Séminaire d’Alexis Gautreau, Ecole Polytechnique, Palaiseau organisé le 18 mai à 11h, amphithéâtre 11, Carreire à Bordeaux. 

« Branched Actin in Cell Migration and Cancer Progression »

Branched actin is generated by the Arp2/3 complex. WAVE is the protein that activates Arp2/3 at the cell cortex. giving rise to lamellipodial protrusions downstream of the small GTPase Rac1. WAVE is tightly regulated within a multiprotein complex called the WAVE Regulatory Complex (WRC). The Rac1-WRC-Arp2/3 controls protrusion lifetime and migration persistence. Cortical branched actin is also essential for the cell’s decision to initiate a new cell cycle. Together these two coupled functions of migration and proliferation explains why the overexpression of cortical branched actin machinery is associated with poor prognosis of cancer patients. Conversely we identified negative regulators of cortical branched actin, whose overexpression was associated with good prognosis. Among them, we identified the Arp2/3 inhibitory protein Arpin and the CYFIP2 subunit of the WRC. Recently we uncovered by proteomics a novel regulator of migration persistence, PPP2R1A, that functions in a feedback loop through a novel machinery, the WAVE Shell Complex (WSC) that contains the Nance-Horan syndrome family protein NHSL1 instead of the Arp2/3 activating WAVE subunit. We show that PPP2R1A is a tumor suppressor gene, whose mutations in tumors inactivate its ability to regulate migration persistence and to interact with the WSC. Together these data indicate that the molecular circuit that controls branched actin polymerization at the cell cortex appears as a critical determinant of cancer progression.

Recent relevant references

Wang Y, … Gautreau AM, Polesskaya A. 2022. PPP2R1A regulates migration persistence through the WAVE shell complex. In preparation.

Polesskaya A, Boutillon A, Yang S, Wang Y, Romero S, Liu Y, Lavielle M, Vacher S, Schnitzler A, Molinie N, Fokin AI, Guerois R, Bièche I, Chen B, David NB, Gautreau AM. 2022. CYFIP2 containing WAVE complexes inhibit cell migration by a competition mechanism. BioRxiv.

Gautreau AM, Fregoso FE, Simanov G, Dominguez R. 2021. Nucleation, Stabilization and Disassembly of Branched Actin Networks. Trends Cell Biol. S0962-8924.

Fokin AI*, David V*, Oguievetskaia K, Derivery E, Stone C, Cao L, Rocques N, Molinie N, Henriot V, Aumont-Nicaise M, Hinckelmann MV, Saudou F, Le Clainche C, Carter AP, Romet-Lemonne G, Gautreau AM. 2021. The Arp1/11 Minifilament of Dynactin primes the Endosomal Arp2/3 Complex. Sci Adv. 7:1-11, eabd5956.

Molinie N, Rubtsova SN, Visweshwaran SP, Rocques N, Polesskaya A, Schnitzler A, Vacher S, Denisov EV, Tashireva LA, Perelmuter  VM, Cherdyntseva NV, Bièche I, Gautreau AM. 2019. Cortical branched actin determines cell cycle progression. Cell Res 29:432-45.