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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.
LanguageEnglish
Pages1159-1171
Number of pages13
JournalNature Cell Biology
Volume20
DOIs
Publication statusPublished - 24 Sep 2018

Fingerprint

Pseudopodia
Cicatrix
Actins
Optogenetics
Chemotaxis
Polymerization
Cell Movement
Theoretical Models

Keywords

  • cell migration
  • lamellipodia
  • RHO signalling

Cite this

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
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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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.",
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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

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, 24.09.2018, p. 1159-1171.

Research output: Contribution to journalArticle

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T1 - Fam49/CYRI interacts with Rac1 and locally suppresses protrusions

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.

PY - 2018/9/24

Y1 - 2018/9/24

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.

KW - cell migration

KW - lamellipodia

KW - RHO signalling

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SN - 1476-4679

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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 Sep 24;20:1159-1171. https://doi.org/10.1038/s41556-018-0198-9