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J. Biol. Chem. 277 (35): 32389-32399

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras via a Histidine Protein Kinase Pathway*

Melanie T. HartsoughDagger , Deborah K. Morrison§, Massimiliano Salerno, Diane Palmieri, Taoufik Ouatas, Michael Mair, Jilma Patrick, and Patricia S. Steeg

From the Women's Cancers Section, Laboratory of Pathology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and the § ABL-Basic Research Program, NCI-Frederick, Frederick, Maryland 21702

The metastasis-suppressive activity of Nm23-H1 was previously correlated with its in vitro histidine protein kinase activity, but physiological substrates have not been identified. We hypothesized that proteins that interact with histidine kinases throughout evolution may represent partners for Nm23-H1 and focused on the interaction of Arabidopsis "two-component" histidine kinase ERS with CTR1. A mammalian homolog of CTR1 was previously reported to be c-Raf; we now report that CTR1 also exhibits homology to the kinase suppressor of Ras (KSR), a scaffold protein for the mitogen-activated protein kinase (MAPK) cascade. Nm23-H1 co-immunoprecipitated KSR from lysates of transiently transfected 293T cells and at endogenous protein expression levels in MDA-MB-435 breast carcinoma cells. Autophosphorylated recombinant Nm23-H1 phosphorylated KSR in vitro. Phosphoamino acid analysis identified serine as the major target, and two peaks of Nm23-H1 phosphorylation were identified upon high performance liquid chromatography analysis of KSR tryptic peptides. Using site-directed mutagenesis, we found that Nm23-H1 phosphorylated KSR serine 392, a 14-3-3-binding site, as well as serine 434 when serine 392 was mutated. Phosphorylated MAPK but not total MAPK levels were reduced in an nm23-H1 transfectant of MDA-MB-435 cells. The data identify a complex in vitro histidine-to-serine protein kinase pathway, which may contribute to signal transduction and metastasis.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Food and Drug Administration, CBER, Division of Therapeutic Proteins, Bethesda, Maryland 20892.

To whom correspondence should be addressed: Bldg. 10, Rm. 2A33, Women's Cancers Section, Laboratory of Pathology, NCI, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-9753; Fax: 301-402-8910; E-mail: steegp@mail.nih.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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