mediated tyrosine phosphorylation of BRCA1 is essential for its stability and function	SIGNOR-275454
P29274	P63092	2	binding	up-regulates activity	0.3	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256766
Q9HAU4	P51668	1	ubiquitination	up-regulates activity	0.702	Our data further show that SMURF2 monoubiquitinates UBCH5 at lysine 144 to form an active complex required for efficient degradation of a RAS family E3, beta transducing repeat containing protein 1 (beta-TrCP1).	SIGNOR-278718
Q9Y281	Q96S53	0	phosphorylation	down-regulates activity	0.321	Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin	SIGNOR-246711
O15264	P45985	0	phosphorylation	up-regulates activity	0.459	p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273956
Q05655	Q15139	1	phosphorylation	up-regulates	0.269	Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta)	SIGNOR-123453
P54792	Q9Y4D1	2	binding	up-regulates	0.2	Importantly, daam1 binds to disheveled (dvl) and thus functions downstream of the frizzled receptors. Little is known of how daam1 is localized and functions in mammalian cells.	SIGNOR-199451
P68400	P43629	1	phosphorylation	up-regulates quantity by stabilization	0.2	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.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. It seems that phosphorylation of 3DL1 by CK does not significantly affect receptor inhibitory function or turnover, at least in the assays that we have used so far.	SIGNOR-276077
Q9UKV5	P06744	2	polyubiquitination	down-regulates quantity by destabilization	0.53	Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF.	SIGNOR-272177
Q9Y6W5	Q96EV8	2	binding	up-regulates activity	0.343	Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1.	SIGNOR-265659
Q13363	P31749	0	phosphorylation	down-regulates quantity	0.483	Co-expression of Pc2 and Akt1 results in both phosphorylation and ubiquitylation of CtBP1, thereby targeting CtBP1 for degradation.\|CtBP1 phosphorylation by Akt1 appears to both decrease dimerization and induce ubiquitylation.	SIGNOR-278304
P27540	P68400	0	phosphorylation	down-regulates	0.34	Here, we show that arnt and alt arnt proteins are differentially phosphorylated by protein kinase ckii in vitro. Phosphorylation had an inhibitory effect on dna-binding to an e-box probe by alt arnt, but not arnt, homodimers. This inhibitory phosphorylation occurs through ser77.	SIGNOR-140034
P00533	P27361	0	phosphorylation	down-regulates	0.557	It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation.	SIGNOR-20549
P84243	P31749	0	phosphorylation	down-regulates activity	0.2	Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro	SIGNOR-98285
O15264	P04637	1	phosphorylation	up-regulates	0.462	In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-72691
Q9Y3V2	Q16665	1	sumoylation	up-regulates	0.457	Rsume,_a small_rwd-containing protein, enhances sumo conjugation and stabilizes hif-1alpha during hypoxia	SIGNOR-158590
Q9UJT9	O15392	2	binding	down-regulates quantity by destabilization	0.307	Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation.	SIGNOR-272436
P06493	P78344	1	phosphorylation	up-regulates activity	0.339	To test whether CDK1 phosphorylates T508, Flag-DAP5 was purified from dox-induced HEK293 cells and incubated with active recombinant JNK2 or CDK1 in the presence of ATP (Fig. 3G). DAP5(T508) was phosphorylated only upon incubation with CDK1 (Fig. 3G).	SIGNOR-266387
P36897	P29353	1	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
P25815	Q9UNE7	0	polyubiquitination	down-regulates quantity by destabilization	0.292	S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.	SIGNOR-272919
P07910	P48729	0	phosphorylation	down-regulates	0.354	A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c.	SIGNOR-133528
P84022	P07437	2	binding	down-regulates activity	0.2	Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin.	SIGNOR-232113
