GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P17252	P23677	1	null	down-regulates activity	0.37	In contrast, phosphorylation of the A isoform with PKC caused a significant decrease in activity whether assayed in the presence or absence of calcium/calmodulin (to _25% of the unphosphorylated enzyme activity).	SIGNOR-248991
P04406	Q5XX13	0	polyubiquitination	up-regulates activity	0.2	Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation.	SIGNOR-277841
Q13547	P19784	0	phosphorylation	up-regulates activity	0.398	Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1.	SIGNOR-250999
P32121	Q02750	0	phosphorylation	up-regulates activity	0.587	Here, we show that activation of serotonin 5-HT2C receptors, which engage Erk1/2 pathway via a _-arrestin-dependent mechanism, promotes MEK-dependent _-arrestin2 phosphorylation at Thr383	SIGNOR-252027
P35568	P17612	0	phosphorylation	down-regulates quantity by destabilization	0.2	Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223	SIGNOR-235675
O15530	P05129	1	phosphorylation	up-regulates	0.2	One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-126072
Q92945	P12931	1	post transcriptional regulation	up-regulates quantity by expression	0.271	We show here that this component of the DCS complex is hnRNP H and that, like hnRNP F and KSRP, hnRNP H is needed for src N1 splicing in vitro.	SIGNOR-261274
Q9UJU2	Q8WVD3	0	polyubiquitination	down-regulates quantity by destabilization	0.307	Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome.	SIGNOR-271595
Q8IX90	P06493	0	phosphorylation	up-regulates activity	0.394	Cdk1 treatment further enhanced the binding of Ska3 2D to Ndc80, suggesting that phosphorylation of other Cdk1 sites in Ska3 further contributes to the Ndc80C-Ska3 interaction, although this contribution is not apparent in our kinetochore localization assay.We next purified the GST-Ndc80C Bonsai construct that lacks the loop region of Ndc80 as well as the coiled coil regions of Ndc80C [17].\|Thus, Ska3 can be phosphorylated by Cdk1 on T358 and T360 sites in vitro.We next tested whether Ska3 was required for Ska1 or Ska2 localization.	SIGNOR-278376
P24941	P23771	1	phosphorylation	down-regulates quantity by destabilization	0.362	Phosphorylation of GATA3 Thr-156 was detected in mouse thymocytes, and cyclin-dependent kinase 2 (CDK2) was identified as a respondent for phosphorylation at Thr-156.	SIGNOR-276634
Q15910	Q9Y297	0	ubiquitination	down-regulates	0.376	_-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs _-trcp-mediated ezh2 degradation.	SIGNOR-204481
Q9UQ80	P19525	0	phosphorylation	up-regulates activity	0.243	Ebp1 itself is phosphorylated by the PKR protein kinase, suggesting that the effects of Ebp1 overexpression evidenced in vivo on eIF2alpha phosphorylation could be achieved by competition between Ebp1 and eIF2alpha for PKR kinase activity.	SIGNOR-279170
P28329	Q9UQM7	0	phosphorylation	up-regulates	0.372	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-96628
O14867	Q8NEZ5	0	ubiquitination	down-regulates quantity	0.282	Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22.	SIGNOR-259331
P61586	Q12774	0	guanine nucleotide exchange factor	up-regulates activity	0.617	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-260533
P28482	Q86UR1	1	phosphorylation	down-regulates	0.326	These results demonstrated a critical role of noxa1 phosphorylation on ser-282 and ser-172 in preventing nox1 hyperactivation through the decrease of noxa1 interaction to nox1 and rac1.	SIGNOR-163659
Q99836	P12931	0	phosphorylation	up-regulates activity	0.445	Because MyD88 was phosphorylated at the tyrosine 58 residue in hemi-ITAM by LPS ( xref ), whether Src phosphorylates MyD88 at the tyrosine 58 residue was examined further, and MyD88 was phosphorylated by Src at Y58 ( xref ).\|Src activates MyD88 by phosphorylation at Y58 via the Src kinase domain.	SIGNOR-279655
P11498	Q16654	0	phosphorylation	down-regulates activity	0.373	PDK4 phosphorylates and inhibits the pyruvate dehydrogenase complex (PDC) which catalyzes the conversion of pyruvate to acetyl-CoA in the glucose oxidation pathway.	SIGNOR-278974
P62877	P03372	1	ubiquitination	down-regulates quantity by destabilization	0.344	I3C-dependent activation of the aryl hydrocarbon receptor (AhR) initiates Rbx-1 E3 ligase-mediated ubiquitination and proteasomal degradation of ERalpha protein.	SIGNOR-271434
Q13188	Q9H2K8	0	phosphorylation	up-regulates	0.291	In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2	SIGNOR-201333
Q13153	Q96P20	1	phosphorylation	up-regulates activity	0.2	Pak1 phosphorylates NLRP3 to promote inflammasome activation.	SIGNOR-277547
P07332	P15311	0	relocalization	up-regulates	0.395	The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin.	SIGNOR-159496
Q92696	P20336	1	lipidation	up-regulates activity	0.569	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265574
