Ser425

Site Information
sIRCssVs_______ SwissProt Entrez-Gene
Blast this site against: NCBI SwissProt PDB
Site Group ID: 448336

In vivo Characterization
Methods used to characterize site in vivo:	[32P] bio-synthetic labeling ( 24 ) , immunoprecipitation ( 8 , 19 ) , mass spectrometry ( 12 , 13 , 14 , 15 , 16 ) , mutation of modification site ( 5 , 19 , 20 , 22 , 24 ) , phospho-antibody ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ) , phosphopeptide mapping ( 24 ) , western blotting ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 17 , 18 , 19 , 20 , 21 , 22 , 23 )
Disease tissue studied:	breast cancer ( 1 , 11 , 17 , 22 , 23 ) , breast adenocarcinoma ( 1 ) , breast cancer, triple negative ( 1 ) , gastric cancer ( 12 , 13 ) , gastric carcinoma ( 12 , 13 ) , liver cancer ( 9 , 18 , 19 ) , hepatocellular carcinoma ( 9 , 18 ) , lung cancer ( 16 , 17 ) , non-small cell lung cancer ( 16 , 17 ) , non-small cell lung adenocarcinoma ( 16 ) , non-small cell squamous cell lung carcinoma ( 16 ) , ovarian cancer ( 8 ) , testicular cancer ( 5 )
Relevant cell line - cell type - tissue:	'stem, embryonic' ( 7 ) , 'stem, mesenchymal' ( 10 ) , Cor-1 ( 6 ) , ES2 (ovarian) ( 8 ) , HaCaT (keratinocyte) ( 19 ) , HEK293T (epithelial) ( 19 ) , HeLa (cervical) ( 3 , 14 , 15 ) , Hep 3B2.1-7 (hepatic) ( 9 , 18 ) , HepG2 (hepatic) ( 19 ) , HLE (hepatic) ( 18 ) , HLF (hepatic) ( 18 ) , HMEC (endothelial) ( 1 , 2 ) , IOSE-398 (ovarian) ( 8 ) , Leydig ( 5 ) , LLC-PK1 (renal) ( 21 ) , MA-10 (testicular) ( 5 ) , MCF-10A (breast cell) ( 22 ) , MCF-7 (breast cell) ( 11 ) , MDA-MB-231 (breast cell) ( 1 , 17 , 23 ) , MDA-MB-468 (breast cell) ( 1 ) , mesangial-kidney ( 20 ) , MKN-45 (gastric) ( 12 , 13 ) , Mv1Lu (pulmonary) ( 24 ) , NCI-H1299 (pulmonary) ( 17 ) , NCI-H1703 (squamous) ( 16 ) , OV2008 (ovarian) ( 8 ) , PLC/PRF/5 (hepatic) ( 18 ) , SKOV-3 (ovarian) ( 8 ) , T47D (breast cell) ( 11 )

Upstream Regulation
Regulatory protein:	GDF11 (human) ( 6 ) , MEK1 (human) ( 20 ) , MSTN (human) ( 6 ) , MURF1 (human) ( 1 ) , RHEB (human) ( 3 ) , SMAD3 (human) ( 4 ) , SP1 (human) ( 4 ) , TSC1 (human) ( 3 )
Treatments:	activin ( 7 ) , ALK5_Inhibitor_I ( 21 ) , angiotensin_2 ( 21 ) , anti-CD44 ( 23 ) , cAMP_analog ( 5 ) , CRM197 ( 21 ) , EGF ( 6 ) , FGF2 ( 6 , 7 , 10 ) , gelatin ( 20 ) , heregulin ( 7 ) , hyaluronan ( 23 ) , IGF-1 ( 7 ) , insulin ( 3 ) , LY2109761 ( 1 , 18 ) , LY294002 ( 1 ) , Nodal ( 8 ) , oncostatin_M ( 2 ) , rapamycin ( 3 ) , SB203580 ( 22 ) , SB431542 ( 10 ) , starvation_medium ( 7 ) , TGF-beta ( 1 , 2 , 3 , 4 , 5 , 10 , 17 , 18 , 20 , 21 , 22 , 23 , 24 ) , Y27632 ( 22 )

Upstream Regulation

Regulatory protein:

GDF11 (human) ( 6 ) , MEK1 (human) ( 20 ) , MSTN (human) ( 6 ) , MURF1 (human) ( 1 ) , RHEB (human) ( 3 ) , SMAD3 (human) ( 4 ) , SP1 (human) ( 4 ) , TSC1 (human) ( 3 )

Treatments:

activin ( 7 ) , ALK5_Inhibitor_I ( 21 ) , angiotensin_2 ( 21 ) , anti-CD44 ( 23 ) , cAMP_analog ( 5 ) , CRM197 ( 21 ) , EGF ( 6 ) , FGF2 ( 6 , 7 , 10 ) , gelatin ( 20 ) , heregulin ( 7 ) , hyaluronan ( 23 ) , IGF-1 ( 7 ) , insulin ( 3 ) , LY2109761 ( 1 , 18 ) , LY294002 ( 1 ) , Nodal ( 8 ) , oncostatin_M ( 2 ) , rapamycin ( 3 ) , SB203580 ( 22 ) , SB431542 ( 10 ) , starvation_medium ( 7 ) , TGF-beta ( 1 , 2 , 3 , 4 , 5 , 10 , 17 , 18 , 20 , 21 , 22 , 23 , 24 ) , Y27632 ( 22 )