P67809	P78527	0	phosphorylation	up-regulates activity	0.338	The DNA-PK subunits and YB-1 phosphorylated at T89 were found colocalized suggesting their in vivo interaction.DNA-PK directly phosphorylates YB-1 and, this way, modulates YB-1 function. Point mutation of YB-1 at this residue abrogated the translocation of YB-1 into the nucleus.	SIGNOR-277611
P35498	P61328	2	binding	down-regulates activity	0.386	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253420
Q7Z460	P30622	2	binding	up-regulates activity	0.725	CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.\|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. \| Both EB1- and cortex-binding domains of CLASP are required to promote MT stability.	SIGNOR-265091
P20783	Q16288	2	binding	up-regulates	0.849	Trkc, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3.	SIGNOR-20699
Q15118	P00558	0	phosphorylation	up-regulates activity	0.428	Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex.	SIGNOR-278365
P05412	Q9UKN1	2	binding	up-regulates activity	0.256	MUC12 promoted the recruitment of c-Jun on the promoter of TGF-β1, leading to its transcription.	SIGNOR-265474
P12931	O60500	1	phosphorylation	up-regulates activity	0.48	Inhibition of Src kinase dependent Nephrin phosphorylation achieved by incubation of WT-Nephrin-overexpressing cells with 1 mum PP2 abolished the positive effect of Nephrin on GSIR (XREF_FIG D).\|We were able to demonstrate a complete prevention of Nephrin phosphorylation, confirming that Nephrin phosphorylation is mediated by Src.	SIGNOR-280129
Q92918	Q13233	1	phosphorylation	up-regulates	0.455	Hpk1 binds and phosphorylates mekk1 directly,	SIGNOR-43996
Q9UQC2	P42336	2	binding	up-regulates	0.466	The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival	SIGNOR-204966
P62714	Q9C0C7	2	binding	up-regulates activity	0.2	We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene.	SIGNOR-272964
Q6UVK1	P17252	0	phosphorylation	up-regulates activity	0.2	Protein kinase C (PKC)-alpha phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr(2256), identifying this residue as a primary phosphorylation site. PKC-alpha-mediated NG2 phosphorylation at Thr(2256) is therefore a key step for initiating cell polarization and motility.	SIGNOR-263162
Q12923	P04626	1	dephosphorylation	down-regulates activity	0.332	Since a previous report showed PTPN13 may dephosphorylate ErbB2 directly, we also examined levels of phospho-ErbB2 (tyr 1248), and we also observed a small effect in the presence of wild-type PTPN13 (XREF_FIG).\|The fact that both ErbB2 and H-RasV12 were potentiated by PTPN13 loss and PTPN13 inhibited MAP kinase signaling downstream of multiple oncogenes (ErbB2, EGFR, H-RasV12), suggest that the phosphatase target that inhibits MAP kinase signaling may not only be limited to ErbB2 tyrosine 1248.	SIGNOR-277087
P23443	Q92934	1	phosphorylation	down-regulates activity	0.295	P70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro apoptotic BAD by producing a reaction that disrupts BAD 's binding to other pro apoptotic molecules thereby allowing cell survival.\|p70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro-apoptotic BAD by producing a reaction that disrupts BAD\u2019s binding to other pro-apoptotic molecules thereby allowing cell survival. xref , xref On the other hand, in a recent study, Li et al showed that increased expression of anti-apoptotic BCL2 was induced in myeloid progenitor cells upon activation of p76S6K, thereby promoting cell survival. xref Further studies are needed to better understand the effect of rapamycin and its derivatives on apoptosis in various cancer cells.	SIGNOR-280016
P11413	O60502	0	deglycosylation	down-regulates activity	0.2	O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth\|O-GlcNAcylation of G6PD activates enzyme activity\|G6PD is dynamically modified by O-GlcNAc at serine 84\|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-267605
Q99836	Q08211	2	binding	up-regulates activity	0.491	We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing.	SIGNOR-260955
O96013	O14713	1	phosphorylation	down-regulates activity	0.2	We further demonstrate that p21 activated kinase 4 (PAK4) can phosphorylate ICAP1 at Ser 10 both in vitro and in cultured cells, and that active PAK4 inhibits ICAP1 nuclear accumulation in a Ser-10-dependent manner.\|We further demonstrate that p21-activated kinase 4 (PAK4) can phosphorylate ICAP1 at Ser-10 both in vitro and in cultured cells, and that active PAK4 inhibits ICAP1 nuclear accumulation in a Ser-10-dependent manner.	SIGNOR-280056
O00623	P51668	2	binding	up-regulates activity	0.626	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.	SIGNOR-253024
P35568	P42338	2	binding	up-regulates activity	0.723	To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1	SIGNOR-235487
O15297	P13051	1	dephosphorylation	down-regulates activity	0.377	PPM1D dephosphorylation of UNG2 is correlated with reduced UNG2 activity on uracil-containing templates.\|This result suggests that PPM1D specifically inhibits UNG2 and not other uracil DNA glycosylases.	SIGNOR-277156
Q5VT25	P24844	1	phosphorylation	up-regulates	0.516	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188781
P67775	P04049	1	dephosphorylation	up-regulates	0.592	Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1.	SIGNOR-141170
P55957	Q16611	2	binding	up-regulates	0.822	We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members.	SIGNOR-92942
Q5TCZ1	Q86UR1	2	binding	up-regulates activity	0.409	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner\|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein\|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264708
P28482	O60674	1	phosphorylation	down-regulates	0.513	We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner	SIGNOR-236331
P49411	Q9H1Y0	2	binding	down-regulates activity	0.423	PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy.	SIGNOR-266383
P01350	P32239	2	binding	up-regulates	0.783	A segment of five amino acids in the second extracellular loop of the cck-b receptor was shown to be essential for the high affinity of the natural peptide agonits, gastrin,	SIGNOR-66987
P35968	P62993	1	relocalization	up-regulates activity	0.686	In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.	SIGNOR-261948
P17252	P48058	1	phosphorylation	up-regulates	0.57	Receptor internalization, altered;intracellular localization	SIGNOR-97554
P04637	Q9H4B4	0	phosphorylation	up-regulates activity	0.706	Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3.	SIGNOR-109239
Q99490	P06241	0	phosphorylation	up-regulates	0.467	We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival.	SIGNOR-147936
Q9UKB1	O00418	1	ubiquitination	down-regulates	0.436	Eef2k was degraded by the ubiquitin-proteasome system through the ubiquitin ligase scf(__trcp) (skp1-cul1-f-box protein, __-transducin repeat-containing protein) to enable rapid resumption of translation elongation. This event required autophosphorylation of eef2k on a canonical __trcp-binding domain	SIGNOR-197730
P13051	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.2	Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.\|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation	SIGNOR-264885
P78352	Q8NFZ3	0	relocalization	up-regulates activity	0.2	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264190
P08237	P01106	0	transcriptional regulation	up-regulates quantity	0.327	C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.	SIGNOR-259988
P31749	P04049	1	phosphorylation	down-regulates	0.7	Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity.	SIGNOR-147963
P29074	P40763	1	dephosphorylation	down-regulates activity	0.255	In terms of molecular mechanisms, we revealed that PTPN4 dephosphorylates pSTAT3 at the Tyr705 residue with a direct interaction, which might provide novel targets for the therapy of CRC.\|Loss of PTPN4 Activates STAT3 to Promote the Tumor Growth in Rectal Cancer.	SIGNOR-277057
P50402	P12931	0	phosphorylation	down-regulates	0.451	Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf	SIGNOR-188308

