Both TEAD-Binding and WW Domains Are Required for the Growth Stimulation and Oncogenic Transformation Activity of Yes-Associated Protein

^{1 1}Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California; ²Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan; and ³Department of Biology and Intercollege Graduate Program in Genetics, The Pennsylvania State University, University Park, Pennsylvania

^* To whom correspondence should be addressed. E-mail: kuguan{at}ucsd.edu.

	Abstract

The Yes-associated protein (YAP) transcription coactivator is a candidate human oncogene and a key regulator of organ size. It is phosphorylated and inhibited by the Hippo tumor suppressor pathway. TEAD family transcription factors were recently shown to play a key role in mediating the biological functions of YAP. Here, we show that the WW domain of YAP has a critical role in inducing a subset of YAP target genes independent of or in cooperation with TEAD. Mutation of the WW domains diminishes the ability of YAP to stimulate cell proliferation and oncogenic transformation. Inhibition of YAP oncogenic-transforming activity depends on intact serine residues 127 and 381, two sites that could be phosphorylated by the Hippo pathway. Furthermore, genetic experiments in Drosophila support that WW domains of YAP and Yki, the fly YAP homologue, have an important role in stimulating tissue growth. Our data suggest a model in which YAP induces gene expression and exerts its biological functions by interacting with transcription factors through both the TEAD-binding and WW domains. [Cancer Res 2009;69(3):OF1–10]

Key Words: growth, oncogenic transformation, WW domain, YAP, Yki

This article has been cited by other articles:

				S. Oh, D. Lee, T. Kim, T.-S. Kim, H. J. Oh, C. Y. Hwang, Y.-Y. Kong, K.-S. Kwon, and D.-S. Lim Crucial Role for Mst1 and Mst2 Kinases in Early Embryonic Development of the Mouse Mol. Cell. Biol., December 1, 2009; 29(23): 6309 - 6320. [Abstract] [Full Text] [PDF]

				X. Zhang, C. C. Milton, P. O. Humbert, and K. F. Harvey Transcriptional Output of the Salvador/Warts/Hippo Pathway Is Controlled in Distinct Fashions in Drosophila melanogaster and Mammalian Cell Lines Cancer Res., August 1, 2009; 69(15): 6033 - 6041. [Abstract] [Full Text] [PDF]

				S. W. Chan, C. J. Lim, L. S. Loo, Y. F. Chong, C. Huang, and W. Hong TEADs Mediate Nuclear Retention of TAZ to Promote Oncogenic Transformation J. Biol. Chem., May 22, 2009; 284(21): 14347 - 14358. [Abstract] [Full Text] [PDF]