Fam49/CYRI interacts with Rac1 and locally suppresses protrusions

Fort, L. et al. (2018) Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nature Cell Biology, 20(10), pp. 1159-1171. (doi: 10.1038/s41556-018-0198-9) (PMID:30250061) (PMCID:PMC6863750)

Abstract

Actin-based protrusions are reinforced through positive feedback, but it is unclear what restricts their size, or limits positive signals when they retract or split. We identify an evolutionarily conserved regulator of actin-based protrusion: CYRI (CYFIP-related Rac interactor) also known as Fam49 (family of unknown function 49). CYRI binds activated Rac1 via a domain of unknown function (DUF1394) shared with CYFIP, defining DUF1394 as a Rac1-binding module. CYRI-depleted cells have broad lamellipodia enriched in Scar/WAVE, but reduced protrusion–retraction dynamics. Pseudopods induced by optogenetic Rac1 activation in CYRI-depleted cells are larger and longer lived. Conversely, CYRI overexpression suppresses recruitment of active Scar/WAVE to the cell edge, resulting in short-lived, unproductive protrusions. CYRI thus focuses protrusion signals and regulates pseudopod complexity by inhibiting Scar/WAVE-induced actin polymerization. It thus behaves like a ‘local inhibitor’ as predicted in widely accepted mathematical models, but not previously identified in cells. CYRI therefore regulates chemotaxis, cell migration and epithelial polarization by controlling the polarity and plasticity of protrusions.

• Item Type: Articles
• Additional Information: We thank CRUK for core funding to L.M.M. (grant A15673), R.H.I. (grant A15672) and S.Z. (C596/A12935), BBSRC for funding to L.H.C. and N.C.O.T. (BB/L022087/1), and NIH for funding to G.S.M. (NIH RO1 EY025205). Fundação para a Ciência e a Tecnologia, Portugal awarded a PhD scholarship (reference SFRH/BD/69003/2010) to J.M.B.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ismail, Dr Shehab and Lilla, Dr Sergio and Thomason, Dr Peter and Machesky, Professor Laura and Bryant, Dr David and Zanivan, Professor Sara and Whitelaw, Mr Jamie and Neilson, Dr Matthew and Insall, Professor Robert and Anderson, Professor Kurt and Fort, Loic and Spence, Dr Heather
• Authors: Fort, L., Batista, J. M., Thomason, P. A., Spence, H. J., Whitelaw, J., Tweedy, L., Greaves, J., Martin, K. J., Anderson, K. I., Brown, P., Lilla, S., Neilson, M. P., Tafelmeyer, P., Zanivan, S., Ismail, S., Bryant, D. M., Tomkinson, N. C.O., Chamberlain, L. H., Mastick, G. S., Insall, R. H., and Machesky, L. M.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Cell Biology
• Publisher: Nature Research
• ISSN: 1465-7392
• ISSN (Online): 1476-4679
• Published Online: 24 September 2018
• Copyright Holders: Copyright © 2018 Springer Nature Limited
• First Published: First published in Nature Cell Biology 20(10):1159-1171
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher