A Common Docking (CD) Domain in Progesterone Receptor‐B Links Rapid Signaling Events to JAK/STAT‐dependent Gene Expression Required for Breast Cancer Cell Proliferation
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Medientyp:
E-Artikel
Titel:
A Common Docking (CD) Domain in Progesterone Receptor‐B Links Rapid Signaling Events to JAK/STAT‐dependent Gene Expression Required for Breast Cancer Cell Proliferation
Beschreibung:
<jats:p>Progesterone receptors (PR) are context‐dependent transcription factors required for mammary gland development. PR target genes include paracrine factors that mediate mammary stem cell selfrenewal. In breast cancer cells, progestin‐bound PRs induce MAPK activation leading to regulation of growth‐promoting genes. Herein, we describe a common docking (CD) domain unique to PR‐B, a motif first described in MAPKs that facilitates direct interactions between MAPKs and MEKs or MAPK‐phosphatases (MKPs). Mutation of the PR‐B CD domain (mCD PR) did not alter progestin‐induced MAPK signaling. However, mCD PR failed to undergo phosphorylation on Ser81, a ck2‐ dependent site required for progestin‐regulation of growth‐promoting genes. PR Ser81 phosphorylation mapped to CD domain‐dependent binding of PR to MKP3. Phospho‐mutant S81A PRs failed to regulate PR‐B‐specific genes, including STAT5 and Wnt1, critical mediators of mammary stem cell expansion. Inhibition of JAK/STAT signaling blocked progestin‐induced STAT5 and Wnt1 expression. Our studies reveal a novel scaffolding action of MKP3 required for ck2‐dependent PR Ser81 phosphorylation. Co‐regulation of select target genes by phospho‐ Ser81 PR and STAT5 is likely a global mechanism required for the activation of growth promoting programs active during mammary gland development and relevant to mechanisms of breast cancer progression.</jats:p>