GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 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
Q9UBE8	Q92793	1	phosphorylation	up-regulates activity	0.557	In vitro kinase assay showed that NLK could phosphorylate the C-terminal domain of CBP.	SIGNOR-280048
Q9GZQ8	Q14596	1	binding	down-regulates	0.557	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1.	SIGNOR-184252
P17612	P49841	1	phosphorylation	down-regulates activity	0.557	Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).	SIGNOR-188577
Q92502	P61586	1	gtpase-activating protein	down-regulates activity	0.557	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-260519
Q92793	P52630	1	acetylation	up-regulates activity	0.557	STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation.	SIGNOR-217891
Q13153	P35222	1	phosphorylation	up-regulates	0.557	Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin	SIGNOR-175944
Q12852	O14733	1	phosphorylation	up-regulates activity	0.556	Collectively, these data suggest the hypothesis that ApoE activates DLK by increasing its levels	SIGNOR-279630
Q6ZN04	O95149	1	polyubiquitination	down-regulates quantity by destabilization	0.556	HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation.	SIGNOR-272079
P68400	P35222	1	phosphorylation	up-regulates activity	0.556	The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability.	SIGNOR-250849
O94989	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.556	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-260541
P17612	Q14643	1	phosphorylation	down-regulates activity	0.556	IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site.	SIGNOR-249996
P48730	O15169	2	binding	up-regulates	0.556	We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms.	SIGNOR-87433
O75914	P04049	1	phosphorylation	up-regulates	0.556	The protein kinase pak3 positively regulates raf-1 activity through phosphorylation of serine 338.	SIGNOR-62043
Q99759	Q13501	1	phosphorylation	up-regulates activity	0.556	MEKK3 overexpression, but not that of a kinase dead mutant, was able to induce the phosphorylation of p62 at T269 and S272 (XREF_FIG), which correlated with mTORC1 activation (XREF_FIG), suggesting that MEKK3 could be a bona fide regulator of p62 phosphorylation and mTORC1 activity.	SIGNOR-279532
P45983	P01106	1	phosphorylation	up-regulates activity	0.556	The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71.	SIGNOR-236018
Q13153	Q15746	1	phosphorylation	down-regulates activity	0.556	P21-activated kinase 1 (PAK1) phosphorylates MLCK, resulting in decreased MLCK activity.	SIGNOR-250317
P08913	P63096	1	binding	up-regulates activity	0.556	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 ≥ -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 ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256698
P19174	P17252	2	phosphorylation	up-regulates	0.556	Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199.	SIGNOR-99310
Q16650	O15409	1	binding	up-regulates activity	0.556	We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein.	SIGNOR-266831
P24394	P42229	1	null	up-regulates	0.556	Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5	SIGNOR-254298
P17252	P19174	2	phosphorylation	down-regulates	0.556	The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl.	SIGNOR-17905
P45983	O43379	2	phosphorylation	down-regulates quantity by destabilization	0.556	WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. \|JNK1 can induce the phosphorylation of WDR62 T1053	SIGNOR-271710
P06493	O15350	1	phosphorylation	down-regulates activity	0.556	Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86.	SIGNOR-99742
Q92615	P11940	1	binding	up-regulates activity	0.556	Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3â€² end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex.	SIGNOR-260940
O15169	P48730	2	binding	up-regulates	0.556	Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).	SIGNOR-87401
O43379	P45983	2	relocalization	up-regulates activity	0.556	In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis	SIGNOR-271718
P52630	P42224	1	binding	up-regulates activity	0.555	We then examined STAT2 acetylation within the b-barrel DBD. A direct interaction between the STAT2-DBD (315485) and STAT1 was detected (Figure 6E) (Li et al., 1997).	SIGNOR-217957
