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)

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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.
Glasgow Author(s) Enlighten ID:Anderson, Professor Kurt and Lilla, Dr Sergio and Thomason, Dr Peter and Spence, Dr Heather and Machesky, Professor Laura and Zanivan, Professor Sara and Insall, Professor Robert and Fort, Loic and Ismail, Dr Shehab and Bryant, Dr David and WHITELAW, Jamie and Neilson, Dr Matthew
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 > Institute of Cancer Sciences
Journal Name:Nature Cell Biology
Publisher:Nature Research
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

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