Ser294

Site Information
APMAPGRsPLATTVM SwissProt Entrez-Gene
Blast this site against: NCBI SwissProt PDB
Site Group ID: 447987

In vivo Characterization
Methods used to characterize site in vivo:	[32P] bio-synthetic labeling ( 20 , 21 ) , electrophoretic mobility shift ( 21 ) , immunoprecipitation ( 2 , 4 , 6 , 7 , 10 ) , mass spectrometry ( 3 , 5 ) , microscopy-colocalization with upstream kinase ( 14 ) , modification-specific antibody ( 6 ) , mutation of modification site ( 6 , 8 , 9 , 10 , 11 , 13 , 14 , 16 , 18 ) , peptide sequencing ( 21 ) , phospho-antibody ( 2 , 4 , 6 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 19 ) , phosphopeptide mapping ( 20 , 21 ) , western blotting ( 2 , 4 , 6 , 7 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 )
Disease tissue studied:	breast cancer ( 2 , 5 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 20 , 21 ) , breast ductal carcinoma ( 5 , 15 ) , HER2 positive breast cancer ( 3 ) , luminal A breast cancer ( 3 ) , ovarian cancer ( 4 )
Relevant cell line - cell type - tissue:	breast ( 3 , 5 ) , C4HD (breast cell) ( 15 ) , COS (fibroblast) ( 7 , 10 ) , ES2 (ovarian) ( 4 ) , HeLa (cervical) ( 6 , 7 , 8 , 10 , 11 , 14 , 18 ) , MCF-7 (breast cell) ( 2 ) , SF9 ( 20 ) , T47D (breast cell) ( 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 )

Upstream Regulation
Regulatory protein:	FGFR2 (human) ( 2 ) , FOXO1A (human) ( 4 ) , RSK2 (human) ( 2 )
Putative in vivo kinases:	CDK2 (human) ( 8 , 10 ) , ERK1 (human) ( 15 , 18 ) , ERK2 (human) ( 15 , 18 ) , MEK1 (human) ( 10 )
Kinases, in vitro:	ERK1 (human) ( 15 ) , ERK2 (human) ( 15 )
Treatments:	AS1842856 ( 4 ) , EGF ( 9 , 10 , 11 , 12 , 16 , 18 ) , heregulin ( 15 ) , KGF ( 2 ) , mifepristone ( 13 ) , MPA ( 15 ) , PD98059 ( 15 ) , PP2 ( 9 ) , progestin_R5020 ( 4 , 6 , 7 , 9 , 10 , 11 , 12 , 14 , 16 , 18 , 19 , 21 ) , SB203580 ( 16 ) , trichostatin_A ( 6 ) , U0126 ( 9 , 12 , 14 , 16 )

Downstream Regulation
Effects of modification on PR:	intracellular localization ( 2 , 11 , 14 ) , protein degradation ( 2 , 11 , 18 ) , sumoylation ( 8 , 10 ) , ubiquitination ( 2 )
Effects of modification on biological processes:	carcinogenesis, altered ( 1 ) , cell adhesion, altered ( 11 ) , cell growth, altered ( 11 ) , transcription, induced ( 1 , 4 , 8 , 10 , 11 )

Disease / Diagnostics Relevance
Relevant diseases:	breast cancer ( 1 )

References
1	Knutson TP, et al. (2017) Posttranslationally modified progesterone receptors direct ligand-specific expression of breast cancer stem cell-associated gene programs. J Hematol Oncol 10, 89 28412963 Curated Info
2	Piasecka D, et al. (2016) Fibroblast growth factor signalling induces loss of progesterone receptor in breast cancer cells. Oncotarget 7, 86011-86025 27852068 Curated Info
3	Mertins P, et al. (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534, 55-62 27251275 Curated Info
4	Diep CH, Knutson TP, Lange CA (2016) Active FOXO1 Is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming. Mol Cancer Res 14, 141-62 26577046 Curated Info
5	Mertins P, et al. (2014) Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels. Mol Cell Proteomics 13, 1690-704 24719451 Curated Info
6	Chung HH, Sze SK, Tay AS, Lin VC (2014) Acetylation at Lysine 183 of Progesterone Receptor by p300 Accelerates DNA Binding Kinetics and Transactivation of Direct Target Genes. J Biol Chem 289, 2180-94 24302725 Curated Info
7	Hagan CR, Knutson TP, Lange CA (2013) A Common Docking Domain in Progesterone Receptor-B links DUSP6 and CK2 signaling to proliferative transcriptional programs in breast cancer cells. Nucleic Acids Res 41, 8926-42 23921636 Curated Info
8	Daniel AR, Lange CA (2009) Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells. Proc Natl Acad Sci U S A 106, 14287-92 19706513 Curated Info
9	Faivre EJ, Daniel AR, Hillard CJ, Lange CA (2008) Progesterone receptor rapid signaling mediates serine 345 phosphorylation and tethering to specificity protein 1 transcription factors. Mol Endocrinol 22, 823-37 18202149 Curated Info
10	Daniel AR, Faivre EJ, Lange CA (2007) Phosphorylation-dependent antagonism of sumoylation derepresses progesterone receptor action in breast cancer cells. Mol Endocrinol 21, 2890-906 17717077 Curated Info
11	Daniel AR, et al. (2007) Linkage of progestin and epidermal growth factor signaling: phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth. Steroids 72, 188-201 17173941 Curated Info
12	Narayanan R, Edwards DP, Weigel NL (2005) Human progesterone receptor displays cell cycle-dependent changes in transcriptional activity. Mol Cell Biol 25, 2885-98 15798179 Curated Info
13	Skildum A, Faivre E, Lange CA (2005) Progesterone receptors induce cell cycle progression via activation of mitogen-activated protein kinases. Mol Endocrinol 19, 327-39 15486045 Curated Info
14	Qiu M, et al. (2003) Mitogen-activated protein kinase regulates nuclear association of human progesterone receptors. Mol Endocrinol 17, 628-42 12554776 Curated Info
15	Labriola L, et al. (2003) Heregulin induces transcriptional activation of the progesterone receptor by a mechanism that requires functional ErbB-2 and mitogen-activated protein kinase activation in breast cancer cells. Mol Cell Biol 23, 1095-111 12529413 Curated Info
16	Shen T, Horwitz KB, Lange CA (2001) Transcriptional hyperactivity of human progesterone receptors is coupled to their ligand-dependent down-regulation by mitogen-activated protein kinase-dependent phosphorylation of serine 294. Mol Cell Biol 21, 6122-31 11509655 Curated Info
17	Knotts TA, et al. (2001) Identification of a phosphorylation site in the hinge region of the human progesterone receptor and additional amino-terminal phosphorylation sites. J Biol Chem 276, 8475-83 11110801 Curated Info
18	Lange CA, Shen T, Horwitz KB (2000) Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. Proc Natl Acad Sci U S A 97, 1032-7 10655479 Curated Info
19	Clemm DL, et al. (2000) Differential hormone-dependent phosphorylation of progesterone receptor A and B forms revealed by a phosphoserine site-specific monoclonal antibody. Mol Endocrinol 14, 52-65 10628747 Curated Info
20	Beck CA, et al. (1996) Stoichiometry and site-specific phosphorylation of human progesterone receptor in native target cells and in the baculovirus expression system. J Biol Chem 271, 19546-55 8702648 Curated Info
21	Zhang Y, et al. (1995) Identification of a group of Ser-Pro motif hormone-inducible phosphorylation sites in the human progesterone receptor. Mol Endocrinol 9, 1029-40 7476977 Curated Info