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  • The EMBO Journal (2004) 23, 111 - 119
  • doi:10.1038/sj.emboj.7600025

Published online: 11 December 2003

Modulation of KSR activity in Caenorhabditis elegans by Zn ions, PAR-1 kinase and PP2A phosphatase

John H Yoder1,3, Huira Chong2, Kun-liang Guan2 and Min Han1

  1. Department of Molecular, Cellular and Developmental Biology, Howard Hughes Medical Institution, University of Colorado, Boulder, CO, USA
  2. Department of Biological Chemistry and The Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA
  3. Present address: Howard Hughes Medical Institute, Laboratory of Molecular Biology, University of Wisconsin, Madison, WI 53706, USA

Correspondence to:

Min Han, Department of Molecular, Cellular and Developmental Biology, Howard Hughes Medical Institution, University of Colorado, Boulder, CO 80309, USA. Tel.: +1 303 735 0375; Fax: +1 303 735 0175; E-mail: mhan@colorado.edu

Received 2 September 2003; Accepted 14 November 2003

Vulval differentiation in Caenorhabditis elegans is controlled by a conserved signal transduction pathway mediated by Ras and a kinase cascade that includes Raf, Mek and MAPK. Activation of this cascade is positively regulated by a number of proteins such as KSR (kinase suppressor of Ras), SUR-8/SOC-2, SUR-6/PP2A-B and CDF-1. We describe the functional characterization of sur-7 and several genes that regulate signaling downstream of ras. We identified sur-7 by isolating a mutation that suppresses an activated ras allele, and showed that SUR-7 is a divergent member of the cation diffusion facilitator family of heavy metal ion transporters that is probably localized to the endoplosmic recticulum membrane and regulates cellular Zn2+ concentrations. Genetic double mutant analyses suggest that the SUR-7-mediated effect is not a general toxic response. Instead, Zn2+ ions target a specific step of the pathway, probably regulation of the scaffolding protein KSR. Biochemical analysis in mammalian cells indicates that high Zn2+ concentration causes a dramatic increase of KSR phosphorylation. Genetic analysis also indicates that PP2A phosphatase and PAR-1 kinase act downstream of Raf to positively and negatively regulate KSR activity, respectively.

  • Keywords:

    • C. elegans,
    • CTAK1,
    • Ras,
    • Raf,
    • sur-6,
    • sur-7,
    • vulval induction