P00519	O60504	1	phosphorylation	up-regulates activity	0.412	Abl kinase interacts with and phosphorylates vinexin.	SIGNOR-280172
Q96GD4	Q9NP77	1	phosphorylation	down-regulates quantity by destabilization	0.254	Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72.	SIGNOR-275529
Q04206	P05231	1	transcriptional regulation	up-regulates quantity by expression	0.692	Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation	SIGNOR-251737
P05067	Q9Y5Z0	0	cleavage	up-regulates activity	0.544	BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.\|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating Î±- and Î²-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform.	SIGNOR-261773
O75061	P11142	1	relocalization	up-regulates activity	0.883	Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane.	SIGNOR-260719
P35580	Q05513	0	phosphorylation	down-regulates	0.269	After egf stimulation, apkc_ translocates from the nucleus to the cytoplasm (figure 3) and is therefore able to interact with myosin ii-b. apkc_ phosphorylates nmhc ii-b on ser1937, which is located on the nonhelical tailpiece, leading to filament disassembly at certain sites of the cell	SIGNOR-146100
P07948	Q12972	1	phosphorylation	down-regulates activity	0.312	Tyrosine phosphorylation of NIPP1 by Lyn was abolished by the Tyr-264 to Asp mutation.	SIGNOR-251405
P49841	Q15853	1	phosphorylation	up-regulates activity	0.283	Although no study has yet correlated the activity of GSK3beta with the activity of USF2 in a certain tumor setting, the findings of the present study would favor the tumor promoting aspects of GSK3beta and USF2 since GSK3beta activated USF2 enhanced cell migration which may be important in terms of tumor cell metastasis.\|Together, these data show that there are two residues within USF2, namely S155 and T230, which can be phosphorylated by GSK3beta.	SIGNOR-278158
P23458	P38484	1	phosphorylation	up-regulates activity	0.66	The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process.	SIGNOR-249491
P01112	P21359	0	gtpase-activating protein	down-regulates activity	0.813	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204357
Q15759	P15336	1	phosphorylation	up-regulates	0.756	Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target	SIGNOR-65586
O15519	Q96J02	0	ubiquitination	down-regulates quantity	0.614	Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation.	SIGNOR-245307
P48730	Q9Y6Q9	1	phosphorylation	up-regulates	0.284	In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1.	SIGNOR-184946
Q8IVT5	P27448	0	phosphorylation	down-regulates activity	0.642	C-TAK1 phosphorylates KSR1 at S392, forming a 14-3-3 binding site.\|In mammalian cells, C-TAK1 has been shown to negatively regulate KSR1 by phosphorylation of Ser392.	SIGNOR-279225
Q92993	Q13315	1	acetylation	up-regulates activity	0.8	Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. \|Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016	SIGNOR-275891
P63000	Q8IYU2	0	ubiquitination	down-regulates quantity by destabilization	0.367	The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain containing E3 ubiquitin-ligase, in the targeting of Rac1 to UPS. HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitylation	SIGNOR-255538
P42771	Q8IXJ9	0	transcriptional regulation	up-regulates quantity by expression	0.3	Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice.	SIGNOR-260119
P28482	Q07343	1	phosphorylation	up-regulates activity	0.268	The short-form PDE4B2 isoenzyme was activated by Erk2 phosphorylation. These functional changes in PDE activity were mimicked by mutation of the target serine for Erk2 phosphorylation to the negatively charged amino acid, aspartic acid.	SIGNOR-275970
O75925	O15111	0	phosphorylation	up-regulates activity	0.38	In addition, we show that IKKalpha is associated with PIAS1 and mediates the S90 phosphorylation of PIAS1.\|Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription.	SIGNOR-278926
P61586	Q2M1Z3	0	gtpase-activating protein	down-regulates activity	0.529	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-260488
P35318	P05549	0	transcriptional regulation	up-regulates quantity by expression	0.267	These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells.	SIGNOR-254048
Q13233	P45985	1	phosphorylation	up-regulates activity	0.729	The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1	SIGNOR-236380
Q15831	Q9H093	1	phosphorylation	up-regulates	0.273	A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold.	SIGNOR-122717
Q14258	P06744	1	ubiquitination	down-regulates quantity by destabilization	0.25	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-272178
P10636	Q96L34	0	phosphorylation	down-regulates activity	0.419	AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A).	SIGNOR-273935
P46108	P52564	0	phosphorylation	up-regulates	0.2	Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily.	SIGNOR-42384
