2. Academic Validation
  3. Fam49/CYRI interacts with Rac1 and locally suppresses protrusions

Fam49/CYRI interacts with Rac1 and locally suppresses protrusions

  • Nat Cell Biol. 2018 Oct;20(10):1159-1171. doi: 10.1038/s41556-018-0198-9.
Loic Fort 1 2,  José Miguel Batista 1 2,  Peter A Thomason 1,  Heather J Spence 1,  Jamie A Whitelaw 1,  Luke Tweedy 1,  Jennifer Greaves 3,  Kirsty J Martin 1,  Kurt I Anderson 1 4,  Peter Brown 1,  Sergio Lilla 1,  Matthew P Neilson 1,  Petra Tafelmeyer 5,  Sara Zanivan 1,  Shehab Ismail 1 2,  David M Bryant 1 2,  Nicholas C O Tomkinson 6,  Luke H Chamberlain 3,  Grant S Mastick 7,  Robert H Insall 8 9,  Laura M Machesky 10 11
Affiliations

Affiliations

  • 1 CRUK Beatson Institute, Glasgow, UK.
  • 2 University of Glasgow Institute of Cancer Sciences, Glasgow, UK.
  • 3 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
  • 4 Francis Crick Institute, London, UK.
  • 5 Hybrigenics Services, Paris, France.
  • 6 WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK.
  • 7 Department of Biology, University of Nevada, Reno, NV, USA.
  • 8 CRUK Beatson Institute, Glasgow, UK. r.insall@beatson.gla.ac.uk.
  • 9 University of Glasgow Institute of Cancer Sciences, Glasgow, UK. r.insall@beatson.gla.ac.uk.
  • 10 CRUK Beatson Institute, Glasgow, UK. l.machesky@beatson.gla.ac.uk.
  • 11 University of Glasgow Institute of Cancer Sciences, Glasgow, UK. l.machesky@beatson.gla.ac.uk.
PMID: 30250061 DOI: 10.1038/s41556-018-0198-9
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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