EGFR Cell Survival Signaling Requires Phosphatidylcholine Biosynthesis

Identification of pro-cell-survival signaling pathways has implications for cancer, cardiovascular and neurodegenerative disease. We show that the Caenorhaditis elegans epidermal growth factor receptor LET-23 has a pro-survival function in counteracting excitotoxicity, and we identify novel molecular players required for this pro-survival signaling. uv1 sensory cells in the C. elegans uterus 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 in C. elegans and find that the LET-60 Ras / MAPK pathway, but not the IP3 receptor pathway, is required for efficient LET-23 EGFR activity in its pro-survival 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 pro-survival function and uncover a role for phosphatidylcholine biosynthetic enzymes in EGFR pro-survival 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.

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