Abstract
Cells respond and adapt to their physical environments and to the mechanical forces that they experience. The translation of physical forces into biochemical signalling pathways is known as mechanotransduction. In this review, we focus on two aspects of mechanotransduction. First, we consider how forces exerted on cell adhesion molecules at the cell surface regulate the RhoA signalling pathway by controlling the activities of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). In the second part of the review, we discuss how the nucleus contributes to mechanotransduction as a physical structure connected to the cytoskeleton. We focus on recent studies that have either severed the connections between the nucleus and the cytoskeleton, or that have entirely removed the nucleus from cells. These actions reduce the levels of active RhoA, thereby altering the mechanical properties of cells and decreasing their ability to generate tension and respond to external mechanical forces.This article is part of a discussion meeting issue ‘Forces in cancer: interdisciplinary approaches in tumour mechanobiology’.
Highlights
Cells are continuously subjected to a wide variety of mechanical forces
Mechanical tension exerted on cells typically signals via cell adhesion molecules to increase RhoA activity
Most attention has been directed towards the activation of specific 7 guanine nucleotide exchange factors (GEFs), but the level of active RhoA reflects the balance between GEF activation and GTPase activating proteins (GAPs) inhibition
Summary
Cells are continuously subjected to a wide variety of mechanical forces. This is well illustrated by tumour cells, which experience many different forces as tumours grow and invade. Squeezing through confined spaces in the ECM exposes tumour cells to significant compressive and tensile forces, which can be sufficient to induce transient rupture of the cells’ nuclei, release of chromatin and induce DNA damage [6,7] Those tumour cells that metastasize to distant sites typically pass into lymphatics or blood vessels by intravasation. The tumour cells need to extravasate out of the circulation and again this will involve a series of different mechanical forces as the cells cross the vessel wall and underlying matrix to enter the target tissue This can be expected to have a different mechanical environment from the tissue of tumour origin. Space limitations prevent us from considering many of these topics and here we will focus on two: how mechanical tension exerted on cell adhesion molecules affects the RhoA signalling pathway, and secondly, the role of the nucleus as a physical structure in mechanotransduction signalling
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