P08631	P42768	1	phosphorylation	up-regulates activity	0.555	Hck induces tyrosine phosphorylation of WASp. Here we show that the Src family kinase Hck induces phosphorylation of WASp-Tyr(291) independently of Cdc42 and that this causes a shift in the mobility of WASp upon SDS-PAGE. A phospho-mimicking mutant, WASp-Y291E, exhibited an enhanced ability to stimulate actin polymerization in a cell-free system and when microinjected into primary macrophages induced extensive filopodium formation with greater efficiency than wild-type WASp or a Y291F mutant. We propose that phosphorylation of Tyr(291) directly regulates WASp function.	SIGNOR-273957
P05412	P17947	1	binding	up-regulates activity	0.555	These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1.	SIGNOR-255660
Q92633	P63096	1	binding	up-regulates activity	0.555	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 ≥ -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 ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256696
Q9GZV5	P84022	1	binding	up-regulates	0.555	Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.	SIGNOR-169841
P23467	Q02763	1	dephosphorylation	down-regulates activity	0.555	Simultaneous inhibition of Tie2 cleavage and VE-PTP synergistically enhances Tie2 activation by up to 10-fold (Fig. 7A).\|Tie2 activation is also importantly regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates Tie2 to inhibit its vascular stabilizing effects .\|Tie2 activation is also importantly regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates Tie2 to inhibit its vascular stabilizing effects.	SIGNOR-277059
P08253	P01137	1	cleavage	up-regulates	0.555	We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-beta (tgf-beta), which constitutes a novel mechanism of tgf-beta activation	SIGNOR-74384
Q05397	P27986	1	binding	up-regulates	0.555	Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors.	SIGNOR-53979
Q04206	P01584	1	transcriptional regulation	down-regulates activity	0.555	Early Inhibition of IL-1 beta Expression by IFN-gamma Is Mediated by Impaired Binding of NF-kappa B to the IL-1 beta Promoter but Is Independent of Nitric Oxide\|We report that IFN-γ suppressed bacterial RNA and LPS induced IL-1β transcription in primary murine macrophages	SIGNOR-251736
P10147	P41597	1	binding	up-regulates activity	0.555	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-251723
Q05513	Q04206	1	phosphorylation	up-regulates	0.555	Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k)	SIGNOR-151432
P48730	Q00535	1	phosphorylation	up-regulates activity	0.555	We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro.	SIGNOR-250798
Q05655	P51828	1	phosphorylation	up-regulates activity	0.555	Immunoprecipitation data indicated that PKCdelta could bind and directly phosphorylate AC7.	SIGNOR-279258
Q9UKE5	Q9NQB0	1	phosphorylation	up-regulates	0.555	Here, we report that tnik is an activating kinase for tcf4 and essential for colorectal cancer growth. Tnik, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of tcf4.	SIGNOR-165946
P28702	Q03181	1	binding	up-regulates	0.555	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105451
P16220	Q9UBK2	1	transcriptional regulation	up-regulates quantity by expression	0.554	CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo	SIGNOR-256150
O14827	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.554	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-260575
P62873	Q00722	1	binding	up-regulates	0.554	Activation of plc-beta 2 by beta gamma subunits may be an important mechanism by which pertussis toxin-sensitive g proteins stimulate plc.	SIGNOR-19447
P24941	O14757	1	phosphorylation	up-regulates	0.554	Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency	SIGNOR-175083
Q7L591	P62993	1	binding	up-regulates activity	0.554	An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.	SIGNOR-268448
P06239	Q08881	1	phosphorylation	up-regulates	0.554	Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. The major site of Lck phosphorylation on Itk was mapped to the conserved tyrosine (Tyr511) in the activation loop of the Itk kinase domain.	SIGNOR-251380
Q6VAB6	P10398	1	binding	up-regulates activity	0.553	In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.	SIGNOR-273875
P53350	Q53EZ4	1	phosphorylation	up-regulates	0.553	Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. s425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436...enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.	SIGNOR-140898
