A Common Docking Domain in Progesterone Receptor-B links DUSP6 and CK2 signaling to proliferative transcriptional programs in breast cancer cells.

Abstract

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.

• Authors: Christy R Hagan, Todd P Knutson, Carol A Lange
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 41 Issue 19 Pg. 8926-42 (Oct 2013) ISSN: 1362-4962 [Electronic] England
• PMID: 23921636 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Progestins
• Receptors, Progesterone
• STAT Transcription Factors
• STAT5 Transcription Factor
• Wnt1 Protein
• progesterone receptor B
• Serine
• Janus Kinases
• Casein Kinase II
• DUSP6 protein, human
• Dual Specificity Phosphatase 6

Topics

• Breast Neoplasms (enzymology, genetics, metabolism)
• Casein Kinase II (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Dual Specificity Phosphatase 6 (metabolism)
• Enhancer Elements, Genetic
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Janus Kinases (metabolism)
• Phosphorylation
• Progestins (pharmacology)
• Protein Interaction Domains and Motifs
• Receptors, Progesterone (chemistry, metabolism)
• S Phase
• STAT Transcription Factors (metabolism)
• STAT5 Transcription Factor (genetics, metabolism)
• Serine (metabolism)
• Signal Transduction
• Transcription, Genetic
• Wnt1 Protein (genetics, metabolism)