Q9Y6D6	P17612	0	phosphorylation	up-regulates activity	0.2	Within 20 min after addition of 8-Br-cAMP, BIG1 accumulated in nuclei, and this effect was blocked by protein kinase A (PKA) inhibitors H-89 and PKI, suggesting a dependence on PKA-catalyzed phosphorylation. \|Mutant BIG1 (S883A) in which Ala replaced Ser-883, a putative PKA phosphorylation site, did not move to the nucleus with cAMP addition, whereas replacement with Asp (S883D) resulted in nuclear accumulation of BIG1 without or with cAMP exposure, consistent with the mechanistic importance of a negative charge at that site	SIGNOR-272146
Q15910	Q16539	0	phosphorylation	down-regulates quantity by destabilization	0.372	Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372	SIGNOR-255663
O60281	P01241	1	transcriptional regulation	up-regulates quantity by expression	0.2	Rat Zn-15 is a transcription factor activating GH gene expression by synergistic interactions with Pit-1, named for 15 DNA-binding zinc fingers, including fingers IX, X, and XI that are responsible for GH promoter binding.	SIGNOR-268969
A0A1B0GVQ0	Q00535	0	phosphorylation	down-regulates quantity by destabilization	0.2	Cdk5 also phosphorylates PSD-95-interacting protein Spine Associated RapGAP (SPAR), resulting in its degradation ([98], Table 2).	SIGNOR-280219
P57078	Q13489	0	polyubiquitination	up-regulates activity	0.355	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation.	SIGNOR-272709
Q9H3M7	P28482	0	phosphorylation	down-regulates quantity by destabilization	0.294	ERK-dependent Txnip ubiquitination and proteasome degradation depended upon phosphorylation of a PXTP motif threonine (Thr349) located within the C-terminal α-arrestin domain and proximal to a previously characterized E3 ubiquitin ligase-binding site.	SIGNOR-277468
P63000	Q9NRY4	0	gtpase-activating protein	down-regulates activity	0.724	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-260493
P01222	Q92911	1	transcriptional regulation	up-regulates quantity by expression	0.38	Iâ€“ uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane	SIGNOR-251995
P60484	Q9UHC7	0	ubiquitination	down-regulates quantity by destabilization	0.43	EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase.\|In fact, epidermal growth factor-stimulated pAKT phosphorylates and subsequently stabilizes MKRN1, which then ubiquitinates and induces the degradation of PTEN.	SIGNOR-278830
Q9NZ42	P34925	1	cleavage	up-regulates	0.2	Ryk activity is modulated through cleavage of its icd by gamma-secretase	SIGNOR-182145
P61586	O94827	0	guanine nucleotide exchange factor	up-regulates activity	0.771	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-260566
Q9Y297	Q13131	0	phosphorylation	down-regulates quantity by destabilization	0.2	Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1.	SIGNOR-277475
P19484	P00519	0	phosphorylation	down-regulates activity	0.2	Our data show that c-Abl promotes TFEB tyrosine phosphorylation and that its inhibition induces TFEB activity.\|c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder Summary The transcription factor EB ( TFEB ) has emerged as a master regulator of lysosomal biogenesis , exocytosis , and autophagy , promoting the clearance of substrates stored in cells .	SIGNOR-279583
P61586	A1A4S6	0	gtpase-activating protein	down-regulates activity	0.668	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-260465
P50613	P24928	1	phosphorylation	down-regulates	0.789	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120024
Q05397	A6NI28	1	phosphorylation	up-regulates activity	0.309	FAK and Src Mediated Phosphorylation of GRAF3 at Y376 Promotes Allosteric Activation.	SIGNOR-280097
O43683	Q13257	1	relocalization	up-regulates activity	0.96	Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity	SIGNOR-252018
P13501	Q9BZS1	0	transcriptional regulation	up-regulates quantity by expression	0.434	Given its role as a potent chemoattractant for T cells, CCL5 can be utilized to attract Tregs to malignant epithelial cells. Wang et al. demonstrated that Forkheadbox protein 3 (FOXP3), a key transcription factor for Tregs, was highly ex- pressed in pancreatic cancer cell lines, which, in turn, upregulated CCL5 expression	SIGNOR-277727
P69905	P14384	0	cleavage	down-regulates activity	0.2	Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity.	SIGNOR-256507
Q9HAV4	P28482	0	phosphorylation	down-regulates activity	0.301	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.	SIGNOR-262984
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
P53355	P12931	0	phosphorylation	down-regulates activity	0.273	Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation.	SIGNOR-276074
P12882	Q06413	0	transcriptional regulation	up-regulates quantity by expression	0.383	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238754