P63092

P43116

2

binding

up-regulates activity

0.435

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

SIGNOR-256756

P62330

Q5JU85

0

guanine nucleotide exchange factor

up-regulates activity

0.457

Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6.

SIGNOR-264906

P43405

Q06124

0

dephosphorylation

down-regulates activity

0.545

Another SHP isoform, SHP-2, has been linked to negative regulation of Syk.|Syk and LAT are differentially dephosphorylated by SHP-2 and SHP-1, respectively.

SIGNOR-277085

O75151

Q14865

2

binding

up-regulates activity

0.56

We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.

SIGNOR-264514

O75626

P13500

1

transcriptional regulation

down-regulates quantity by repression

0.2

Blimp-1 binds to the proinflammatory cytokine/chemokine genes, Il-6 and Ccl2, and negatively regulates their expression.

SIGNOR-271679

Q16659

O60229

1

phosphorylation

up-regulates activity

0.406

The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements.

SIGNOR-263094

P17252

P49768

1

phosphorylation

up-regulates activity

0.264

A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis.

SIGNOR-249236

O00198

Q07817

2

binding

down-regulates

0.603

Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1.

SIGNOR-47797

Q8IVT5

Q7KZI7

0

phosphorylation

down-regulates activity

0.315

In vivo, MARK2 appears to negatively regulate KSR1 in insulin sensitivity.|These data suggest that MARK2 phosphorylates KSR1 on Ser392, which has been shown previously to function as a negative regulatory site xref .

SIGNOR-279343

Q00535

P08908

1

phosphorylation

down-regulates quantity by destabilization

0.27

Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT 1A receptor via phosphorylation|5-HT1AR was phosphorylated by the Cdk5-p35 complex at Thr314 in the third cytoplasmic loop.

SIGNOR-264406

P06493

P15531

1

phosphorylation

up-regulates

0.266

Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates.

SIGNOR-160493

Q9Y2H1

O75385

1

phosphorylation

down-regulates quantity

0.2

STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination

SIGNOR-270348

Q9HCM9

Q96BY2

2

binding

up-regulates quantity by stabilization

0.483

TRIM39 stabilizes MOAP-1 by inhibiting the poly-ubiquitination process of MOAP-1.In this study, we report the identification and characterization of TRIM39 as a binding partner of MOAP-1. TRIM39 is the first regulator of MOAP-1 protein stability identified.

SIGNOR-272911

Q9Y253

Q96PM5

0

monoubiquitination

down-regulates activity

0.581

Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709).

SIGNOR-272733

P63000

Q3KR16

0

guanine nucleotide exchange factor

up-regulates activity

0.297

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260568

Q99942

O43511

1

ubiquitination

down-regulates quantity by destabilization

0.2

E3 ubiquitin ligase Rma1 is involved in Pendrin degradation

SIGNOR-271497

P24723

P49840

1

phosphorylation

down-regulates

0.321

Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9

SIGNOR-115730

Q5T447

Q9H2D6

1

polyubiquitination

down-regulates quantity by destabilization

0.438

Here, we identify a novel Tara-binding protein HECTD3, a putative member of HECT E3 ubiquitin ligases. HECTD3 directly binds Tara in vitro and forms a complex with Tara in vivo. Overexpression of HECTD3 enhances the ubiquitination of Tara in vivo and promotes the turnover of Tara, whereas depletion of HECTD3 by small interfering RNA decreases Tara degradation.

SIGNOR-271770

Q15418

Q16821

1

phosphorylation

up-regulates activity

0.43

The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates.

SIGNOR-249036

P17676

P06702

1

transcriptional regulation

up-regulates quantity by expression

0.2

Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells.

SIGNOR-254044

P28702

P48552

2

binding

up-regulates

0.603

Receptor interacting protein 140 (rip140) is a coregulator for a large number of transcription factors. Rip140 interacts with retinoic acid receptor (rar) and retinoid x receptor (rxr) with or without ligands

SIGNOR-95160

Q03112

Q15389

1

transcriptional regulation

up-regulates quantity by expression

0.2

We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2

SIGNOR-266059

P14635

A6NLU0

0

ubiquitination

down-regulates quantity by destabilization

0.32

We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis.

SIGNOR-271476

Q9UQM7

Q9Y618

1

phosphorylation

down-regulates

0.2

We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation.

SIGNOR-191773

P60709

Q5T1M5

2

binding

up-regulates activity

0.2

However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin.

SIGNOR-260595

P50570

P15498

2

binding

up-regulates quantity by stabilization

0.488

Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability.

SIGNOR-259080

O95819

Q13233

1

phosphorylation

up-regulates

0.558

Hpk1 binds and phosphorylates mekk1 directly

SIGNOR-44040

Q92765

Q9H1J5

2

binding

down-regulates

0.484

We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos,

SIGNOR-51798

P67775

P10415

1

dephosphorylation

up-regulates activity

0.47

The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A.

SIGNOR-248624

O43353

Q13568

1

phosphorylation

up-regulates

0.304

Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay

SIGNOR-196524

Q13464

P45983

1

phosphorylation

up-regulates activity

0.296

Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter.

SIGNOR-123717

Q01453

P23229

2

binding

up-regulates activity

0.385

PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types.

SIGNOR-251895

P06127

P17252

0

phosphorylation

up-regulates

0.339

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

SIGNOR-85179

P04637

Q6PCD5

0

ubiquitination

up-regulates quantity by stabilization

0.361

RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage.

