title: Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK.
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.
authors.affiliation: Chiron Corporation, 4560 Horton Street, Emeryville, California 94608, USA.
authors.forename: W
authors.initials: W
authors.lastname: Yu
authors.forename: W J
authors.initials: WJ
authors.lastname: Fantl
authors.forename: G
authors.initials: G
authors.lastname: Harrowe
authors.forename: L T
authors.initials: LT
authors.lastname: Williams
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D051379:Mice; D008845:Microinjections; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D011494:Protein Kinases; C097199:KSR-1 protein kinase; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins