Epidermal Growth Factor Receptor Cell Survival Signaling Requires Phosphatidylcholine Biosynthesis.
Identification of pro-cell survival signaling pathways has implications for cancer, cardiovascular, and neurodegenerative disease. We show that theCaenorhabditis elegansepidermal growth factor receptor LET-23 (LET-23 EGFR) has a prosurvival function in counteracting excitotoxicity, and we identify novel molecular players required for this prosurvival signaling. uv1 sensory cells in theC. elegansuterus undergo excitotoxic death in response to activation of the OSM-9/OCR-4 TRPV channel by the endogenous agonist nicotinamide. Activation of LET-23 EGFR can effectively prevent this excitotoxic death. We investigate the roles of signaling pathways known to act downstream of LET-23 EGFR inC. elegansand find that the LET-60 Ras/MAPK pathway, but not the IP3receptor pathway, is required for efficient LET-23 EGFR activity in its prosurvival function. However, activation of LET-60 Ras/MAPK pathway does not appear to be sufficient to fully mimic LET-23 EGFR activity. We screen for genes that are required for EGFR prosurvival function and uncover a role for phosphatidylcholine biosynthetic enzymes in EGFR prosurvival function. Finally, we show that exogenous application of phosphatidylcholine is sufficient to prevent some deaths in this excitotoxicity model. Our work implicates regulation of lipid synthesis downstream of EGFR in cell survival and death decisions.
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802.
Matt
http://orcid.org/0000-0003-1184-4033
M
Crook
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802.
Awani
A
Upadhyay
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802.
Liyana J
LJ
Ido
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802 wxh21@psu.edu.
Wendy
http://orcid.org/0000-0002-5566-4758
W
Hanna-Rose
TRPV; necrosis; phospholipid; pmt-1; pnc-1