CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation

Le, A. H., Yelland, T., Paul, N. R., Fort, L., Nikolaou, S., Ismail, S. and Machesky, L. M. (2021) CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation. Journal of Cell Biology, 220(9), e202012114. (doi: 10.1083/jcb.202012114) (PMID:34165494) (PMCID:PMC8236918)

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.

• Item Type: Articles
• Additional Information: The authors thank Cancer Research UK for core funding (A17196 and A31287) and funding to L.M. Machesky (A24452) and S. Ismail (A19257).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Paul, Dr Nikki and Nikolaou, Savvas and Machesky, Professor Laura and Fort, Loic and Ismail, Dr Shehab
• Authors: Le, A. H., Yelland, T., Paul, N. R., Fort, L., Nikolaou, S., Ismail, S., and Machesky, L. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Cell Biology
• Publisher: Rockefeller University Press
• ISSN: 0021-9525
• ISSN (Online): 1540-8140
• Published Online: 24 June 2021
• Copyright Holders: Copyright © 2021 Le et al.
• First Published: First published in Journal of Cell Biology 220(9): e202012114
• Publisher Policy: Reproduced under a Creative Commons License