title: Modulation of KSR activity in Caenorhabditis elegans by Zn ions, PAR-1 kinase and PP2A phosphatase.
abstract: 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 Zn(2+) concentrations. Genetic double mutant analyses suggest that the SUR-7-mediated effect is not a general toxic response. Instead, Zn(2+) ions target a specific step of the pathway, probably regulation of the scaffolding protein KSR. Biochemical analysis in mammalian cells indicates that high Zn(2+) 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.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Howard Hughes Medical Institution, University of Colorado, Boulder, CO, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Yoder
authors.forename: Huira
authors.initials: H
authors.lastname: Chong
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.forename: Min
authors.initials: M
authors.lastname: Han
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D016384:Consensus Sequence; D004627:Embryonic Induction; D004721:Endoplasmic Reticulum / Q000737:chemistry; D005260:Female; D017238:Genes, Helminth; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014844:Vulva / Q000196:embryology; D015032:Zinc / Q000378:metabolism* / Q000633:toxicity; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D011994:Recombinant Proteins; C488489:SUR-7 protein, C elegans; C409406:PAR-1 protein, C elegans; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D010749:Phosphoprotein Phosphatases; D018631:ras Proteins; D015032:Zinc