O43295	Q92558	1	binding	up-regulates	0.553	Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo.	SIGNOR-95967
P28482	P02686	1	phosphorylation	down-regulates	0.553	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-22420
P07948	P46527	1	phosphorylation	down-regulates	0.553	We previously reported that y88 phosphorylation of p27(kip1) by oncogenic tyrosine kinases impairs p27(kip1)-mediated cdk inhibition, and initiates its ubiquitin-dependent proteasomal degradation.	SIGNOR-172904
Q16671	Q04771	1	binding	up-regulates	0.553	See table2	SIGNOR-121593
O14827	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.553	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-260573
P17252	P14598	1	phosphorylation	up-regulates	0.553	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89178
Q13546	O43318	1	binding	up-regulates activity	0.553	RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex	SIGNOR-256022
Q8IZL8	P04150	1	transcriptional regulation	up-regulates quantity by expression	0.553	MNAR functionally interacts with both NH2- and COOH-terminal GR domains to modulate transactivation	SIGNOR-251681
P09619	Q05397	1	phosphorylation	up-regulates	0.553	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.	SIGNOR-167658
Q86YT6	Q9NR61	1	ubiquitination	up-regulates activity	0.553	Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.	SIGNOR-209626
Q53G59	Q9NQW1	1	binding	up-regulates activity	0.553	By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division.	SIGNOR-272014
Q149N8	P12004	1	ubiquitination	up-regulates	0.553	We provide evidence that similar to rad5, shprh physically interacts with the human rad6rad18 and mms2ubc13 protein complexes, and importantly, we show that it exhibits an ubiquitin ligase activity and mediates mms2ubc13-dependent polyubiquitylation of pcna. Thus, shprh is a functional homolog of rad5.	SIGNOR-187757
P51587	Q9Y253	1	binding	up-regulates	0.553	Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates	SIGNOR-204538
Q9Y3C5	Q96J02	1	binding	up-regulates activity	0.553	Rnf11, together with tax1bp1 and itch, is an essential component of an a20 ubiquitin-editing protein complex; rnf11 is required for a20 to interact with and inactivate rip1 to inhibit tnf-mediated nf-_kb activation.	SIGNOR-183188
P41595	P50148	1	binding	up-regulates activity	0.553	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 ≥ -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 ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257138
P02679	P02751	1	binding	down-regulates activity	0.553	Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a).	SIGNOR-251970
P12931	P23528	1	phosphorylation	down-regulates	0.553	Tyrosine phosphorylation of cofilin at y68 by v-src leads to its degradation through ubiquitin-proteasome pathway	SIGNOR-188352
P68400	P11831	1	phosphorylation	up-regulates activity	0.552	Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.\| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated.	SIGNOR-250955
P28482	P10415	1	phosphorylation	up-regulates quantity by stabilization	0.552	Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation.	SIGNOR-74931
P49336	P46531	1	phosphorylation	down-regulates	0.552	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-130640
P43405	P40763	1	phosphorylation	up-regulates activity	0.552	The current study indicates that the plasma cell malignancy is also associated with Syk-activated STAT3 directly downstream of reelin-induced integrin \u03b21 engagement and FAK/Src activation (Figure xref ).\|The integrin-activated spleen tyrosine kinase (Syk) was shown to promote STAT3 phosphorylation [42, 44].	SIGNOR-279298
Q8N726	P06748	2	binding	down-regulates quantity by destabilization	0.552	The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division	SIGNOR-245077
P06748	Q8N726	2	binding	up-regulates activity	0.552	The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division	SIGNOR-245073
P30559	P50148	1	binding	up-regulates activity	0.552	OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq).	SIGNOR-270332
Q01851	P03372	1	binding	up-regulates activity	0.552	The POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect.	SIGNOR-241275
