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J. Biol. Chem., Vol. 283, Issue 41, 27534-27546, October 10, 2008

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Mst2 and Lats Kinases Regulate Apoptotic Function of Yes Kinase-associated Protein (YAP)^*

Tsutomu Oka, Virginia Mazack, and Marius Sudol¹

From the Laboratory of Signal Transduction and Proteomic Profiling, Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822 and the Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029

The Hippo pathway in Drosophila controls the size and shape of organs. In the fly, activation of this pathway conveys growth-inhibitory signals and promotes apoptosis in epithelial cells. We "reconstituted" the Hippo pathway in a human epithelial cell line and showed that, in contrast to flies, the activation of this pathway results in anti-apoptotic signals. We have shown that in human embryonic kidney (HEK) 293 cells, the complex formation between transcriptional co-activators YAPs (Yes kinase-associated proteins) and Lats kinases requires the intact WW domains of YAPs, as well as intact Pro-Pro-AA-Tyr (where AA is any amino acid) motifs in Lats kinases. These kinases cooperate with the upstream Mst2 kinase to phosphorylate YAPs at Ser-127. Overexpression of YAP2 in HEK293 cells promoted apoptosis, whereas the Mst2/Lats1-induced phosphorylation of YAP partially rescued the cells from apoptotic death. Apoptotic signaling of YAP2 was mediated via stabilization of p73, which formed a complex with YAP2. All components of the Hippo pathway that we studied were localized in the cytoplasm, with the exception of YAP, which also localized in the nucleus. The localization of YAP2 in the nucleus was negatively controlled by the Lats1 kinase. Our apoptotic "readout" of the Hippo pathway in embryonic kidney cells represents a useful experimental system for the identification of the putative upstream receptor, membrane protein, or extracellular factor that initiates an entire signaling cascade and ultimately controls the size of organs.

Received for publication, June 6, 2008 , and in revised form, July 16, 2008.

^* This work was supported by two Breast Cancer Coalition grants from the Pennsylvania Department of Health (to M. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1. The recombinant plasmids reported in this paper have been deposited in the Add-gene plasmid repository (www.addgene.org).

¹ To whom correspondence should be addressed: 100 N. Academy Ave., Danville, PA 17822-2608. Fax: 570-271-6701; E-mail: msudol1{at}geisinger.edu.

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