P24928	Q14004	0	phosphorylation	up-regulates activity	0.541	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.\|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273054
O00429	P00519	0	phosphorylation	up-regulates activity	0.26	In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation.	SIGNOR-277328
Q16539	Q14934	1	phosphorylation	down-regulates activity	0.402	P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity.	SIGNOR-250107
P49841	P03372	1	phosphorylation	up-regulates	0.34	The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex.	SIGNOR-139316
Q92598	P19784	0	phosphorylation	down-regulates activity	0.327	Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. \| the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro.	SIGNOR-251008
Q15751	P62195	1	ubiquitination	down-regulates quantity	0.2	HERC1 interacts with and ubiquitinates nascent PSMC5.\|PSMC5 produced in the absence of PAAF1 is presumably misfolded (consistent with its aggregation in the PURE system), triggering PSMC5 degradation by a HERC1-independent pathway.	SIGNOR-278812
Q00987	Q06187	0	phosphorylation	down-regulates activity	0.278	Phosphorylation of MDM2 by BTK suppresses its ubiquitination activity.	SIGNOR-278330
P43694	Q9UI47	1	transcriptional regulation	up-regulates quantity by expression	0.25	GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter	SIGNOR-265490
O15350	P45983	0	phosphorylation	up-regulates activity	0.42	Therefore, it is likely that p73 recruitment to the \u0394Np73 promoter is mediated by its JNK-1-dependent phosphorylation.	SIGNOR-279219
P49840	P17612	0	phosphorylation	down-regulates	0.372	Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a.	SIGNOR-83221
O60260	O00429	1	ubiquitination	down-regulates quantity	0.2	Parkin interacts with and subsequently ubiquitinates Drp1, thus promoting its proteasome dependent degradation .\|We have demonstrated that parkin promotes Drp1 degradation after OGDR insult.	SIGNOR-278589
O75154	P06493	0	phosphorylation	up-regulates quantity	0.2	FIP3 is phosphorylated on S102 in a cell cycle-dependent manner. We identify four sites of phosphorylation of FIP3 in vivo, S-102, S-280, S-347 and S-450 and identify S-102 as a target for Cdk1-cyclin B in vitro. Of these, we show that S-102 is phosphorylated in metaphase and is dephosphorylated as cells enter telophase.	SIGNOR-273588
P29474	P00519	0	phosphorylation	up-regulates activity	0.2	Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS.	SIGNOR-277519
Q8TEW0	Q7KZI7	0	phosphorylation	up-regulates	0.493	Gab1 brings par1 and par3 into a transient complex, stimulating par3 phosphorylation by par1	SIGNOR-198742
P08631	Q92556	1	phosphorylation	up-regulates	0.606	We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts.	SIGNOR-138154
P35548	Q9Y458	0	transcriptional regulation	down-regulates quantity by repression	0.309	the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22.	SIGNOR-265567
P07948	P31995	1	phosphorylation	up-regulates activity	0.2	Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation	SIGNOR-262676
P17612	P52888	1	phosphorylation	up-regulates activity	0.307	PKA phosphorylation is suggested to play a regulatory role in EP24.15 enzyme activity. Mutation analysis of each putative PKA site, in vitro phosphorylation, and phosphopeptide mapping indicated serine 644 as the phosphorylation site. The most dramatic change upon PKA phosphorylation was a substrate-specific, 7-fold increase in both K(m) and k(cat) for GnRH.	SIGNOR-250060
P62805	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265376
Q12913	O43561	1	dephosphorylation	down-regulates activity	0.353	Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation	SIGNOR-248696
Q07820	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.5	MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1.	SIGNOR-251242
P48729	P30304	1	phosphorylation	down-regulates	0.333	Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a	SIGNOR-164734
P12931	O14874	1	phosphorylation	up-regulates activity	0.2	Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells.	SIGNOR-275583
Q8N3U4	P53350	0	dephosphorylation	down-regulates activity	0.737	Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.\|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase	SIGNOR-275534
Q9H0M0	Q4VCS5	1	ubiquitination	up-regulates quantity by stabilization	0.275	Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130	SIGNOR-275847
O15194	Q15797	1	dephosphorylation	down-regulates activity	0.498	Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.\|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. \|The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248314
P49841	Q99684	1	phosphorylation	down-regulates quantity by destabilization	0.2	GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation.	SIGNOR-277465
P53779	O14733	0	phosphorylation	up-regulates	0.582	Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19).	SIGNOR-137609