P18031	P40763	1	dephosphorylation	down-regulates activity	0.552	PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.	SIGNOR-248427
P43405	P78314	1	phosphorylation	up-regulates activity	0.552	By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk.	SIGNOR-246596
P63096	Q08828	1	binding	down-regulates activity	0.552	GTP-bound, active WT Gαi1 acts to inhibit AC, resulting in a decreased concentration of intracellular cAMP.	SIGNOR-256498
P28482	P46695	1	phosphorylation	up-regulates	0.552	Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors.	SIGNOR-93740
Q05086	Q14160	1	polyubiquitination	down-regulates quantity by destabilization	0.552	Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase	SIGNOR-272573
Q9HAU4	P36894	1	ubiquitination	down-regulates	0.552	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-192898
P08631	P16885	1	phosphorylation	up-regulates activity	0.552	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249364
P09769	Q05397	1	phosphorylation	up-regulates	0.552	Phosphorylated on tyrosine residues upon activation. Phosphorylation at tyr-925 is important for interaction with grb2 and depends on the complex formation between fak and the src-kinase fgr.	SIGNOR-94405
Q13153	P53350	1	phosphorylation	up-regulates	0.552	We show here that pak1 is required for cell proliferation, mitotic progression and plk1 activity in hela cells. phosphorylation of plk1 on ser 49 is important for metaphase-associated events.	SIGNOR-178353
Q16539	P22415	1	phosphorylation	up-regulates activity	0.552	Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes	SIGNOR-185572
P48729	O75581	1	phosphorylation	up-regulates	0.552	We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.Site ii, like site i, was phosphorylated, as detected by means of a phospho-specific antibody (ab1493, for phosphorylated t1493 in lrp6)	SIGNOR-143034
P31749	Q9BVI0	1	phosphorylation	down-regulates	0.552	Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function.	SIGNOR-252529
Q9UPT6	Q16584	1	binding	up-regulates	0.552	These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3jip3 increases mlk3-stimulated jnk activity.	SIGNOR-73909
Q9BXH1	Q92843	1	binding	down-regulates	0.552	Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133814
Q52LW3	P61586	1	gtpase-activating protein	down-regulates activity	0.552	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-260484
Q14145	Q96HS1	1	binding	down-regulates quantity by destabilization	0.552	Keap1-dependent ubiquitination of PGAM5 results in proteasome-dependent degradation of PGAM5. Keap1 is a Bric-a-Brac (BTB) 2 -Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex.	SIGNOR-272645
P54646	Q92574	1	phosphorylation	up-regulates	0.551	Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity.	SIGNOR-119541
P42345	Q96EB6	1	phosphorylation	down-regulates activity	0.551	These results demonstrate that the inhibition of SIRT1 by mTOR fosters survival of DNA damage-induced prematurely senescent squamous cell carcinoma cells via Bfl-1/A1 in the absence of functional p53.\|This process involved the mTOR-dependent phosphorylation of SIRT1 at serine 47, resulting in the inhibition of the deacetylase activity of SIRT1.	SIGNOR-280047
Q96JH7	P55072	1	binding	up-regulates activity	0.551	Golgi biogenesis requires two distinct p97ATPase-mediated membrane fusion, the p97/p47 and p97/p37 pathways. \|We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97.	SIGNOR-265039
O95382	Q99683	2	phosphorylation	up-regulates quantity by stabilization	0.551	ASK2 Activates ASK1 by Phosphorylation	SIGNOR-260832
Q5S007	P26038	1	phosphorylation	up-regulates activity	0.551	This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process.	SIGNOR-154498
Q15154	Q9BV73	1	relocalization	up-regulates	0.551	Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1	SIGNOR-133334
P17612	P08151	1	phosphorylation	down-regulates	0.551	We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1.	SIGNOR-253539
P63167	Q9C0C7	1	binding	down-regulates	0.551	The beclin 1vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1interacting protein ambra1 and dynein light chains 1/2.	SIGNOR-168255
O75688	O43318	1	dephosphorylation	down-regulates activity	0.551	In vitro, PP2Cbeta-1 dephosphorylated and inactivated TAK1.	SIGNOR-277154
Q02363	Q99081	1	binding	down-regulates activity	0.551	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241131

