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

Siamak A Kamranvar,Deepesh Kumar Gupta,Ying Huang,Rajesh Kumar Gupta,Staffan Johansson

doi:10.18632/oncotarget.9003

Siamak A Kamranvar, Deepesh Kumar Gupta + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.9003

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Journal: Oncotarget	Publication Date: Apr 26, 2016
Citations: 24	License type: cc-by

Affiliation: Uppsala University

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.

Highlights

Integrin-mediated cell adhesion to extracellular matrix (ECM) is required for the proliferation of normal adherent cells [1,2,3]
Adhesion to extracellular matrix is required for cell cycle progression through the G1 phase and for the completion of cytokinesis in normal adherent cells
In order to characterize the mechanisms underlying the requirement for cell-ECM adhesion to complete cytokinesis in human non-transformed fibroblasts, we first monitored the entire process in isolated mitotic BJ cells after re-seeding in fibronectin- or Pluronic-coated plates using live-cell imaging (Figure 1A, Supplementary Videos S1 and S2)

Summary

Introduction

Integrin-mediated cell adhesion to extracellular matrix (ECM) is required for the proliferation of normal adherent cells [1,2,3]. Cooperating signals from integrins and growth factor receptors regulate the G1-S transition of the cell cycle [8, 9] and thereby serve as a major control mechanism to avoid unregulated cell proliferation. At this checkpoint, integrin-mediated signaling is a prerequisite for the induction of cyclin D1dependent Cdk4/6 and cyclin E-dependent Cdk kinase activity and the following initiation of DNA synthesis [10]. The process of cytokinesis begins during early anaphase and proceeds sequentially in three distinct stages: cleavage furrow formation and ingression, formation and stabilization of midbody and eventually abscission [17, 18]. Contraction of an actomyosin ring causes ingression of the connected plasma membrane [19], which results in the formation of a thin intercellular bridge of densely packed microtubules oriented in antiparallel manner from the centrally located structure called midbody [20]

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