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

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Abstract

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.

Introduction

One of the most intriguing features of actin-associated adhesions is the adaptation of their morphology, composition and function to mechanical perturbation. It appears that mechanical stress already intervenes on the level of activation of single integrins, the basic components of a transmembrane contact with the extracellular matrix (ECM). Integrins are αβ heterodimers assembled from 18 different α and 8 distinct β subunits that combine to 24 currently identified cell receptors in mammals binding to different ECM proteins (Hynes, 2002; Luo et al., 2007; Sheppard, 2000). In addition, integrins have been shown to interact with cell surface ligands, transmembrane proteins, soluble proteases, pathogens, and growth factors (van der Flier and Sonnenberg, 2001). Their crucial role in a plethora of biological processes is appreciated from the pathological consequences following integrin defects (Bosserhoff, 2006; Danen and Sonnenberg, 2003) and from the often severe phenotypes of integrin subunit knockout animals (Bouvard et al., 2001; De Arcangelis and Georges-Labouesse, 2000; Hynes, 2002). It is evident that integrins are more than simple anchors with the ECM; they act as bidirectional cell receptors receiving and transmitting signals from both sides of the plasma membrane, a property generally referred to as inside-out and outside-in signaling (Calderwood, 2004; Ginsberg et al., 2005; Luo et al., 2007; Schwartz, 2001).

This signaling role becomes clear from the mechanosensitive maturation of adhesion structures. To resist forces that are million times stronger than the individual molecular bond, cells reinforce their adhesions by triggering a cascade of maturation events, starting with integrin clustering into nascent adhesions that further develop into focal complexes when associating with actin filaments (Galbraith et al., 2007). Increasing intracellular stress that needs to be balanced by a mechanically resistant substrate leads to the development of contractile cytoplasmic stress fibers and enlargement of focal complexes into focal adhesions (Bershadsky et al., 2006). Different theories have been established to explain the nature of the stress sensor(s) within adhesion structures and of the signal generator(s) that convert mechanical into biochemical cues (Bershadsky et al., 2006; Giannone and Sheetz, 2006). One of these models predicts the presence of cytosolic proteins within the adhesion plaque that act as molecular switches and change their conformation/activation state when force is applied (Giannone and Sheetz, 2006).

Adhesion-mediated mechanical switches and signal generators are not necessarily localized within the cell. Pioneer studies from the Burridge laboratory have identified fibronectin (FN) as a mechanosensitive protein that becomes unfolded upon cell traction and then reveals cryptic sites for auto-fibrillogenesis (Vogel and Baneyx, 2003; Zhong et al., 1998). ECM protein unfolding may similarly reveal specific integrin-binding sites and thus change cell adhesion-dependent responses such as cell migration, proliferation, survival, and differentiation as well as ECM organization and remodeling (Ingber, 2003; Vogel, 2006; Vogel and Sheetz, 2006). Another mechanism of how adhesion-mediated cell forces are translated into biochemical signals is the direct liberation/activation of growth factors that are integral parts of the ECM; this was recently demonstrated for latent transforming growth factor (TGF-β) activation by epithelial cells (Jenkins et al., 2006) and by contractile fibroblasts (Wipff et al., 2007). In the present review, we will focus on the possible mechanisms of latent TGF-β activation by cell integrins.

Section snippets

TGF-β – paradigm of a pleiotrophic growth factor

A variety of growth factor pathways closely associate with integrins (Miyamoto et al., 1996); αvβ3 integrin has been shown to directly interact with the transmembrane receptors for VEGF, PDGF and insulin-like growth factor (Schneller et al., 1997; Soldi et al., 1999), and α5β1 integrin interacts with the EGF receptor (Miyamoto et al., 1996; Soldi et al., 1999). Of all growth factors that cooperate with integrins, the biology and activation of TGF-β appears to be the most complex. TGF-β belongs

Integrins and TGF-β1 – a close relationship

More recently, integrins have been shown to bind to and in several cases to activate latent TGF-β1; binding comprises all αv integrins (αvβ1, αvβ3, αvβ5, αvβ6, αvβ8), integrins α5β1, α8β1 and the platelet integrin αIIbβ3 (Ludbrook et al., 2003; Sheppard, 2005). At present, integrins αvβ5, αvβ6, and αvβ8, a yet unidentified β1 integrin and possibly αvβ3 integrin have been reported to participate in activating latent TGF-β1 (for references see Table 1).

What is the physiological relevance of

Latent TGF-β1 activation by integrin-mediated cell traction

Pioneering work from the laboratories of Sheppard and Rifkin demonstrated that the epithelial integrin αvβ6 can directly activate latent TGF-β1 independently from any proteolytic activity (Munger et al., 1999) and both groups have refined the underlying mechanism over the past years (Annes et al., 2004; Jenkins et al., 2006). Very recently, another work elucidated that integrin αvβ5, a not further identified β1 integrin and possibly αvβ3 integrin can directly activate TGF-β1 in myofibroblasts,

Conclusions and future perspectives

When J. Keski-Oja discussed the groundbreaking finding by Rifkin and coworkers that activation of latent TGF-β1 by αvβ6 integrin requires incorporation of the LLC into the ECM (Annes et al., 2004), he formulated the title of his commentary as an hypothesis: ‘TGF-β activation by traction?’ (Keski-Oja et al., 2004). Now, three years later it appears appropriate to provide this phrase with an exclamation mark, at least with respect to the TGF-β1 isoform. But not all integrins that bind to LAP-β1

Acknowledgments

We thank Dr. J.-J. Meister (Laboratory of Cell Biophysics, EPFL, Lausanne, Switzerland) for his continuous support and for providing laboratory facilities, and Mrs. J. Smith-Clerc for outstanding technical assistance. The work is supported by grants (to B. Hinz) from the Swiss National Science Foundation (#3100A0-102150/1 and #3100A0-113733/1), from the Gebert Rüf Stiftung, from the Service Académique, EPFL, and from the Competence Centre for Materials Science and Technology (CCMX) of the ETH

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