Q9UBE8

Q92793

1

phosphorylation

up-regulates activity

0.557

In vitro kinase assay showed that NLK could phosphorylate the C-terminal domain of CBP.

SIGNOR-280048

Q9GZQ8

Q14596

1

binding

down-regulates

0.557

We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1.

SIGNOR-184252

P17612

P49841

1

phosphorylation

down-regulates activity

0.557

Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).

SIGNOR-188577

Q92502

P61586

1

gtpase-activating protein

down-regulates activity

0.557

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-260519

Q92793

P52630

1

acetylation

up-regulates activity

0.557

STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation.

SIGNOR-217891

Q13153

P35222

1

phosphorylation

up-regulates

0.557

Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin

SIGNOR-175944

Q12852

O14733

1

phosphorylation

up-regulates activity

0.556

Collectively, these data suggest the hypothesis that ApoE activates DLK by increasing its levels

SIGNOR-279630

Q6ZN04

O95149

1

polyubiquitination

down-regulates quantity by destabilization

0.556

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

SIGNOR-272079

P68400

P35222

1

phosphorylation

up-regulates activity

0.556

The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability.

SIGNOR-250849

O94989

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.556

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-260541

P17612

Q14643

1

phosphorylation

down-regulates activity

0.556

IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site.

SIGNOR-249996

P48730

O15169

2

binding

up-regulates

0.556

We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms.

SIGNOR-87433

O75914

P04049

1

phosphorylation

up-regulates

0.556

The protein kinase pak3 positively regulates raf-1 activity through phosphorylation of serine 338.

SIGNOR-62043

Q99759

Q13501

1

phosphorylation

up-regulates activity

0.556

MEKK3 overexpression, but not that of a kinase dead mutant, was able to induce the phosphorylation of p62 at T269 and S272 (XREF_FIG), which correlated with mTORC1 activation (XREF_FIG), suggesting that MEKK3 could be a bona fide regulator of p62 phosphorylation and mTORC1 activity.

SIGNOR-279532

P45983

P01106

1

phosphorylation

up-regulates activity

0.556

The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71.

SIGNOR-236018

Q13153

Q15746

1

phosphorylation

down-regulates activity

0.556

P21-activated kinase 1 (PAK1) phosphorylates MLCK, resulting in decreased MLCK activity.

SIGNOR-250317

P08913

P63096

1

binding

up-regulates activity

0.556

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 ≥ -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 ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256698

P19174

P17252

2

phosphorylation

up-regulates

0.556

Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199.

SIGNOR-99310

Q16650

O15409

1

binding

up-regulates activity

0.556

We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein.

SIGNOR-266831

P24394

P42229

1

null

up-regulates

0.556

Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5

SIGNOR-254298

P17252

P19174

2

phosphorylation

down-regulates

0.556

The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl.

SIGNOR-17905

P45983

O43379

2

phosphorylation

down-regulates quantity by destabilization

0.556

WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053

SIGNOR-271710

P06493

O15350

1

phosphorylation

down-regulates activity

0.556

Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86.

SIGNOR-99742

Q92615

P11940

1

binding

up-regulates activity

0.556

Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3â€² end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex.

SIGNOR-260940

O15169

P48730

2

binding

up-regulates

0.556

Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).

SIGNOR-87401

O43379

P45983

2

relocalization

up-regulates activity

0.556

In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis

SIGNOR-271718

P52630

P42224

1

binding

up-regulates activity

0.555

We then examined STAT2 acetylation within the b-barrel DBD. A direct interaction between the STAT2-DBD (315485) and STAT1 was detected (Figure 6E) (Li et al., 1997).

SIGNOR-217957

P08631

P42768

1

phosphorylation

up-regulates activity

0.555

Hck induces tyrosine phosphorylation of WASp. Here we show that the Src family kinase Hck induces phosphorylation of WASp-Tyr(291) independently of Cdc42 and that this causes a shift in the mobility of WASp upon SDS-PAGE. A phospho-mimicking mutant, WASp-Y291E, exhibited an enhanced ability to stimulate actin polymerization in a cell-free system and when microinjected into primary macrophages induced extensive filopodium formation with greater efficiency than wild-type WASp or a Y291F mutant. We propose that phosphorylation of Tyr(291) directly regulates WASp function.

