SYM-02: Mechanobiology

ACTOMYOSIN CONTRACTILITY IS ESSENTIAL FOR CONTACT INHIBITION OF KERATINOCYTE PROLIFERATION

Hiroaki Hirata1,2, Mikhail Samsonov2, Masahiro Sokabe1

1Nagoya University, Japan;
2R-Pharm Japan

Keratinocytes form multiple layers in the epidermis, providing a stable environmental barrier in the skin. Confluence-dependent inhibition of keratinocyte proliferation, termed contact inhibition, is crucial for epidermal homeostasis: loss of the contact inhibition in keratinocytes is thought to cause keratinocyte carcinomas, the second most common type of cancers in the United States. It has been appreciated that E-cadherin-mediated cell-cell adhesion plays a central role in inducing contact inhibition in epithelial cells. In addition, a growing body of research has revealed that intracellular and extracellular mechanical cues that modulate cytoskeletal tension affect proliferation of confluent epithelial cells. Here we report that among epithelial cells, keratinocytes possess a unique, actomyosin-dependent mechanism for contact inhibition. When actomyosin was inhibited, contact inhibition of keratinocytes was abrogated. While beta-catenin- and YAP-mediated gene transcription promotes proliferation of keratinocytes, actomyosin activity in confluent keratinocytes attenuated nuclear accumulation of beta-catenin and YAP, thereby inducing contact inhibition. Confluent keratinocytes developed E-cadherin-mediated punctate adhesion complexes, to which radial actin cables were connected via alpha-catenin. Eliminating the actinto-E-cadherin linkage by depleting alpha-catenin increased proliferation of confluent keratinocytes. By contrast, their proliferation was attenuated by enforced activation of RhoA-regulated actomyosin or by external application of pulling force to ligated E-cadherin, suggesting that tensile stress at E-cadherin-mediated adhesion complexes inhibits proliferation of confluent keratinocytes. While proliferation of most adherent cells is regulated by mechanical interaction between cells and extracellular matrices, keratinocytes forming multiple epithelial layers might have developed a distinct mechanism mediated by tension at cell-cell junctions to regulate cell proliferation.
 

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