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J. Biol. Chem., Vol. 279, Issue 23, 24444-24451, June 4, 2004

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Human Mob Proteins Regulate the NDR1 and NDR2 Serine-Threonine Kinases^*

Eric Devroe, Hediye Erdjument-Bromage, Paul Tempst, and Pamela A. Silver¶

From the Department of Systems Biology, Harvard Medical School and Department of Cancer Cell Biology, The Dana-Farber Cancer Institute, Boston, Massachusetts 02115 and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Human NDR1 (nuclear Dbf2-related) is a widely expressed nuclear serine-threonine kinase that has been implicated in cell proliferation and/or tumor progression. Here we present molecular characterization of the human NDR2 serine-threonine kinase, which shares 87% sequence identity with NDR1. NDR2 is expressed in most human tissues with the highest expression in the thymus. In contrast to NDR1, NDR2 is excluded from the nucleus and exhibits a punctate cytoplasmic distribution. The differential localization of NDR1 and NDR2 suggests that each kinase may serve distinct functions. Thus, to identify proteins that interact with NDR1 or NDR2, epitope-tagged kinases were immunoprecipitated from Jurkat T-cells. Two uncharacterized proteins that are homologous to the Saccharomyces cerevisiae kinase regulators Mob1 and Mob2 were identified. We demonstrate that NDR1 and NDR2 partially colocalize with human Mob2 in HeLa cells and confirm the NDR-Mob interactions in cell extracts. Interestingly, NDR1 and NDR2 form stable complexes with Mob2, and this association dramatically stimulates NDR1 and NDR2 catalytic activity. In summary, this work identifies a unique class of human kinase-activating subunits that may be functionally analagous to cyclins.

Received for publication, February 24, 2004 , and in revised form, April 1, 2004.

^* This work was supported by a Howard Hughes Medical Institute predoctoral fellowship (to E. D.), a NCI Cancer Center Support grant from the National Institutes of Health (to P. T.), and the Claudia Adams Barr Fund and Novartis/Dana-Farber Cancer Institute Drug Discovery Program (to P. A. 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.

^¶ To whom correspondence should be addressed. Tel.: 617-632-5102; Fax: 617-632-5103; E-mail: pamela_silver{at}dfci.harvard.edu.

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