SIGNOR-273957

P05412

P17947

1

binding

up-regulates activity

0.555

These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1.

SIGNOR-255660

Q92633

P63096

1

binding

up-regulates activity

0.555

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 ≥ -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 ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256696

Q9GZV5

P84022

1

binding

up-regulates

0.555

Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.

SIGNOR-169841

P23467

Q02763

1

dephosphorylation

down-regulates activity

0.555

Simultaneous inhibition of Tie2 cleavage and VE-PTP synergistically enhances Tie2 activation by up to 10-fold (Fig. 7A).|Tie2 activation is also importantly regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates Tie2 to inhibit its vascular stabilizing effects .|Tie2 activation is also importantly regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates Tie2 to inhibit its vascular stabilizing effects.

SIGNOR-277059

P08253

P01137

1

cleavage

up-regulates

0.555

We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-beta (tgf-beta), which constitutes a novel mechanism of tgf-beta activation

SIGNOR-74384

Q05397

P27986

1

binding

up-regulates

0.555

Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors.

SIGNOR-53979

Q04206

P01584

1

transcriptional regulation

down-regulates activity

0.555

Early Inhibition of IL-1 beta Expression by IFN-gamma Is Mediated by Impaired Binding of NF-kappa B to the IL-1 beta Promoter but Is Independent of Nitric Oxide|We report that IFN-γ suppressed bacterial RNA and LPS induced IL-1β transcription in primary murine macrophages

SIGNOR-251736

P10147

P41597

1

binding

up-regulates activity

0.555

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-251723

Q05513

Q04206

1

phosphorylation

up-regulates

0.555

Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k)

SIGNOR-151432

P48730

Q00535

1

phosphorylation

up-regulates activity

0.555

We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro.

SIGNOR-250798

Q05655

P51828

1

phosphorylation

up-regulates activity

0.555

Immunoprecipitation data indicated that PKCdelta could bind and directly phosphorylate AC7.

SIGNOR-279258

Q9UKE5

Q9NQB0

1

phosphorylation

up-regulates

0.555

Here, we report that tnik is an activating kinase for tcf4 and essential for colorectal cancer growth. Tnik, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of tcf4.

SIGNOR-165946

P28702

Q03181

1

binding

up-regulates

0.555

Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology

SIGNOR-105451

P16220

Q9UBK2

1

transcriptional regulation

up-regulates quantity by expression

0.554

CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo

SIGNOR-256150

O14827

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.554

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-260575

P62873

Q00722

1

binding

up-regulates

0.554

Activation of plc-beta 2 by beta gamma subunits may be an important mechanism by which pertussis toxin-sensitive g proteins stimulate plc.

SIGNOR-19447

P24941

O14757

1

phosphorylation

up-regulates

0.554

Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency

SIGNOR-175083

Q7L591

P62993

1

binding

up-regulates activity

0.554

An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.

SIGNOR-268448

P06239

Q08881

1

phosphorylation

up-regulates

0.554

Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. The major site of Lck phosphorylation on Itk was mapped to the conserved tyrosine (Tyr511) in the activation loop of the Itk kinase domain.

SIGNOR-251380

Q6VAB6

P10398

1

binding

up-regulates activity

0.553

In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.

SIGNOR-273875

P53350

Q53EZ4

1

phosphorylation

up-regulates

0.553

Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. s425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436...enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.

SIGNOR-140898

O43295

Q92558

1

binding

up-regulates

0.553

Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo.