SIGNOR-271944

P27361

P02686

1

phosphorylation

down-regulates

0.502

Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence.

SIGNOR-143481

P10147

P51681

2

binding

up-regulates activity

0.745

The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days.

SIGNOR-251724

P56545

P12830

1

transcriptional regulation

down-regulates quantity by repression

0.381

Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner

SIGNOR-261578

P19235

P18031

0

dephosphorylation

down-regulates activity

0.459

In vivo interaction between EPO-R and PTP1B suggested that PTP1B dephosphorylates the EPO-R intracellularly.|Protein tyrosine phosphatase 1B participates in the down-regulation of erythropoietin receptor signalling.

SIGNOR-276994

O94991

Q13635

2

binding

down-regulates activity

0.2

SLITRK5 interacts with SHH and PTCH1. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation.

SIGNOR-268438

P48729

O14503

1

phosphorylation

down-regulates quantity by destabilization

0.2

CK1α-mediated phosphorylation of DEC1 on a conserved degron is required for DEC1 degradation.

SIGNOR-276851

P29375

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.273

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271565

P42685

P38398

1

phosphorylation

up-regulates quantity by stabilization

0.2

Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. Rak-mediated tyrosine phosphorylation of BRCA1 is essential for its stability and function

SIGNOR-275454

P29274

P63092

2

binding

up-regulates activity

0.3

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

SIGNOR-256766

Q9HAU4

P51668

1

ubiquitination

up-regulates activity

0.702

Our data further show that SMURF2 monoubiquitinates UBCH5 at lysine 144 to form an active complex required for efficient degradation of a RAS family E3, beta transducing repeat containing protein 1 (beta-TrCP1).

SIGNOR-278718

Q9Y281

Q96S53

0

phosphorylation

down-regulates activity

0.321

Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin

SIGNOR-246711

O15264

P45985

0

phosphorylation

up-regulates activity

0.459

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

SIGNOR-273956

Q05655

Q15139

1

phosphorylation

up-regulates

0.269

Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta)

SIGNOR-123453

P54792

Q9Y4D1

2

binding

up-regulates

0.2

Importantly, daam1 binds to disheveled (dvl) and thus functions downstream of the frizzled receptors. Little is known of how daam1 is localized and functions in mammalian cells.

SIGNOR-199451

P68400

P43629

1

phosphorylation

up-regulates quantity by stabilization

0.2

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.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. It seems that phosphorylation of 3DL1 by CK does not significantly affect receptor inhibitory function or turnover, at least in the assays that we have used so far.

SIGNOR-276077

Q9UKV5

P06744

2

polyubiquitination

down-regulates quantity by destabilization

0.53

Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF.

SIGNOR-272177

Q9Y6W5

Q96EV8

2

binding

up-regulates activity

0.343

Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1.

SIGNOR-265659

Q13363

P31749

0

phosphorylation

down-regulates quantity

0.483

Co-expression of Pc2 and Akt1 results in both phosphorylation and ubiquitylation of CtBP1, thereby targeting CtBP1 for degradation.|CtBP1 phosphorylation by Akt1 appears to both decrease dimerization and induce ubiquitylation.

SIGNOR-278304

P27540

P68400

0

phosphorylation

down-regulates

0.34

Here, we show that arnt and alt arnt proteins are differentially phosphorylated by protein kinase ckii in vitro. Phosphorylation had an inhibitory effect on dna-binding to an e-box probe by alt arnt, but not arnt, homodimers. This inhibitory phosphorylation occurs through ser77.

SIGNOR-140034

P00533

P27361

0

phosphorylation

down-regulates

0.557

It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation.

SIGNOR-20549

P84243

P31749

0

phosphorylation

down-regulates activity

0.2

Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro

SIGNOR-98285

O15264

P04637

1

phosphorylation

up-regulates

0.462

In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.

SIGNOR-72691

Q9Y3V2

Q16665

1

sumoylation

up-regulates

0.457

Rsume,_a small_rwd-containing protein, enhances sumo conjugation and stabilizes hif-1alpha during hypoxia

SIGNOR-158590

Q9UJT9

O15392

2

binding

down-regulates quantity by destabilization

0.307

Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation.

