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J. Biol. Chem., Vol. 277, Issue 35, 32389-32399, August 30, 2002
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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.
Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase
Suppressor of Ras via a Histidine Protein Kinase Pathway*
,
*
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.
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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