title: RIN1 orchestrates the activation of RAB5 GTPases and ABL tyrosine kinases to determine the fate of EGFR.
abstract: Stimulation of epidermal growth factor receptor (EGFR) initiates RAS signaling simultaneously with EGFR internalization. Endocytosed EGFR is then either recycled or degraded. EGFR fate is determined in part by the RAS effector RIN1, a guanine nucleotide exchange factor (GEF) for RAB5 GTPases. EGFR degradation was slowed by RIN1 silencing, enhanced by RIN1 overexpression and accelerated by RIN1 localization to the plasma membrane. RIN1 also directly activates ABL tyrosine kinases, which regulate actin remodeling, a function not previously connected to endocytosis. We report that RIN1-RAB5 signaling favors EGFR downregulation over EGFR recycling, whereas RIN1-ABL signaling stabilizes EGFR and inhibits macropinocytosis. RIN1(QM), a mutant that blocks ABL activation, caused EGF-stimulated membrane ruffling, actin remodeling, dextran uptake and EGFR degradation. An ABL kinase inhibitor phenocopied these effects in cells overexpressing RIN1. EGFR activation also promotes RIN1 interaction with BIN1, a membrane bending protein. These findings suggest that RIN1 orchestrates RAB5 activation, ABL kinase activation and BIN1 recruitment to determine EGFR fate.
authors.affiliation: Molecular Biology Institute, Jonsson Comprehensive Cancer Center and Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095,  USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Balaji
authors.forename: Chelsea
authors.initials: C
authors.lastname: Mooser
authors.forename: Christine M
authors.initials: CM
authors.lastname: Janson
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Bliss
authors.forename: Houmehr
authors.initials: H
authors.lastname: Hojjat
authors.forename: John
authors.initials: J
authors.lastname: Colicelli
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C092117:RIN1 protein, human; D066246:ErbB Receptors; D016315:Proto-Oncogene Proteins c-abl; D020696:rab5 GTP-Binding Proteins