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; Laura M Machesky

doi:10.1038/s41556-018-0198-9

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 InsallLaura M Machesky

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42 Citations (Scopus)

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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 language	English
Pages (from-to)	1159-1171
Number of pages	13
Journal	Nature Cell Biology
Volume	20
Early online date	24 Sept 2018
DOIs	https://doi.org/10.1038/s41556-018-0198-9
Publication status	Published - Oct 2018
Externally published	Yes

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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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Jennifer Greaves, PhD
- Centre for Health and Life Sciences - Associate Professor in Cell Biology
Person: Teaching and Research

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

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

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title = "Fam49/CYRI interacts with Rac1 and locally suppresses protrusions",

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.",

author = "Loic Fort and Batista, {Jos{\'e} Miguel} and Thomason, {Peter A} and Spence, {Heather J} and Whitelaw, {Jamie A} and Luke Tweedy and Jennifer Greaves and Martin, {Kirsty J} and Anderson, {Kurt I} and Peter Brown and Sergio Lilla and Neilson, {Matthew P} and Petra Tafelmeyer and Sara Zanivan and Shehab Ismail and Bryant, {David M} and Tomkinson, {Nicholas C O} and Chamberlain, {Luke H} and Mastick, {Grant S} and Insall, {Robert H} and Machesky, {Laura M}",

note = "Copyright {\textcopyright} 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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AU - Fort, Loic

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.

PY - 2018/10

Y1 - 2018/10

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.

U2 - 10.1038/s41556-018-0198-9

DO - 10.1038/s41556-018-0198-9

M3 - Article

C2 - 30250061

SN - 1465-7392

VL - 20

SP - 1159

EP - 1171

JO - Nature Cell Biology

JF - Nature Cell Biology

ER -

Fam49/CYRI interacts with Rac1 and locally suppresses protrusions

Abstract

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Jennifer Greaves, PhD

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