Focal adhesion complex proteins in epidermis and squamous cell carcinoma

Abstract

Focal adhesions (FAs) are large, integrin-containing, multi-protein assemblies spanning the plasma membrane that link the cellular cytoskeleton to surrounding extracellular matrix. They play critical roles in adhesion and cell signaling and are major regulators of epithelial homeostasis, tissue response to injury, and tumorigenesis. Most integrin subunits and their associated FA proteins are expressed in skin, and murine genetic models have provided insight into the functional roles of FAs in normal and neoplastic epidermis. Here, we discuss the roles of these proteins in normal epidermal proliferation, adhesion, wound healing, and cancer. While many downstream signaling mechanisms remain unclear, the critically important roles of FAs are highlighted by the development of therapeutics targeting FAs for human cancer.

Keywords: Extracellular Matrix; Focal Adhesion; Integrin; Skin; Squamous Cell Carcinoma.

Figure 1. Depiction of focal adhesion structure, key phosphorylation events and therapeutics targeting individual focal adhesion proteins for treatment of cSCC. (A) In normal basal keratinocytes, integrin binding to the ECM initiates Talin binding to the membrane proximal NPxY motif (Y783) and Kindlin binding to the membrane distal NPxY motif (Y795). FAK is recruited to the adhesion and undergoes auto-phosphorylation at Y397. Src kinase phosphorylates both NPxY tyrosines on the β1 integrin tail and phosphorylates active FAK at Y925. It remains controversial whether ILK phosphorylates β1 integrin at these same sites. This adhesion assembly and phosphorylation sequence ultimately promote cell cycle progression and inhibit differentiation and apoptosis programs. (B) Three current strategies in development for treatment of cSCC are blocking β1 integrin with a P5D2 blocking antibody, inhibiting ILK kinase activity using QLT0267, and inhibiting FAK kinase activity using PF-562,271 or GSK2256098.