P17252

P23677

1

null

down-regulates activity

0.37

In contrast, phosphorylation of the A isoform with PKC caused a significant decrease in activity whether assayed in the presence or absence of calcium/calmodulin (to _25% of the unphosphorylated enzyme activity).

SIGNOR-248991

P04406

Q5XX13

0

polyubiquitination

up-regulates activity

0.2

Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation.

SIGNOR-277841

Q13547

P19784

0

phosphorylation

up-regulates activity

0.398

Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1.

SIGNOR-250999

P32121

Q02750

0

phosphorylation

up-regulates activity

0.587

Here, we show that activation of serotonin 5-HT2C receptors, which engage Erk1/2 pathway via a _-arrestin-dependent mechanism, promotes MEK-dependent _-arrestin2 phosphorylation at Thr383

SIGNOR-252027

P35568

P17612

0

phosphorylation

down-regulates quantity by destabilization

0.2

Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223

SIGNOR-235675

O15530

P05129

1

phosphorylation

up-regulates

0.2

One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.

SIGNOR-126072

Q92945

P12931

1

post transcriptional regulation

up-regulates quantity by expression

0.271

We show here that this component of the DCS complex is hnRNP H and that, like hnRNP F and KSRP, hnRNP H is needed for src N1 splicing in vitro.

SIGNOR-261274

Q9UJU2

Q8WVD3

0

polyubiquitination

down-regulates quantity by destabilization

0.307

Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome.

SIGNOR-271595

Q8IX90

P06493

0

phosphorylation

up-regulates activity

0.394

Cdk1 treatment further enhanced the binding of Ska3 2D to Ndc80, suggesting that phosphorylation of other Cdk1 sites in Ska3 further contributes to the Ndc80C-Ska3 interaction, although this contribution is not apparent in our kinetochore localization assay.We next purified the GST-Ndc80C Bonsai construct that lacks the loop region of Ndc80 as well as the coiled coil regions of Ndc80C [17].|Thus, Ska3 can be phosphorylated by Cdk1 on T358 and T360 sites in vitro.We next tested whether Ska3 was required for Ska1 or Ska2 localization.

SIGNOR-278376

P24941

P23771

1

phosphorylation

down-regulates quantity by destabilization

0.362

Phosphorylation of GATA3 Thr-156 was detected in mouse thymocytes, and cyclin-dependent kinase 2 (CDK2) was identified as a respondent for phosphorylation at Thr-156.

SIGNOR-276634

Q15910

Q9Y297

0

ubiquitination

down-regulates

0.376

_-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs _-trcp-mediated ezh2 degradation.

SIGNOR-204481

Q9UQ80

P19525

0

phosphorylation

up-regulates activity

0.243

Ebp1 itself is phosphorylated by the PKR protein kinase, suggesting that the effects of Ebp1 overexpression evidenced in vivo on eIF2alpha phosphorylation could be achieved by competition between Ebp1 and eIF2alpha for PKR kinase activity.

SIGNOR-279170

P28329

Q9UQM7

0

phosphorylation

up-regulates

0.372

We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.

SIGNOR-96628

O14867

Q8NEZ5

0

ubiquitination

down-regulates quantity

0.282

Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22.

SIGNOR-259331

P61586

Q12774

0

guanine nucleotide exchange factor

up-regulates activity

0.617

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-260533

P28482

Q86UR1

1

phosphorylation

down-regulates

0.326

These results demonstrated a critical role of noxa1 phosphorylation on ser-282 and ser-172 in preventing nox1 hyperactivation through the decrease of noxa1 interaction to nox1 and rac1.

SIGNOR-163659

Q99836

P12931

0

phosphorylation

up-regulates activity

0.445

Because MyD88 was phosphorylated at the tyrosine 58 residue in hemi-ITAM by LPS ( xref ), whether Src phosphorylates MyD88 at the tyrosine 58 residue was examined further, and MyD88 was phosphorylated by Src at Y58 ( xref ).|Src activates MyD88 by phosphorylation at Y58 via the Src kinase domain.

SIGNOR-279655

P11498

Q16654

0

phosphorylation

down-regulates activity

0.373

PDK4 phosphorylates and inhibits the pyruvate dehydrogenase complex (PDC) which catalyzes the conversion of pyruvate to acetyl-CoA in the glucose oxidation pathway.

SIGNOR-278974

P62877

P03372

1

ubiquitination

down-regulates quantity by destabilization

0.344

I3C-dependent activation of the aryl hydrocarbon receptor (AhR) initiates Rbx-1 E3 ligase-mediated ubiquitination and proteasomal degradation of ERalpha protein.

