Fam49/CYRI interacts with Rac1 and locally suppresses protrusions

Loic Fort, José Miguel Batista, Peter A Thomason, Heather J Spence, Jamie A Whitelaw, Luke Tweedy, Jennifer Greaves, Kirsty J Martin, Kurt I Anderson, Peter Brown, Sergio Lilla, Matthew P Neilson, Petra Tafelmeyer, Sara Zanivan, Shehab Ismail, David M Bryant, Nicholas C O Tomkinson, Luke H Chamberlain, Grant S Mastick, Robert H Insall & 1 others Laura M Machesky

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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.

Original languageEnglish
Pages (from-to)1159-1171
Number of pages13
JournalNature Cell Biology
Volume20
Early online date24 Sep 2018
DOIs
Publication statusPublished - Oct 2018
Externally publishedYes

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Pseudopodia
Cicatrix
Actins
Optogenetics
Chemotaxis
Polymerization
Cell Movement
Theoretical Models

Bibliographical note

Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

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Fort, L., Batista, J. M., Thomason, P. A., Spence, H. J., Whitelaw, J. A., Tweedy, L., ... Machesky, L. M. (2018). Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nature Cell Biology, 20, 1159-1171. https://doi.org/10.1038/s41556-018-0198-9

Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. / Fort, Loic; Batista, José Miguel; Thomason, Peter A; Spence, Heather J; Whitelaw, Jamie A; Tweedy, Luke; Greaves, Jennifer; Martin, Kirsty J; Anderson, Kurt I; Brown, Peter; Lilla, Sergio; Neilson, Matthew P; Tafelmeyer, Petra; Zanivan, Sara; Ismail, Shehab; Bryant, David M; Tomkinson, Nicholas C O; Chamberlain, Luke H; Mastick, Grant S; Insall, Robert H; Machesky, Laura M.

In: Nature Cell Biology, Vol. 20, 10.2018, p. 1159-1171.

Research output: Contribution to journalArticle

Fort, L, Batista, JM, Thomason, PA, Spence, HJ, Whitelaw, JA, Tweedy, L, Greaves, J, Martin, KJ, Anderson, KI, Brown, P, Lilla, S, Neilson, MP, Tafelmeyer, P, Zanivan, S, Ismail, S, Bryant, DM, Tomkinson, NCO, Chamberlain, LH, Mastick, GS, Insall, RH & Machesky, LM 2018, 'Fam49/CYRI interacts with Rac1 and locally suppresses protrusions' Nature Cell Biology, vol. 20, pp. 1159-1171. https://doi.org/10.1038/s41556-018-0198-9
Fort L, Batista JM, Thomason PA, Spence HJ, Whitelaw JA, Tweedy L et al. Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nature Cell Biology. 2018 Oct;20:1159-1171. https://doi.org/10.1038/s41556-018-0198-9
Fort, Loic ; Batista, José Miguel ; Thomason, Peter A ; Spence, Heather J ; Whitelaw, Jamie A ; Tweedy, Luke ; Greaves, Jennifer ; Martin, Kirsty J ; Anderson, Kurt I ; Brown, Peter ; Lilla, Sergio ; Neilson, Matthew P ; Tafelmeyer, Petra ; Zanivan, Sara ; Ismail, Shehab ; Bryant, David M ; Tomkinson, Nicholas C O ; Chamberlain, Luke H ; Mastick, Grant S ; Insall, Robert H ; Machesky, Laura M. / Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. In: Nature Cell Biology. 2018 ; Vol. 20. pp. 1159-1171.
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AU - Batista, José Miguel

AU - Thomason, Peter A

AU - Spence, Heather J

AU - Whitelaw, Jamie A

AU - Tweedy, Luke

AU - Greaves, Jennifer

AU - Martin, Kirsty J

AU - Anderson, Kurt I

AU - Brown, Peter

AU - Lilla, Sergio

AU - Neilson, Matthew P

AU - Tafelmeyer, Petra

AU - Zanivan, Sara

AU - Ismail, Shehab

AU - Bryant, David M

AU - Tomkinson, Nicholas C O

AU - Chamberlain, Luke H

AU - Mastick, Grant S

AU - Insall, Robert H

AU - Machesky, Laura M

N1 - Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

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N2 - 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.

AB - 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.

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