SIGNOR-95967

P28482

P02686

1

phosphorylation

down-regulates

0.553

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-22420

P07948

P46527

1

phosphorylation

down-regulates

0.553

We previously reported that y88 phosphorylation of p27(kip1) by oncogenic tyrosine kinases impairs p27(kip1)-mediated cdk inhibition, and initiates its ubiquitin-dependent proteasomal degradation.

SIGNOR-172904

Q16671

Q04771

1

binding

up-regulates

0.553

See table2

SIGNOR-121593

O14827

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.553

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-260573

P17252

P14598

1

phosphorylation

up-regulates

0.553

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

SIGNOR-89178

Q13546

O43318

1

binding

up-regulates activity

0.553

RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex

SIGNOR-256022

Q8IZL8

P04150

1

transcriptional regulation

up-regulates quantity by expression

0.553

MNAR functionally interacts with both NH2- and COOH-terminal GR domains to modulate transactivation

SIGNOR-251681

P09619

Q05397

1

phosphorylation

up-regulates

0.553

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

SIGNOR-167658

Q86YT6

Q9NR61

1

ubiquitination

up-regulates activity

0.553

Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.

SIGNOR-209626

Q53G59

Q9NQW1

1

binding

up-regulates activity

0.553

By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division.

SIGNOR-272014

Q149N8

P12004

1

ubiquitination

up-regulates

0.553

We provide evidence that similar to rad5, shprh physically interacts with the human rad6rad18 and mms2ubc13 protein complexes, and importantly, we show that it exhibits an ubiquitin ligase activity and mediates mms2ubc13-dependent polyubiquitylation of pcna. Thus, shprh is a functional homolog of rad5.

SIGNOR-187757

P51587

Q9Y253

1

binding

up-regulates

0.553

Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates

SIGNOR-204538

Q9Y3C5

Q96J02

1

binding

up-regulates activity

0.553

Rnf11, together with tax1bp1 and itch, is an essential component of an a20 ubiquitin-editing protein complex; rnf11 is required for a20 to interact with and inactivate rip1 to inhibit tnf-mediated nf-_kb activation.

SIGNOR-183188

P41595

P50148

1

binding

up-regulates activity

0.553

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 ≥ -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 ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257138

P02679

P02751

1

binding

down-regulates activity

0.553

Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a).

SIGNOR-251970

P12931

P23528

1

phosphorylation

down-regulates

0.553

Tyrosine phosphorylation of cofilin at y68 by v-src leads to its degradation through ubiquitin-proteasome pathway

SIGNOR-188352

P68400

P11831

1

phosphorylation

up-regulates activity

0.552

Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated.

SIGNOR-250955

P28482

P10415

1

phosphorylation

up-regulates quantity by stabilization

0.552

Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation.

SIGNOR-74931

P49336

P46531

1

phosphorylation

down-regulates

0.552

Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.

SIGNOR-130640

P43405

P40763

1

phosphorylation

up-regulates activity

0.552

The current study indicates that the plasma cell malignancy is also associated with Syk-activated STAT3 directly downstream of reelin-induced integrin \u03b21 engagement and FAK/Src activation (Figure xref ).|The integrin-activated spleen tyrosine kinase (Syk) was shown to promote STAT3 phosphorylation [42, 44].

SIGNOR-279298

Q8N726

P06748

2

binding

down-regulates quantity by destabilization

0.552

The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division

SIGNOR-245077

P06748

Q8N726

2

binding

up-regulates activity

0.552

The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division

SIGNOR-245073

P30559

P50148

1

binding

up-regulates activity

0.552

OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq).

SIGNOR-270332

Q01851

P03372

1

binding

up-regulates activity

0.552

The POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect.

SIGNOR-241275

P18031

P40763

1

dephosphorylation

down-regulates activity

0.552

PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.

SIGNOR-248427

P43405

P78314

1

phosphorylation

up-regulates activity

0.552

By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk.

SIGNOR-246596

P63096

Q08828

1

binding

down-regulates activity

0.552

GTP-bound, active WT Gαi1 acts to inhibit AC, resulting in a decreased concentration of intracellular cAMP.

