CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation |
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| Authors: | Anh Hoang Le Tamas Yelland Nikki R. Paul Loic Fort Savvas Nikolaou Shehab Ismail Laura M. Machesky |
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| Affiliation: | 1. Cancer Research UK Beatson Institute, Bearsden, Glasgow, UK ; 2. Institute of Cancer Sciences, University of Glasgow, Bearsden, Glasgow, UK ; 3. Department of Cell and Developmental Biology, Medical Research Building III, Vanderbilt University, Nashville, TN ; S. Ismail’s present address is Department of Chemistry, Katholieke Universiteit Leuven, Heverlee, Belgium. |
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| Abstract: | The Scar/WAVE complex drives actin nucleation during cell migration. Interestingly, the same complex is important in forming membrane ruffles during macropinocytosis, a process mediating nutrient uptake and membrane receptor trafficking. Mammalian CYRI-B is a recently described negative regulator of the Scar/WAVE complex by RAC1 sequestration, but its other paralogue, CYRI-A, has not been characterized. Here, we implicate CYRI-A as a key regulator of macropinosome formation and integrin internalization. We find that CYRI-A is transiently recruited to nascent macropinosomes, dependent on PI3K and RAC1 activity. CYRI-A recruitment precedes RAB5A recruitment but follows sharply after RAC1 and actin signaling, consistent with it being a local inhibitor of actin polymerization. Depletion of both CYRI-A and -B results in enhanced surface expression of the α5β1 integrin via reduced internalization. CYRI depletion enhanced migration, invasion, and anchorage-independent growth in 3D. Thus, CYRI-A is a dynamic regulator of macropinocytosis, functioning together with CYRI-B to regulate integrin trafficking. |
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