title: Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration.
abstract: Integrin trafficking from and to the plasma membrane controls many aspects of cell behavior including cell motility, invasion, and cytokinesis. Recruitment of integrin cargo to the endocytic machinery is regulated by the small GTPase Rab21, but the detailed molecular mechanisms underlying integrin cargo recruitment are yet unknown. Here we identify an important role for p120RasGAP (RASA1) in the recycling of endocytosed α/β1-integrin heterodimers to the plasma membrane. Silencing of p120RasGAP attenuated integrin recycling and augmented cell motility. Mechanistically, p120RasGAP interacted with the cytoplasmic domain of integrin α-subunits via its GAP domain and competed with Rab21 for binding to endocytosed integrins. This in turn facilitated exit of the integrin from Rab21- and EEA1-positive endosomes to drive recycling. Our results assign an unexpected role for p120RasGAP in the regulation of integrin traffic in cancer cells and reveal a new concept of competitive binding of Rab GTPases and GAP proteins to receptors as a regulatory mechanism in trafficking.
authors.affiliation: Turku Centre for Biotechnology, Turku 20521, Finland.
authors.forename: Anja
authors.initials: A
authors.lastname: Mai
authors.forename: Stefan
authors.initials: S
authors.lastname: Veltel
authors.forename: Teijo
authors.initials: T
authors.lastname: Pellinen
authors.forename: Artur
authors.initials: A
authors.lastname: Padzik
authors.forename: Eleanor
authors.initials: E
authors.lastname: Coffey
authors.forename: Varpu
authors.initials: V
authors.lastname: Marjomäki
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D003593:Cytoplasm / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020729:p120 GTPase Activating Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D016023:Integrins; C557248:RASA1 protein, human; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; D020729:p120 GTPase Activating Protein; C546392:rab21 protein, mouse; D020691:rab GTP-Binding Proteins