Authors
Siew Wee Chan*, Chun Jye Lim*, Li Shen Loo, Yaan Fun Chong, Caixia Huang, Wanjin Hong

* These two authors contributed equally to this study.

Abstract
The transcriptional coactivators YAP and TAZ are downstream targets inhibited by the Hippo tumor suppressor pathway. The expression level of TAZ is recently shown to be elevated in invasive breast cancer cells and some primary breast cancers. TAZ is important for breast cancer cell migration, invasion and tumorigenesis, but the underlying mechanism is not defined. In this study, we show that TAZ interacts with TEAD transcriptional factors. Knockdown of TEADs suppresses TAZ-mediated oncogenic transformation of MCF10A cells. Uncoupling TAZ from Hippo regulation by S89A mutation enhances its transforming ability. Several residues located in the N-terminal region of TAZ are identified to be important for interaction with TEADs and these same residues are equally important for TAZ to transform MCF10A cells. Mechanistically, TAZ mutants defective in interaction with TEADs fail to accumulate in the nucleus. Live cell imaging of EGFP-TAZ and its mutant defective in TEAD interaction suggests that TEAD interaction mediates nuclear retention. These results reveal a novel mechanism for TEADs to regulate nuclear retention and thus transforming ability of TAZ.

Figure Legend: A model to depict two major mechanisms regulating the distribution and function activity of TAZ. Hippo pathway and 14-3-3 proteins mediate cytoplasmic sequestration, whereas TEAD interaction drives nuclear retention of TAZ.

Published in Journal of Biological Chemistry, 2009 Mar 26. [Epub ahead of print]

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