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J. Biol. Chem., Vol. 283, Issue 9, 5496-5509, February 29, 2008

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Tumor Suppressor LATS1 Is a Negative Regulator of Oncogene YAP^*

From the Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada

LATS (large tumor suppressor) or warts is a Ser/Thr kinase that belongs to the Ndr/LATS subfamily of AGC (protein kinase A/PKG/PKC) kinases. It is a tumor suppressor gene originally isolated from Drosophila and recently isolated from mice and humans. Drosophila or mice mutant for LATS develop tumors in various tissues. Recent studies in Drosophila demonstrate that LATS is a central player of an emerging tumor suppressor pathway called the Hippo-LATS/Warts pathway that suppresses tumor growth by regulating cell proliferation, cell growth, and cell death. Although tremendous progress has been made toward understanding the roles of LATS in tumorigenesis, the kinase substrates of LATS or downstream target proteins mediating LATS function remain largely unknown. In this study, we have provided convincing evidence that the LATS1 tumor suppressor can bind to and phosphorylate transcription regulator and oncogene YAP in vitro and in vivo. We have also identified HX(R/H/K)XX(S/T) as the consensus phosphorylation sequence for LATS/Ndr kinase substrates. Significantly, we have discovered that LATS1 inactivates YAP oncogenic function by suppressing its transcription regulation of cellular genes via sequestration of YAP in the cytoplasm after phosphorylation of YAP. Finally, by using microarray analysis, we have also identified many oncogenes or tumor suppressor genes up-regulated or down-regulated by YAP. These research findings will have profound impacts on our understanding of the molecular mechanism of the LATS tumor suppressor and the emerging Hippo-LATS/Warts pathway.

Received for publication, November 5, 2007 , and in revised form, December 22, 2007.

^* This work was supported by Canadian Institute of Health Research (CIHR) Grant 77726, a CIHR New Investigator Award, and an Ontario Ministry of Research and Innovation, Canada, Early Researcher Award (to X. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Richardson Lab 201, 88 Stuart St., Kingston, Ontario K7L 3N6, Canada. Tel.: 613-533-6000 (ext. 75998); Fax: 613-533-2970; E-mail: yang{at}cliff.path.queensu.ca.

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