Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Richard K. Assoian

Second Advisor

Christopher S. Chen

Abstract

Cell-matrix and cell-cell adhesions are often characterized as functionally distinct adhesion systems within the cell that mediate different proliferative outcomes. In contrast to the widely accepted pro-proliferative effect of cell-matrix adhesion, the proliferative effect of cadherin-dependent cell-cell adhesion remains unresolved. While the majority of studies demonstrate that cadherins mediate contact inhibition of proliferation, there have also been compelling reports of cadherins stimulating cell cycling. Here, we show that matrix stiffness is the mechanistic basis for crosstalk between N-cadherin at cell-cell junctions and focal adhesion kinase (FAK) at cell-matrix adhesions, and that this interplay between adhesive systems modulates the proliferative role of N-cadherin.

We demonstrate that N-cadherin is induced in smooth muscle cells (SMCs) following vascular injury, an in vivo model of tissue stiffening and proliferation. Complementary experiments on deformable polyacrylamide hydrogels demonstrate that stiffness-mediated activation of a FAK-p130Cas-Rac signaling pathway results in induction of N-cadherin. To understand the functional consequence of this adhesion-dependent crosstalk in cell proliferation, we next used micropatterned islands of different shapes and sizes to control cell-cell contact and cell-matrix adhesion, respectively. Paired and unpaired SMCs on micropatterned substrates of different areas show that N-cadherin stimulates proliferation by relaxing the spreading requirement for proliferation. In vivo SMC deletion of N-cadherin strongly reduces injury-induced cycling. Moreover, SMC-specific deletion of FAK inhibits proliferation after vascular injury, and this is accompanied by reduced induction of N-cadherin. We conclude that stiffness- and FAK-dependent induction of N-cadherin connects cell-matrix to cell-cell adhesion and overrides the spreading requirement for proliferation.

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