Multiple ERK substrates execute single biological processes in Caenorhabditis elegans germ-line development.
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 germ line utilizes the well-conserved RAS-ERK signaling pathway in multiple different contexts. Here, we present an integrated functional genomic approach that identified 30 ERK substrates, each of which functions to regulate one or more of seven distinct biological processes during C. elegans germ-line 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. 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.
Arur
Swathi
S
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Ohmachi
Mitsue
M
Nayak
Sudhir
S
Hayes
Matthew
M
Miranda
Alejandro
A
Hay
Amanda
A
Golden
Andy
A
Schedl
Tim
T
D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D005854:Germ Cells / Q000201:enzymology*; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008322:Mammals / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D013379:Substrate Specificity
D029742:Caenorhabditis elegans Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; C085697:mpk-1 protein, C elegans; D038362:Glycogen Synthase Kinase 3