SIGNOR-272436

P06493

P78344

1

phosphorylation

up-regulates activity

0.339

To test whether CDK1 phosphorylates T508, Flag-DAP5 was purified from dox-induced HEK293 cells and incubated with active recombinant JNK2 or CDK1 in the presence of ATP (Fig. 3G). DAP5(T508) was phosphorylated only upon incubation with CDK1 (Fig. 3G).

SIGNOR-266387

P36897

P29353

1

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

P25815

Q9UNE7

0

polyubiquitination

down-regulates quantity by destabilization

0.292

S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.

SIGNOR-272919

P07910

P48729

0

phosphorylation

down-regulates

0.354

A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c.

SIGNOR-133528

P84022

P07437

2

binding

down-regulates activity

0.2

Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin.

SIGNOR-232113

P67809

P78527

0

phosphorylation

up-regulates activity

0.338

The DNA-PK subunits and YB-1 phosphorylated at T89 were found colocalized suggesting their in vivo interaction.DNA-PK directly phosphorylates YB-1 and, this way, modulates YB-1 function. Point mutation of YB-1 at this residue abrogated the translocation of YB-1 into the nucleus.

SIGNOR-277611

P35498

P61328

2

binding

down-regulates activity

0.386

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253420

Q7Z460

P30622

2

binding

up-regulates activity

0.725

CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability.

SIGNOR-265091

P20783

Q16288

2

binding

up-regulates

0.849

Trkc, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3.

SIGNOR-20699

Q15118

P00558

0

phosphorylation

up-regulates activity

0.428

Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex.

SIGNOR-278365

P05412

Q9UKN1

2

binding

up-regulates activity

0.256

MUC12 promoted the recruitment of c-Jun on the promoter of TGF-β1, leading to its transcription.

SIGNOR-265474

P12931

O60500

1

phosphorylation

up-regulates activity

0.48

Inhibition of Src kinase dependent Nephrin phosphorylation achieved by incubation of WT-Nephrin-overexpressing cells with 1 mum PP2 abolished the positive effect of Nephrin on GSIR (XREF_FIG D).|We were able to demonstrate a complete prevention of Nephrin phosphorylation, confirming that Nephrin phosphorylation is mediated by Src.

SIGNOR-280129

Q92918

Q13233

1

phosphorylation

up-regulates

0.455

Hpk1 binds and phosphorylates mekk1 directly,

SIGNOR-43996

Q9UQC2

P42336

2

binding

up-regulates

0.466

The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival

SIGNOR-204966

P62714

Q9C0C7

2

binding

up-regulates activity

0.2

We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene.

SIGNOR-272964

Q6UVK1

P17252

0

phosphorylation

up-regulates activity

0.2

Protein kinase C (PKC)-alpha phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr(2256), identifying this residue as a primary phosphorylation site. PKC-alpha-mediated NG2 phosphorylation at Thr(2256) is therefore a key step for initiating cell polarization and motility.

SIGNOR-263162

Q12923

P04626

1

dephosphorylation

down-regulates activity

0.332

Since a previous report showed PTPN13 may dephosphorylate ErbB2 directly, we also examined levels of phospho-ErbB2 (tyr 1248), and we also observed a small effect in the presence of wild-type PTPN13 (XREF_FIG).|The fact that both ErbB2 and H-RasV12 were potentiated by PTPN13 loss and PTPN13 inhibited MAP kinase signaling downstream of multiple oncogenes (ErbB2, EGFR, H-RasV12), suggest that the phosphatase target that inhibits MAP kinase signaling may not only be limited to ErbB2 tyrosine 1248.

SIGNOR-277087

P23443

Q92934

1

phosphorylation

down-regulates activity

0.295

P70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro apoptotic BAD by producing a reaction that disrupts BAD 's binding to other pro apoptotic molecules thereby allowing cell survival.|p70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro-apoptotic BAD by producing a reaction that disrupts BAD\u2019s binding to other pro-apoptotic molecules thereby allowing cell survival. xref , xref On the other hand, in a recent study, Li et al showed that increased expression of anti-apoptotic BCL2 was induced in myeloid progenitor cells upon activation of p76S6K, thereby promoting cell survival. xref Further studies are needed to better understand the effect of rapamycin and its derivatives on apoptosis in various cancer cells.

