Growth control by intracellular tension and extracellular stiffness

Abstract

Integrin-mediated cell attachment to the extracellular matrix is an established regulator of the cell cycle, and the best-characterized targets of this process are the cyclin D1 gene and members of the cip and kip (cip/kip) family of cdk inhibitors. Manipulation of intracellular tension affects the same targets, supporting the idea that integrin activation and intracellular tension are closely related. Several signaling cascades, including FAK, Rho GTPases and ERK, transmit the integrin and tensional signals to pathways controlling the cell cycle. However, the experimental approaches that have generated these results alter cell adhesion and tension in ways that do not reflect the subtlety of those occurring in vivo. Increasing emphasis is therefore being placed on approaches that use micropatterning to control cell spreading, and deformable substrata to model the compliance of biological tissue.

Figure 1. Integrin-mediated signaling pathways to the cyclin D1 gene

Well characterized integrin-mediated pathways that regulate cyclin D1 gene expression. The figure diagrams the primary pathways discussed in this review.

Figure 2. Tensional sensing in cell proliferation

The figure shows a working model of how changes in ECM compliance affect signal transduction and G1 phase cell cycle events. Highly compliant substrata such as relaxed collagen gels (left) inhibit cyclin D1 expression and also upregulate the cdk inhibitors that prevent cdk2 activation. Intermediate compliances (middle) allow for Rac-dependent cyclin D1 induction, but this is not sufficient for Rb phosphorylation and S phase entry (our unpublished results). Low ECM compliances (right) as seen when cells are plated on non-deformable substrata or relatively stiff deformable substrata lead to FAK autophosphorylation, ERK-dependent cyclin D1 gene expression, Rho activity, the appearance of actin stress fibers and cell cycling.