Defining the role of integrin alphavbeta6 in cancer

Abstract

Integrins are a large family of heterodimeric transmembrane receptors that mediate cell-substratum adhesion. alphavbeta6 is an epithelial-specific integrin that is a receptor for the extracellular matrix (ECM) proteins fibronectin, vitronectin, tenascin and the latency associated peptide (LAP) of TGF-beta. Integrin alphavbeta6 is not expressed in healthy adult epithelia but is upregulated during wound healing and in cancer. alphavbeta6 has been shown to modulate invasion, inhibit apoptosis, regulate the expression of matrix metalloproteases (MMPs) and activate TGF-beta1. There is increasing evidence, primarily from in vitro studies, that suggest that alphavbeta6 may actually promote carcinoma progression. In this review we summarize what has been learnt in the past few years about the role of alphavbeta6 in cancer progression.

Fig. (1)

The 8α and 18β subunits form 24 distinct integrin heterodimers. Integrin β6 can only partner with αv.

Fig. (2)

Activation of different matrix metalloproteinases by αvβ6 in various cancers. Activation of MMP9 has the highest prevalence.

Fig. (3)

The TGF-β1 LLC. (A) TGF-β1 is found at the cell membrane as a large latent complex (LLC). The LLC comprises of TGF-β1, the latency-associated protein (LAP), and LTBP1 which belongs to the fibrillin superfamily. LTBP1 anchors the LLC to the ECM. TGF-β1 is inactive in this form. (B) Activation of TGF-β by αvβ6. Integrin αvβ6 binds to the RGD sequence in LAP inducing a conformational change and the binding of αvβ6 to the actin cytoskeleton. The binding to αvβ6 to the actin cytoskeleton further induces a conformational change that releases TGF-β1 from LAP. The unbound TGF-β1 is now active and can go and bind its receptor and activate the TGF-β1 signaling cascade.