SIGNOR-271434

Q13188

Q9H2K8

0

phosphorylation

up-regulates

0.291

In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2

SIGNOR-201333

Q13153

Q96P20

1

phosphorylation

up-regulates activity

0.2

Pak1 phosphorylates NLRP3 to promote inflammasome activation.

SIGNOR-277547

P07332

P15311

0

relocalization

up-regulates

0.395

The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin.

SIGNOR-159496

Q92696

P20336

1

lipidation

up-regulates activity

0.569

Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional

SIGNOR-265574

P00519

O60504

1

phosphorylation

up-regulates activity

0.412

Abl kinase interacts with and phosphorylates vinexin.

SIGNOR-280172

Q96GD4

Q9NP77

1

phosphorylation

down-regulates quantity by destabilization

0.254

Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72.

SIGNOR-275529

Q04206

P05231

1

transcriptional regulation

up-regulates quantity by expression

0.692

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

SIGNOR-251737

P05067

Q9Y5Z0

0

cleavage

up-regulates activity

0.544

BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating Î±- and Î²-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform.

SIGNOR-261773

O75061

P11142

1

relocalization

up-regulates activity

0.883

Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane.

SIGNOR-260719

P35580

Q05513

0

phosphorylation

down-regulates

0.269

After egf stimulation, apkc_ translocates from the nucleus to the cytoplasm (figure 3) and is therefore able to interact with myosin ii-b. apkc_ phosphorylates nmhc ii-b on ser1937, which is located on the nonhelical tailpiece, leading to filament disassembly at certain sites of the cell

SIGNOR-146100

P07948

Q12972

1

phosphorylation

down-regulates activity

0.312

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

SIGNOR-251405

P49841

Q15853

1

phosphorylation

up-regulates activity

0.283

Although no study has yet correlated the activity of GSK3beta with the activity of USF2 in a certain tumor setting, the findings of the present study would favor the tumor promoting aspects of GSK3beta and USF2 since GSK3beta activated USF2 enhanced cell migration which may be important in terms of tumor cell metastasis.|Together, these data show that there are two residues within USF2, namely S155 and T230, which can be phosphorylated by GSK3beta.

SIGNOR-278158

P23458

P38484

1

phosphorylation

up-regulates activity

0.66

The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process.

SIGNOR-249491

P01112

P21359

0

gtpase-activating protein

down-regulates activity

0.813

Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation

SIGNOR-204357

Q15759

P15336

1

phosphorylation

up-regulates

0.756

Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target

SIGNOR-65586

O15519

Q96J02

0

ubiquitination

down-regulates quantity

0.614

Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation.

SIGNOR-245307

P48730

Q9Y6Q9

1

phosphorylation

up-regulates

0.284

In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1.

SIGNOR-184946

Q8IVT5

P27448

0

phosphorylation

down-regulates activity

0.642

C-TAK1 phosphorylates KSR1 at S392, forming a 14-3-3 binding site.|In mammalian cells, C-TAK1 has been shown to negatively regulate KSR1 by phosphorylation of Ser392.

SIGNOR-279225

Q92993

Q13315

1

acetylation

up-regulates activity

0.8

Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. |Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016

SIGNOR-275891

P63000

Q8IYU2

0

ubiquitination

down-regulates quantity by destabilization

0.367

The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain containing E3 ubiquitin-ligase, in the targeting of Rac1 to UPS. HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitylation

SIGNOR-255538

P42771

Q8IXJ9

0

transcriptional regulation

up-regulates quantity by expression

0.3

Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice.

SIGNOR-260119

P28482

Q07343

1

phosphorylation

up-regulates activity

0.268

The short-form PDE4B2 isoenzyme was activated by Erk2 phosphorylation. These functional changes in PDE activity were mimicked by mutation of the target serine for Erk2 phosphorylation to the negatively charged amino acid, aspartic acid.

SIGNOR-275970

O75925

O15111

0

phosphorylation

up-regulates activity

0.38

In addition, we show that IKKalpha is associated with PIAS1 and mediates the S90 phosphorylation of PIAS1.|Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription.

SIGNOR-278926

P61586

Q2M1Z3

0

gtpase-activating protein

down-regulates activity

0.529

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-260488

P35318

P05549

0

transcriptional regulation

up-regulates quantity by expression

0.267

These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells.

SIGNOR-254048

Q13233

P45985

1

phosphorylation

up-regulates activity

0.729

The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1

SIGNOR-236380

Q15831

Q9H093

1

phosphorylation

up-regulates

0.273

A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold.

