Focal-adhesion-independent integrin-αv regulation of FAK and c-Myc is necessary for 3D skin formation and tumor invasion

Integrins play crucial roles in epithelial adhesion, proliferation, wound healing and cancer. In the epidermis, the roles of many integrin subunits are incompletely defined and mechanistic details regarding their functions are lacking. We performed a multiplexed small hairpin (sh)RNA screen to define roles for each subunit in human organotypic skin. We show that integrin-alpha v (also known as ITGAV) heterodimers are essential for epidermal generation, with integrin-alpha v loss driving a keratinocyte G1-S cell cycle block. Surprisingly, integrin alpha v is not localized within keratinocyte focal adhesions, and instead maintains proliferation by controlling cellular (c)-Myc translation through FAK, p38 beta and p90RSK1. These phenotypes depend only on the binding partners of integrin-alpha v - integrin beta 5 and integrin beta 6 (also known as ITGB5 and ITGB6, respectively). Through inducible depletion of integrin alpha v in both normal organotypic epidermis and Ras-driven invasive neoplasia, we show that integrin alpha v is required for de novo tissue generation and neoplastic invasion but that it is dispensable for epidermal maintenance. Heterodimers of integrin alpha v with integrin beta 5 (integrin alpha v beta 5) or integrin beta 6 (integrin alpha v beta 6) are required to similar extents for neoplastic invasion, thus identifying integrin alpha v beta 5 and integrin alpha v beta 6 heterodimers as potential therapeutic targets for epidermal squamous cell carcinoma.