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J. Biol. Chem., Vol. 281, Issue 20, 14361-14369, May 19, 2006

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Hsp90 Recognizes a Common Surface on Client Kinases^*

Ami Citri, Daniel Harari, Galit Shohat^¶, Parameswaran Ramakrishnan^||, Judith Gan, Sara Lavi, Miriam Eisenstein^**, Adi Kimchi^¶, David Wallach^||, Shmuel Pietrokovski, and Yosef Yarden, Incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology¹

From the Departments of Biological Regulation, ^¶Molecular Genetics, ^||Biological Chemistry, ^**Chemical Research Support, and Molecular Genetics, Weizmann Institute of Science, Rehovot 97100, Israel, and Bioinformatics Support Unit, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel

Hsp90 is a highly abundant chaperone whose clientele includes hundreds of cellular proteins, many of which are central players in key signal transduction pathways and the majority of which are protein kinases. In light of the variety of Hsp90 clientele, the mechanism of selectivity of the chaperone toward its client proteins is a major open question. Focusing on human kinases, we have demonstrated that the chaperone recognizes a common surface in the amino-terminal lobe of kinases from diverse families, including two newly identified clients, NFB-inducing kinase and death-associated protein kinase, and the oncoprotein HER2/ErbB-2. Surface electrostatics determine the interaction with the Hsp90 chaperone complex such that introduction of a negative charge within this region disrupts recognition. Compiling information on the Hsp90 dependence of 105 protein kinases, including 16 kinases whose relationship to Hsp90 is first examined in this study, reveals that surface features, rather than a contiguous amino acid sequence, define the capacity of the Hsp90 chaperone machine to recognize client kinases. Analyzing Hsp90 regulation of two major signaling cascades, the mitogen-activated protein kinase and phosphatidylinositol 3-kinase, leads us to propose that the selectivity of the chaperone to specific kinases is functional, namely that Hsp90 controls kinases that function as hubs integrating multiple inputs. These lessons bear significance to pharmacological attempts to target the chaperone in human pathologies, such as cancer.

Received for publication, November 28, 2005 , and in revised form, March 13, 2006.

^* This work was supported by grants from the European Community, NCI, National Institutes of Health (CA72981), the Prostate Cancer Association of Israel, and the Willner Family Center for Vascular Biology. 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 a supplemental table and references.

¹ To whom correspondence should be addressed: Dept. of Biological Regulation, Weizmann Institute of Science, Rehovot 97100, Israel. Tel.: 972-8-9343974; Fax: 972-8-9342488; E-mail: yosef.yarden{at}weizmann.ac.il.

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