Mechano-reciprocity is maintained between physiological boundaries by tuning signal flux through the Rho-associated protein kinase

Abstract

The mechanical properties of the ECM strongly influence the behavior of all cell types within a given tissue. Increased matrix tension promotes epithelial cell proliferation by engaging mitogenic mechanotransduction signaling including the Salvador/Warts/Hippo, PI 3-kinase, Rho, Wnt and MAP kinase pathways. The Rho signaling pathways in particular are capable of increasing intra-cellular tension by elevating the production and contractility of the actomyosin cytoskeleton, which counteracts tension changes within the matrix in a process termed mechano-reciprocity. We have discovered that Rho-ROCK signaling increases the production of ECM through paracrine signaling between the epithelium and fibroblasts and also the remodeling of the ECM by regulating focal adhesion dynamics in fibroblasts. These two phenomena together cause increased ECM tension. Enhanced mechano-reciprocity results in ever-increasing intra- and extra-cellular tension in a vicious cycle that promotes cell proliferation and tumor progression. These insights reveal that inhibiting mechano-reciprocity, reducing ECM tension and targeting cancer-associated fibroblasts in a coordinated fashion has potential as cancer therapy.

Keywords: 14-3-3ζ; MYPT; ROCK; Rho; cancer; extra-cellular matrix; fibroblasts; mechanoreciprocity; mechanotransduction; wound healing.

Figure 1.

Mechanosensing through engagement of integrins with the ECM causes mechanotransduction, by activation of Talin and autophosphorylation of FAK, which initiates several intra-cellular signal transduction pathways, including PI 3-kinase/Akt and ROCK signaling. Mechanotransduction gives rise to increased actin polymerization and actomyosin contractility, establishing mechano-reciprocity, which in turn leads to paracrine signaling between the parenchyma and the stroma, increasing ECM production and remodeling.

Figure 2.

ROCK activation enhances intracellular tension in epidermal cells by activating MLC and LIM kinases. It also increases extracellular tension by elevating ECM production by dermal fibroblasts. ROCK activation in dermal fibroblasts promotes ECM remodeling by regulating focal adhesion dynamics and fibroblast migration. In both contexts, 14-3-3ζ limits signal flux through ROCK, thereby maintaining mechano-reciprocity between normal physiological boundaries, permitting normal wound healing and protecting against tumor formation. This figure has been adapted from ref. .