SIGNOR-122717

Q14258

P06744

1

ubiquitination

down-regulates quantity by destabilization

0.25

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-272178

P10636

Q96L34

0

phosphorylation

down-regulates activity

0.419

AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A).

SIGNOR-273935

P46108

P52564

0

phosphorylation

up-regulates

0.2

Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily.

SIGNOR-42384

Q9Y6D6

P17612

0

phosphorylation

up-regulates activity

0.2

Within 20 min after addition of 8-Br-cAMP, BIG1 accumulated in nuclei, and this effect was blocked by protein kinase A (PKA) inhibitors H-89 and PKI, suggesting a dependence on PKA-catalyzed phosphorylation. |Mutant BIG1 (S883A) in which Ala replaced Ser-883, a putative PKA phosphorylation site, did not move to the nucleus with cAMP addition, whereas replacement with Asp (S883D) resulted in nuclear accumulation of BIG1 without or with cAMP exposure, consistent with the mechanistic importance of a negative charge at that site

SIGNOR-272146

Q15910

Q16539

0

phosphorylation

down-regulates quantity by destabilization

0.372

Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372

SIGNOR-255663

O60281

P01241

1

transcriptional regulation

up-regulates quantity by expression

0.2

Rat Zn-15 is a transcription factor activating GH gene expression by synergistic interactions with Pit-1, named for 15 DNA-binding zinc fingers, including fingers IX, X, and XI that are responsible for GH promoter binding.

SIGNOR-268969

A0A1B0GVQ0

Q00535

0

phosphorylation

down-regulates quantity by destabilization

0.2

Cdk5 also phosphorylates PSD-95-interacting protein Spine Associated RapGAP (SPAR), resulting in its degradation ([98], Table 2).

SIGNOR-280219

P57078

Q13489

0

polyubiquitination

up-regulates activity

0.355

CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation.

SIGNOR-272709

Q9H3M7

P28482

0

phosphorylation

down-regulates quantity by destabilization

0.294

ERK-dependent Txnip ubiquitination and proteasome degradation depended upon phosphorylation of a PXTP motif threonine (Thr349) located within the C-terminal α-arrestin domain and proximal to a previously characterized E3 ubiquitin ligase-binding site.

SIGNOR-277468

P63000

Q9NRY4

0

gtpase-activating protein

down-regulates activity

0.724

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-260493

P01222

Q92911

1

transcriptional regulation

up-regulates quantity by expression

0.38

Iâ€“ uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane

SIGNOR-251995

P60484

Q9UHC7

0

ubiquitination

down-regulates quantity by destabilization

0.43

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

SIGNOR-278830

Q9NZ42

P34925

1

cleavage

up-regulates

0.2

Ryk activity is modulated through cleavage of its icd by gamma-secretase

SIGNOR-182145

P61586

O94827

0

guanine nucleotide exchange factor

up-regulates activity

0.771

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-260566

Q9Y297

Q13131

0

phosphorylation

down-regulates quantity by destabilization

0.2

Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1.

SIGNOR-277475

P19484

P00519

0

phosphorylation

down-regulates activity

0.2

Our data show that c-Abl promotes TFEB tyrosine phosphorylation and that its inhibition induces TFEB activity.|c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder Summary The transcription factor EB ( TFEB ) has emerged as a master regulator of lysosomal biogenesis , exocytosis , and autophagy , promoting the clearance of substrates stored in cells .

SIGNOR-279583

P61586

A1A4S6

0

gtpase-activating protein

down-regulates activity

0.668

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-260465

P50613

P24928

1

phosphorylation

down-regulates

0.789

Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.

SIGNOR-120024

Q05397

A6NI28

1

phosphorylation

up-regulates activity

0.309

FAK and Src Mediated Phosphorylation of GRAF3 at Y376 Promotes Allosteric Activation.

SIGNOR-280097

O43683

Q13257

1

relocalization

up-regulates activity

0.96

Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity

SIGNOR-252018

P13501

Q9BZS1

0

transcriptional regulation

up-regulates quantity by expression

0.434

Given its role as a potent chemoattractant for T cells, CCL5 can be utilized to attract Tregs to malignant epithelial cells. Wang et al. demonstrated that Forkheadbox protein 3 (FOXP3), a key transcription factor for Tregs, was highly ex- pressed in pancreatic cancer cell lines, which, in turn, upregulated CCL5 expression

SIGNOR-277727

P69905

P14384

0

cleavage

down-regulates activity

0.2

Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity.

SIGNOR-256507

Q9HAV4

P28482

0

phosphorylation

down-regulates activity

0.301

Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.

