A Common Docking Domain in Progesterone Receptor-B links DUSP6 and CK2 signaling to proliferative transcriptional programs in breast cancer cells.
Progesterone receptors (PR) are transcription factors relevant to breast cancer biology. Herein, we describe an N-terminal common docking (CD) domain in PR-B, a motif first described in mitogen-activated protein kinases. Binding studies revealed PR-B interacts with dual-specificity phosphatase 6 (DUSP6) via the CD domain. Mutation of the PR-B CD domain (mCD) attenuated cell cycle progression and expression of PR-B target genes (including STAT5A and Wnt1); mCD PR-B failed to undergo phosphorylation on Ser81, a ck2-dependent site required for expression of these genes. PR-B Ser81 phosphorylation was dependent on binding with DUSP6 and required for recruitment of a transcriptional complex consisting of PR-B, DUSP6 and ck2 to an enhancer region upstream of the Wnt1 promoter. STAT5 was present at this site in the absence or presence of progestin. Furthermore, phospho-Ser81 PR-B was recruited to the STAT5A gene upon progestin treatment, suggestive of a feed-forward mechanism. Inhibition of JAK/STAT-signaling blocked progestin-induced STAT5A and Wnt1 expression. Our studies show that DUSP6 serves as a scaffold for ck2-dependent PR-B Ser81 phosphorylation and subsequent PR-B-specific gene selection in coordination with STAT5. Coregulation of select target genes by PR-B and STAT5 is likely a global mechanism required for growth promoting programs relevant to mammary stem cell biology and cancer.
Departments of Medicine and Pharmacology, Cell Signaling Program; Masonic Cancer Center, University of Minnesota, Cancer Cardiology Research Building, 2231 6th Street SE, Minneapolis, MN 55455, USA.
Christy R
CR
Hagan
Todd P
TP
Knutson
Carol A
CA
Lange
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D010766:Phosphorylation; D011372:Progestins / Q000494:pharmacology; D054730:Protein Interaction Domains and Motifs; D011980:Receptors, Progesterone / Q000737:chemistry / Q000378:metabolism*; D016196:S Phase; D050791:STAT Transcription Factors / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism
D011372:Progestins; D011980:Receptors, Progesterone; D050791:STAT Transcription Factors; D050799:STAT5 Transcription Factor; D051155:Wnt1 Protein; C097314:progesterone receptor B; D012694:Serine; D053612:Janus Kinases; D047390:Casein Kinase II; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6