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WW Domain Binding Protein-2, an E6-Associated Protein Interacting Protein, Acts as a Coactivator of Estrogen and Progesterone Receptors

Department of Biochemistry and Molecular Biology (S.C.D., S.R., O.Y.K., A.I., J.Su., J.Sl., Z.N.), University of Miami School of Medicine, Miami, Florida 33136; and Department of Molecular and Cellular Biology (B.W.O.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Zafar Nawaz, Ph.D., Department of Biochemistry and Molecular Biology, Braman Breast Cancer Institute (M-877), University of Miami School of Medicine, Batchelor’s Building, Room 416, 1580 Northwest 10th Avenue, Miami, Florida 33136. E-mail: znawaz{at}med.miami.edu.

WW domain binding protein-2 (WBP-2) was cloned as an E6-associated protein interacting protein, and its role in steroid hormone receptors functions was investigated. We show that WBP-2 specifically enhanced the transactivation functions of progesterone receptor (PR) and estrogen receptor (ER), whereas it did not have any significant effect on the androgen receptor, glucocorticoid receptor, or the activation functions of p53 and VP-16. Depletion of endogenous WBP-2 with small interfering RNAs indicated that WBP-2 was required for the proper functioning of PR and ER. We also demonstrated that WBP-2 contains an intrinsic activation domain. Moreover, chromatin immunoprecipitation assays demonstrate the hormone-dependent recruitment of WBP-2 onto an estrogen-responsive promoter. Mutational analysis suggests that one of three polyproline (PY) motifs of WBP-2 is essential for its coactivation and intrinsic activation functions. We show that WBP-2 and E6-associated protein each enhance PR function, and their effect on PR action are additive when coexpressed, suggesting a common signaling pathway. In this study, we also demonstrate that the WBP-2 binding protein, Yes kinase-associated protein (YAP) enhances PR transactivation, but YAP’s coactivation function is absolutely dependent on WBP-2. Taken together, our data establish the role of WBP-2 and YAP as coactivators for ER and PR transactivation pathways.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  GR  |  PR  |  AR

Coregulators:   E6AP

Ligands:   Dexamethasone  |  17β-Estradiol  |  Progesterone  |  R1881

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