Integrins and the activation of latent transforming growth factor β1 – An intimate relationship

Integrins are crucial for the ability of cells to sense mechanical perturbations and to transmit intracellular stress to their environment. We here review the more recently discovered role of integrins in activating the pleiotrophic cytokine transforming growth factor beta 1 (TGF-β1). TGF-β1 controls tissue homeostasis in embryonic and normal adult tissues and contributes to the development of fibrosis, cancer, autoimmune and vascular diseases when being mis-regulated. In most of these conditions, active TGF-β1 is generated by dissociation from a large latent protein complex that sequesters latent TGF-β1 in the extracellular matrix (ECM). Two main models are proposed how integrins contribute to latent TGF-β1 activation: (1) In a protease-dependent mechanism, integrins αvβ8 and αvβ3 are suggested to simultaneously bind the latent TGF-β1 complex and proteinases. This close vicinity at the cell surface improves enzymatic cleavage of the latent complex to release active TGF-β1. (2) Integrins αvβ3, αvβ5, αvβ6, and αvβ8 appear to change the conformation of the latent TGF-β1 complex by transmitting cell traction forces. This action requires association of the latent complex with a mechanically resistant ECM and is independent from proteolysis. Understanding that different integrins use different mechanisms to activate latent TGF-β1 opens new possibilities to develop cell-specific therapeutic strategies for TGF-β1-induced pathologies.