SIGNOR-280016

P11413

O60502

0

deglycosylation

down-regulates activity

0.2

O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth|O-GlcNAcylation of G6PD activates enzyme activity|G6PD is dynamically modified by O-GlcNAc at serine 84|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-267605

Q99836

Q08211

2

binding

up-regulates activity

0.491

We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing.

SIGNOR-260955

O96013

O14713

1

phosphorylation

down-regulates activity

0.2

We further demonstrate that p21 activated kinase 4 (PAK4) can phosphorylate ICAP1 at Ser 10 both in vitro and in cultured cells, and that active PAK4 inhibits ICAP1 nuclear accumulation in a Ser-10-dependent manner.|We further demonstrate that p21-activated kinase 4 (PAK4) can phosphorylate ICAP1 at Ser-10 both in vitro and in cultured cells, and that active PAK4 inhibits ICAP1 nuclear accumulation in a Ser-10-dependent manner.

SIGNOR-280056

O00623

P51668

2

binding

up-regulates activity

0.626

Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.

SIGNOR-253024

P35568

P42338

2

binding

up-regulates activity

0.723

To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1

SIGNOR-235487

O15297

P13051

1

dephosphorylation

down-regulates activity

0.377

PPM1D dephosphorylation of UNG2 is correlated with reduced UNG2 activity on uracil-containing templates.|This result suggests that PPM1D specifically inhibits UNG2 and not other uracil DNA glycosylases.

SIGNOR-277156

Q5VT25

P24844

1

phosphorylation

up-regulates

0.516

More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.

SIGNOR-188781

P67775

P04049

1

dephosphorylation

up-regulates

0.592

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

SIGNOR-141170

P55957

Q16611

2

binding

up-regulates

0.822

We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members.

SIGNOR-92942

Q5TCZ1

Q86UR1

2

binding

up-regulates activity

0.409

Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation

SIGNOR-264708

P28482

O60674

1

phosphorylation

down-regulates

0.513

We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner

SIGNOR-236331

P49411

Q9H1Y0

2

binding

down-regulates activity

0.423

PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy.

SIGNOR-266383

P01350

P32239

2

binding

up-regulates

0.783

A segment of five amino acids in the second extracellular loop of the cck-b receptor was shown to be essential for the high affinity of the natural peptide agonits, gastrin,

SIGNOR-66987

P35968

P62993

1

relocalization

up-regulates activity

0.686

In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.

SIGNOR-261948

P17252

P48058

1

phosphorylation

up-regulates

0.57

Receptor internalization, altered;intracellular localization

SIGNOR-97554

P04637

Q9H4B4

0

phosphorylation

up-regulates activity

0.706

Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3.

SIGNOR-109239

Q99490

P06241

0

phosphorylation

up-regulates

0.467

We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival.

SIGNOR-147936

Q9UKB1

O00418

1

ubiquitination

down-regulates

0.436

Eef2k was degraded by the ubiquitin-proteasome system through the ubiquitin ligase scf(__trcp) (skp1-cul1-f-box protein, __-transducin repeat-containing protein) to enable rapid resumption of translation elongation. This event required autophosphorylation of eef2k on a canonical __trcp-binding domain

SIGNOR-197730

P13051

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation

SIGNOR-264885

P78352

Q8NFZ3

0

relocalization

up-regulates activity

0.2

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

SIGNOR-264190

P08237

P01106

0

transcriptional regulation

up-regulates quantity

0.327

C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.

SIGNOR-259988

P31749

P04049

1

phosphorylation

down-regulates

0.7

Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity.

SIGNOR-147963

P29074

P40763

1

dephosphorylation

down-regulates activity

0.255

In terms of molecular mechanisms, we revealed that PTPN4 dephosphorylates pSTAT3 at the Tyr705 residue with a direct interaction, which might provide novel targets for the therapy of CRC.|Loss of PTPN4 Activates STAT3 to Promote the Tumor Growth in Rectal Cancer.

SIGNOR-277057

P50402

P12931

0

phosphorylation

down-regulates

0.451

Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf

SIGNOR-188308