CYRI (FAM49) proteins are local inhibitors of Scar/WAVE induced lamellipodia that bind directly to active Rac1

Fort, L.; Batista, J.; Thomason, P. A.; Spence, H. J.; Greaves, J.; Martin, K. J.; Anderson, K. I.; Brown, P.; Lilla, S.; Neilson, M. P.; Tafelmeyer, P.; Zanivan, S.; Ismail, S.; Tomkinson, N. C. O.; Chamberlain, L. H.; Insall, R. H.; Machesky, L. M.

doi:10.1101/164905

bioRxiv · 10.1101/164905

CYRI (FAM49) proteins are local inhibitors of Scar/WAVE induced lamellipodia that bind directly to active Rac1

Fort, L.·Batista, J.·Thomason, P. A.·Spence, H. J.·Greaves, J.·Martin, K. J.·Anderson, K. I.·Brown, P.·Lilla, S.·Neilson, M. P.·Tafelmeyer, P.·Zanivan, S.·Ismail, S.·Tomkinson, N. C. O.·Chamberlain, L. H.·Insall, R. H.·Machesky, L. M.

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Abstract

Actin-based protrusions driving cell migration are reinforced through positive feedback, but it is unclear how the cell restricts the eventual size of a protrusion or limits positive signals to cause splitting or retraction. We have identified an evolutionarily conserved regulator of the protrusion machinery, which we name CYRI (CYFIP-related Rac interacting) protein. CYRI shows sequence similarity to the Scar/WAVE complex member CYFIP in a Domain of Unknown Function, DUF1394. CYRI binds specifically to activated Rac1 via a common motif shared with CYFIP, establishing DUF1394 as a new Rac1 binding domain. CYRI-depleted cells have broad, Scar/WAVE-enriched lamellipodia and enhanced Rac1 signaling. Conversely, CYRI overexpression suppresses spreading and dramatically sharpens protrusions into unproductive needles. CYRI proteins use dynamic inhibition of Scar/WAVE induced actin to focus positive protrusion signals and regulate pseudopod complexity. CYRI behaves like a \"local inhibitor\" predicted and described in widely accepted mathematical models, but not previously identified in living cells.

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Fort, L., Batista, J., Thomason, P. A., Spence, H. J., Greaves, J., Martin, K. J., Anderson, K. I., Brown, P., Lilla, S., Neilson, M. P., Tafelmeyer, P., Zanivan, S., Ismail, S., Tomkinson, N. C. O., Chamberlain, L. H., Insall, R. H., Machesky, L. M.. 2017-11-29. CYRI (FAM49) proteins are local inhibitors of Scar/WAVE induced lamellipodia that bind directly to active Rac1. https://doi.org/10.1101/164905

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