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Modulation of KSR activity in Caenorhabditis elegans by Zn ions, PAR‐1 kinase and PP2A phosphatase
Author(s) -
Yoder John H,
Chong Huira,
Guan Kunliang,
Han Min
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600025
Subject(s) - caenorhabditis elegans , biology , protein phosphatase 2 , phosphatase , microbiology and biotechnology , signal transduction , mapk/erk pathway , kinase , phosphorylation , scaffold protein , protein kinase a , biochemistry , gene
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.