SIGNOR-262984

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

P53355

P12931

0

phosphorylation

down-regulates activity

0.273

Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation.

SIGNOR-276074

P12882

Q06413

0

transcriptional regulation

up-regulates quantity by expression

0.383

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238754

P24928

Q14004

0

phosphorylation

up-regulates activity

0.541

Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence

SIGNOR-273054

O00429

P00519

0

phosphorylation

up-regulates activity

0.26

In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation.

SIGNOR-277328

Q16539

Q14934

1

phosphorylation

down-regulates activity

0.402

P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity.

SIGNOR-250107

P49841

P03372

1

phosphorylation

up-regulates

0.34

The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex.

SIGNOR-139316

Q92598

P19784

0

phosphorylation

down-regulates activity

0.327

Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro.

SIGNOR-251008

Q15751

P62195

1

ubiquitination

down-regulates quantity

0.2

HERC1 interacts with and ubiquitinates nascent PSMC5.|PSMC5 produced in the absence of PAAF1 is presumably misfolded (consistent with its aggregation in the PURE system), triggering PSMC5 degradation by a HERC1-independent pathway.

SIGNOR-278812

Q00987

Q06187

0

phosphorylation

down-regulates activity

0.278

Phosphorylation of MDM2 by BTK suppresses its ubiquitination activity.

SIGNOR-278330

P43694

Q9UI47

1

transcriptional regulation

up-regulates quantity by expression

0.25

GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter

SIGNOR-265490

O15350

P45983

0

phosphorylation

up-regulates activity

0.42

Therefore, it is likely that p73 recruitment to the \u0394Np73 promoter is mediated by its JNK-1-dependent phosphorylation.

SIGNOR-279219

P49840

P17612

0

phosphorylation

down-regulates

0.372

Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a.

SIGNOR-83221

O60260

O00429

1

ubiquitination

down-regulates quantity

0.2

Parkin interacts with and subsequently ubiquitinates Drp1, thus promoting its proteasome dependent degradation .|We have demonstrated that parkin promotes Drp1 degradation after OGDR insult.

SIGNOR-278589

O75154

P06493

0

phosphorylation

up-regulates quantity

0.2

FIP3 is phosphorylated on S102 in a cell cycle-dependent manner. We identify four sites of phosphorylation of FIP3 in vivo, S-102, S-280, S-347 and S-450 and identify S-102 as a target for Cdk1-cyclin B in vitro. Of these, we show that S-102 is phosphorylated in metaphase and is dephosphorylated as cells enter telophase.

SIGNOR-273588

P29474

P00519

0

phosphorylation

up-regulates activity

0.2

Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS.

SIGNOR-277519

Q8TEW0

Q7KZI7

0

phosphorylation

up-regulates

0.493

Gab1 brings par1 and par3 into a transient complex, stimulating par3 phosphorylation by par1

SIGNOR-198742

P08631

Q92556

1

phosphorylation

up-regulates

0.606

We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts.

SIGNOR-138154

P35548

Q9Y458

0

transcriptional regulation

down-regulates quantity by repression

0.309

the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22.

SIGNOR-265567

P07948

P31995

1

phosphorylation

up-regulates activity

0.2

Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation

SIGNOR-262676

P17612

P52888

1

phosphorylation

up-regulates activity

0.307

PKA phosphorylation is suggested to play a regulatory role in EP24.15 enzyme activity. Mutation analysis of each putative PKA site, in vitro phosphorylation, and phosphopeptide mapping indicated serine 644 as the phosphorylation site. The most dramatic change upon PKA phosphorylation was a substrate-specific, 7-fold increase in both K(m) and k(cat) for GnRH.

SIGNOR-250060

P62805

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265376

Q12913

O43561

1

dephosphorylation

down-regulates activity

0.353

Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation

SIGNOR-248696

Q07820

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.5

MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1.

SIGNOR-251242

P48729

P30304

1

phosphorylation

down-regulates

0.333

Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a

SIGNOR-164734

P12931

O14874

1

phosphorylation

up-regulates activity

0.2

Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells.

SIGNOR-275583

Q8N3U4

P53350

0

dephosphorylation

down-regulates activity

0.737

Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase

SIGNOR-275534

Q9H0M0

Q4VCS5

1

ubiquitination

up-regulates quantity by stabilization

0.275

Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130

SIGNOR-275847

O15194

Q15797

1

dephosphorylation

down-regulates activity

0.498

Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)

SIGNOR-248314

P49841

Q99684

1

phosphorylation

down-regulates quantity by destabilization

0.2

GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation.

SIGNOR-277465

P53779

O14733

0

phosphorylation

up-regulates

0.582

Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19).

SIGNOR-137609