Functional genomic identification of novel ERK substrates in Caenorhabditis elegans germ cell development

Swathi Arur 1 Mitsue Ohmachi 1 Sudhir Nayak 3 Andy Golden 4 Tim Schedl 2
1Genetics, UT MD Anderson Cancer Center, Houston
2Genetics, Washington university School of Medicine, Saint Louis, MO
3Biology, The College of New Jersey, New Jersey
4Laboratory of Biochemistry, NIH/NIDDK, Bethesda

RAS-extracellular signal regulated kinase (ERK) signaling governs multiple aspects of cell fate specification, cellular transitions and growth by regulating downstream substrates through phosphorylation. Understanding how perturbations to the ERK-signaling pathway lead to developmental disorders and cancer hinges critically on identification of the substrates. Yet, only a limited number of substrates have been identified that function in vivo to execute ERK regulated processes. The Caenorhabditis elegans germline utilizes the well-conserved RAS-ERK signaling pathway in multiple different contexts. Here we present an integrated functional genomic approach that identified 30 novel ERK substrates, each of which functions to regulate one or more of seven distinct biological processes during C elegans germline development. Our results provide evidence for three themes that underlie the robustness and specificity of biological outcomes controlled by ERK signaling in C elegans that are likely relevant to ERK signaling in other organisms: (i) multiple diverse ERK substrates function to control each individual biological process; (ii) different combinations of substrates function to control distinct biological processes; and (iii) regulatory feedback loops between ERK and its substrates help reinforce or attenuate ERK activation. Novel substrates identified here have conserved orthologs in humans, suggesting that insights from these studies will contribute to our understanding of human diseases involving deregulated ERK-activity.









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