SIGNOR-256498

P28482

P46695

1

phosphorylation

up-regulates

0.552

Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors.

SIGNOR-93740

Q05086

Q14160

1

polyubiquitination

down-regulates quantity by destabilization

0.552

Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase

SIGNOR-272573

Q9HAU4

P36894

1

ubiquitination

down-regulates

0.552

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

SIGNOR-192898

P08631

P16885

1

phosphorylation

up-regulates activity

0.552

The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.

SIGNOR-249364

P09769

Q05397

1

phosphorylation

up-regulates

0.552

Phosphorylated on tyrosine residues upon activation. Phosphorylation at tyr-925 is important for interaction with grb2 and depends on the complex formation between fak and the src-kinase fgr.

SIGNOR-94405

Q13153

P53350

1

phosphorylation

up-regulates

0.552

We show here that pak1 is required for cell proliferation, mitotic progression and plk1 activity in hela cells. phosphorylation of plk1 on ser 49 is important for metaphase-associated events.

SIGNOR-178353

Q16539

P22415

1

phosphorylation

up-regulates activity

0.552

Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes

SIGNOR-185572

P48729

O75581

1

phosphorylation

up-regulates

0.552

We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.Site ii, like site i, was phosphorylated, as detected by means of a phospho-specific antibody (ab1493, for phosphorylated t1493 in lrp6)

SIGNOR-143034

P31749

Q9BVI0

1

phosphorylation

down-regulates

0.552

Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function.

SIGNOR-252529

Q9UPT6

Q16584

1

binding

up-regulates

0.552

These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3jip3 increases mlk3-stimulated jnk activity.

SIGNOR-73909

Q9BXH1

Q92843

1

binding

down-regulates

0.552

Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.

SIGNOR-133814

Q52LW3

P61586

1

gtpase-activating protein

down-regulates activity

0.552

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-260484

Q14145

Q96HS1

1

binding

down-regulates quantity by destabilization

0.552

Keap1-dependent ubiquitination of PGAM5 results in proteasome-dependent degradation of PGAM5. Keap1 is a Bric-a-Brac (BTB) 2 -Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex.

SIGNOR-272645

P54646

Q92574

1

phosphorylation

up-regulates

0.551

Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity.

SIGNOR-119541

P42345

Q96EB6

1

phosphorylation

down-regulates activity

0.551

These results demonstrate that the inhibition of SIRT1 by mTOR fosters survival of DNA damage-induced prematurely senescent squamous cell carcinoma cells via Bfl-1/A1 in the absence of functional p53.|This process involved the mTOR-dependent phosphorylation of SIRT1 at serine 47, resulting in the inhibition of the deacetylase activity of SIRT1.

SIGNOR-280047

Q96JH7

P55072

1

binding

up-regulates activity

0.551

Golgi biogenesis requires two distinct p97ATPase-mediated membrane fusion, the p97/p47 and p97/p37 pathways. |We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97.

SIGNOR-265039

O95382

Q99683

2

phosphorylation

up-regulates quantity by stabilization

0.551

ASK2 Activates ASK1 by Phosphorylation

SIGNOR-260832

Q5S007

P26038

1

phosphorylation

up-regulates activity

0.551

This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process.

SIGNOR-154498

Q15154

Q9BV73

1

relocalization

up-regulates

0.551

Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1

SIGNOR-133334

P17612

P08151

1

phosphorylation

down-regulates

0.551

We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1.

SIGNOR-253539

P63167

Q9C0C7

1

binding

down-regulates

0.551

The beclin 1vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1interacting protein ambra1 and dynein light chains 1/2.

SIGNOR-168255

O75688

O43318

1

dephosphorylation

down-regulates activity

0.551

In vitro, PP2Cbeta-1 dephosphorylated and inactivated TAK1.

SIGNOR-277154

Q02363

Q99081

1

binding

down-regulates activity

0.551

All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.

SIGNOR-241131