Downstream Regulation
Effects of modification on SMAD3:	activity, induced ( 18 ) , protein conformation ( 18 )
Effects of modification on biological processes:	cell motility, altered ( 18 ) , signaling pathway regulation ( 9 ) , transcription, altered ( 24 ) , transcription, induced ( 5 )

References
1	Sami E, Paul BT, Koziol JA, ElShamy WM (2020) The immunosuppressive microenvironment in BRCA1-IRIS-overexpressing TNBC tumors is induced by bidirectional interaction with tumor-associated macrophages. Cancer Res 31911557 Curated Info
2	Junk DJ, et al. (2017) Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling. Oncogene 36, 4001-4013 28288136 Curated Info
3	Thien A, et al. (2015) TSC1 activates TGF-β-Smad2/3 signaling in growth arrest and epithelial-to-mesenchymal transition. Dev Cell 32, 617-30 25727005 Curated Info
4	Palumbo-Zerr K, et al. (2015) Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis. Nat Med 21, 150-8 25581517 Curated Info
5	Park E, et al. (2014) Transforming Growth Factor-β1 Signaling Represses Testicular Steroidogenesis through Cross-Talk with Orphan Nuclear Receptor Nur77. PLoS One 9, e104812 25140527 Curated Info
6	Williams G, et al. (2013) Transcriptional basis for the inhibition of neural stem cell proliferation and migration by the TGFβ-family member GDF11. PLoS One 8, e78478 24244313 Curated Info
7	Singh AM, et al. (2012) Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell 10, 312-26 22385658 Curated Info
8	Fu G, Peng C (2011) Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells. Oncogene 30, 3953-66 21532621 Curated Info
9	Seong HA, Manoharan R, Ha H (2011) B-MYB positively regulates serine-threonine kinase receptor-associated protein (STRAP) activity through direct interaction. J Biol Chem 286, 7439-56 21148321 Curated Info
10	Handorf AM, Li WJ (2011) Fibroblast growth factor-2 primes human mesenchymal stem cells for enhanced chondrogenesis. PLoS One 6, e22887 21818404 Curated Info
11	Zelivianski S, Cooley A, Kall R, Jeruss JS (2010) Cyclin-dependent kinase 4-mediated phosphorylation inhibits smad3 activity in cyclin d-overexpressing breast cancer cells. Mol Cancer Res 8, 1375-87 20736297 Curated Info
12	Moritz A (2010) CST Curation Set: 9281; Year: 2010; Biosample/Treatment: cell line, MKN-45/DMSO &'\|\|' Su11274; Disease: gastric carcinoma; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[STY]) Curated Info
13	Moritz A (2010) CST Curation Set: 9236; Year: 2010; Biosample/Treatment: cell line, MKN-45/calyculin_A & pervanadate; Disease: gastric carcinoma; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[STY]) Curated Info
14	Moritz A (2010) CST Curation Set: 9245; Year: 2010; Biosample/Treatment: cell line, HeLa/UV; Disease: cervical adenocarcinoma; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[STY]) Curated Info
15	Moritz A (2010) CST Curation Set: 9239; Year: 2010; Biosample/Treatment: cell line, HeLa/nocodazole; Disease: cervical adenocarcinoma; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[STY]) Curated Info
16	Moritz A (2010) CST Curation Set: 9242; Year: 2010; Biosample/Treatment: cell line, NCI-H1703/untreated; Disease: non-small cell lung cancer; SILAC: -; Specificities of Antibodies Used to Purify Peptides prior to LCMS: p[STY]) Curated Info
17	Adorno M, et al. (2009) A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell 137, 87-98 19345189 Curated Info
18	Fransvea E, Mazzocca A, Antonaci S, Giannelli G (2009) Targeting transforming growth factor (TGF)-betaRI inhibits activation of beta1 integrin and blocks vascular invasion in hepatocellular carcinoma. Hepatology 49, 839-50 19115199 Curated Info
19	Guo X, et al. (2008) Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-beta signaling. Oncogene 27, 7235-47 18794808 Curated Info
20	Hayashida T, et al. (2007) MAP-kinase activity necessary for TGFbeta1-stimulated mesangial cell type I collagen expression requires adhesion-dependent phosphorylation of FAK tyrosine 397. J Cell Sci 120, 4230-40 18032789 Curated Info
21	Chen J, Chen JK, Neilson EG, Harris RC (2006) Role of EGF receptor activation in angiotensin II-induced renal epithelial cell hypertrophy. J Am Soc Nephrol 17, 1615-23 16641152 Curated Info
22	Kamaraju AK, Roberts AB (2005) Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo. J Biol Chem 280, 1024-36 15520018 Curated Info
23	Bourguignon LY, Singleton PA, Zhu H, Zhou B (2002) Hyaluronan promotes signaling interaction between CD44 and the transforming growth factor beta receptor I in metastatic breast tumor cells. J Biol Chem 277, 39703-12 12145287 Curated Info
24	Liu X, et al. (1997) Transforming growth factor beta-induced phosphorylation of Smad3 is required for growth inhibition and transcriptional induction in epithelial cells. Proc Natl Acad Sci U S A 94, 10669-74 9380693 Curated Info