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Curr Biol. 1998 Jan 1;8(1):56-64.

Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK.

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1
Chiron Corporation, 4560 Horton Street, Emeryville, California 94608, USA.

Abstract

BACKGROUND:

Genetic screens in Drosophila melanogaster and Caenorhabditis elegans identified the kinase suppressor of Ras, Ksr, as a new component in the Ras intracellular signaling pathway. In these organisms, mutations in Ksr resulted in attenuation of Ras-mediated signaling. Homologs of Ksr have also been isolated from mice and humans; their precise role in Ras signaling is not well defined. Here, we present data showing interactions between the murine form of Ksr (mKsr-1) and other components of the Ras pathway.

RESULTS:

To gain insight into the biological function of Ksr, we used a yeast two-hybrid screen and found an interaction between the carboxy-terminal region of mKsr-1 and mitogen-activated protein (MAP) kinase kinase 1 (MAPKK-1 or MEK-1). An interaction was also detected between MAP kinase (also called extracellular signal-regulated kinase; ERK), and the amino-terminal region of mKsr-1. These interactions were recapitulated in COS-7 cells. Further, when COS-7 cells were transfected with either full-length mKsr-1 or only its carboxy-terminal region, an inhibition of serum-stimulated MAP kinase activation was observed. Microinjection of full-length mKsr-1 or its carboxy-terminal, but not its amino-terminal region, blocked serum-induced DNA synthesis in rat embryo fibroblasts. Co-injection of mKsr-1 with MEK-1 reversed the blockade.

CONCLUSIONS:

Together with the data from genetic analyses, our findings lead us to propose that mKsr-1 may control MAP kinase signaling by serving as a scaffold protein that links MEK and its substrate ERK.

PMID:
9427629
DOI:
10.1016/s0960-9822(98)70020-x
[Indexed for MEDLINE]
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