Integrin signaling via FAK-Src controls cytokinetic abscission by decelerating PLK1 degradation and subsequent recruitment of CEP55 at the midbody

Abstract

Adhesion to extracellular matrix is required for cell cycle progression through the G1 phase and for the completion of cytokinesis in normal adherent cells. Cancer cells acquire the ability to proliferate anchorage-independently, a characteristic feature of malignantly transformed cells. However, the molecular mechanisms underlying this escape of the normal control mechanisms remain unclear. The current study aimed to identify adhesion-induced reactions regulating the cytokinesis of non-transformed human fibroblasts.The adhesion-dependent control of cytokinesis was found to occur at a late stage close to the abscission, during which the endosomal sorting complex required for transport (ESCRT) severs the thin intercellular bridge connecting two nascent daughter cells. CEP55, a key protein involved in the abscission process, was localized at the midbody in both adherent and non-adherent fibroblasts, but it was unable to efficiently recruit ALIX, TSG101, and consequently the ESCRT-III subunit CHMP4B was missing in the non-adherent cells. PLK1, a kinase that prevents premature recruitment of CEP55 to the midbody, disappeared from this site more rapidly in the non-adherent cells. A FAK-Src signaling pathway downstream of integrin-mediated cell adhesion was found to decelerate both PLK1 degradation and CEP55 accumulation at the midbody. These data identify the regulation of PLK1 and CEP55 as steps where integrins exert control over the cytokinetic abscission.

FAK inhibitors induce cell multinucleation and dramatically increase pro‐tumoral cytokine expression in RAW 264.7 macrophages

“…Inhibiting FAK with FAK inhibitor PF562271 increased the degradation of PLK1 and enhanced the premature recruitment of CEP55, resulting in abscission failure. Incubating cells in suspension with a lack of integrin‐FAK signaling had the same effects on abscission as inhibiting FAK using PF562271 . According to these findings, it is likely that the furrow regression observed in this study was a result of the inhibitory effects of FAK inhibitors on the abscission process via multiple pathways, probably including the FAK‐Rac1 pathway and the integrin‐FAK‐PLK1‐CEP55 pathway.…”

“…We note that Kamranvar et al . did not report furrowing suppression by FAK inhibitor in their study. They used BJ fibroblast cells and, in this study, we used RAW 264.7 macrophages.…”

“…The other is BJ fibroblasts are more resistant to the inhibitory effect of Rac1 on contractile ring constriction, so that FAK inhibitor did not show suppression of furrowing ingression in the study by Kamranvar et al . .…”

“…Taneja et al [10] explored how focal adhesions shape the cleavage furrow and reported that FAK inhibitor PF573228 increased focal adhesions and reduced furrow ingression from the bottom of the cell in HeLa cells and epithelial cells. Kamranvar et al [11] reported that integrin signaling via FAK-Src was involved in abscission via the proper timing of stepwise recruitment of midbody proteins. Treating mitotic cells with FAK inhibitor PF562271 disturbed the temporal regulation of these proteins and caused abscission failure in human fibroblasts [11].…”

Regulating a key mitotic regulator, polo‐like kinase 1 (PLK1)

“…Inhibition of PLK1 causes CEP55 to prematurely translocate to the midbody, causing abscission failure. The likely reason for this failure is that aberrant midbody architecture arises and the inability to target ESCRT‐III components to the midbody, such as ALIX and TSG101 (Kamranvar et al, ; Morita et al, ). Thus, PLK1 seems to regulate cytokinesis progression and faithful abscission through its ability to recruit midbody components in an orderly manner by phosphorylation of substrates.…”