Cortical branched actin determines cell cycle progression

Abstract

The actin cytoskeleton generates and senses forces. Here we report that branched actin networks from the cell cortex depend on ARPC1B-containing Arp2/3 complexes and that they are specifically monitored by type I coronins to control cell cycle progression in mammary epithelial cells. Cortical ARPC1B-dependent branched actin networks are regulated by the RAC1/WAVE/ARPIN pathway and drive lamellipodial protrusions. Accordingly, we uncover that the duration of the G1 phase scales with migration persistence in single migrating cells. Moreover, cortical branched actin more generally determines S-phase entry by integrating soluble stimuli such as growth factors and mechanotransduction signals, ensuing from substratum rigidity or stretching of epithelial monolayers. Many tumour cells lose this dependence for cortical branched actin. But the RAC1-transformed tumour cells stop cycling upon Arp2/3 inhibition. Among all genes encoding Arp2/3 subunits, ARPC1B overexpression in tumours is associated with the poorest metastasis-free survival in breast cancer patients. Arp2/3 specificity may thus provide diagnostic and therapeutic opportunities in cancer.

Restrained activation of CYFIP2-containing WAVE complexes controls membrane protrusions and cell migration

“…The cell polarity, visualized by labeling Golgi apparatus, was not perturbed in these acini (Fig.4J). Similar results were previously obtained when ARPIN was inactivated [25]. CYFIP2 thus behaves like the well-established inhibitory protein of cell migration, ARPIN.…”

“…Importantly, same results were obtained with two single siRNA sequences for each gene (Fig.S4), indicating that these results were not due to off-targets. Such a phenotype, characterized by increased migration persistence of single MCF10A cells, was previously observed upon activation of RAC1 or upon depletion of the Arp2/3 inhibitory protein ARPIN [25].…”

“…CYFIP2 thus behaves like the well-established inhibitory protein of cell migration, ARPIN. The RAC1-WAVE-Arp2/3 pathway does not only control cell migration, but also cell cycle progression in these settings [25].…”

Interpretable deep learning of label-free live cell images uncovers functional hallmarks of highly-metastatic melanoma

“…S14). Recent work has suggested mechanistic links between enhanced branched actin formation in pseudopdial cell compartments and enhanced cell cycle progression (Mohan et al, 2019;Molinie et al, 2019), especially in micrometastases. Therefore, we lean towards an interpretation that connects the predicted metastatic efficiency under pseudopod formation to increased proliferation and survival.…”

Arp2/3 complex-mediated actin assembly drives microtubule-independent motility and phagocytosis in the evolutionarily divergent amoebaNaegleria

“…Moreover, in environments where other organisms produce actin toxins, it is possible some of these additional genes encode toxin-resistant actins, similar to the strategy used by Chlamydomonas reinhardtii (Onishi et al, 2016). Naegleria's two Arp2 genes indicate the potential to form multiple types of Arp2/3 complexes, which could be optimized for different tasks like in mammalian cells (Molinie et al, 2019). Our analysis does not support robust expression for one of these Arp2s in amoebae or flagellates, so a significant role for multiple Arp2/3 complexes seems unlikely for these life stages.…”