Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration |
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| Authors: | Anja Mai Stefan Veltel Teijo Pellinen Artur Padzik Eleanor Coffey Varpu Marjom?ki Johanna Ivaska |
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| Affiliation: | 1Turku Centre for Biotechnology, Turku 20521, Finland;2VTT Technical Research Centre of Finland, Medical Biotechnology, Turku 20520, Finland;3Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä 40500, Finland;4Department of Biochemistry and Food Chemistry, University of Turku, Turku 20521, Finland |
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| 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. |
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