title: Dynein-mediated trafficking negatively regulates LET-23 EGFR signaling.
abstract: Epidermal Growth Factor Receptor (EGFR) signaling is essential for animal development and increased signaling underlies many human cancers. Identifying the genes and cellular processes that regulate EGFR signaling in vivo will help elucidate how this pathway can become inappropriately activated. Caenorhabditis elegans vulva development provides an in vivo model to genetically dissect EGFR signaling. Here we identified a mutation in dhc-1, the heavy chain of the cytoplasmic dynein minus-end directed microtubule motor, in a genetic screen for regulators of EGFR signaling. Despite the many cellular functions of dynein, DHC-1 is a strong negative regulator of EGFR signaling during vulva induction. DHC-1 is required in the signal-receiving cell, genetically functions upstream or in parallel to LET-23 EGFR. LET-23 EGFR accumulates in cytoplasmic foci in dhc-1 mutants consistent with mammalian cell studies whereby dynein has been shown to regulate late endosome trafficking of EGFR with the Rab7 GTPase. However, we found different distributions of LET-23 EGFR foci in rab-7 versus dhc-1 mutants, suggesting that dynein functions at an earlier step of LET-23 EGFR trafficking to the lysosome than RAB-7. Our results demonstrate an in vivo role for dynein in limiting LET-23 EGFR signaling via endosomal trafficking.
authors.affiliation: Division of Endocrinology and Metabolism, Departments of Medicine, and Anatomy and Cell Biology, McGill University, and the Program in Experimental Therapeutics and Metabolism, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada, H4A 3J1.
authors.forename: Olga
authors.initials: O
authors.lastname: Skorobogata
authors.affiliation: Division of Endocrinology and Metabolism, Departments of Medicine, and Anatomy and Cell Biology, McGill University, and the Program in Experimental Therapeutics and Metabolism, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada, H4A 3J1.
authors.forename: Jassy
authors.initials: J
authors.lastname: Meng
authors.affiliation: Division of Endocrinology and Metabolism, Departments of Medicine, and Anatomy and Cell Biology, McGill University, and the Program in Experimental Therapeutics and Metabolism, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada, H4A 3J1.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Gauthier
authors.affiliation: Division of Endocrinology and Metabolism, Departments of Medicine, and Anatomy and Cell Biology, McGill University, and the Program in Experimental Therapeutics and Metabolism, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada, H4A 3J1 christian.rocheleau@mcgill.ca.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Rocheleau