Integrins and the activation of latent transforming growth factor β1 – An intimate relationship
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
References (109)
- et al.
Integrin-mediated transforming growth factor-beta activation regulates homeostasis of the pulmonary epithelial-mesenchymal trophic unit
Am. J. Pathol.
(2006) - et al.
Increased expression of integrin alphavbeta5 induces the myofibroblastic differentiation of dermal fibroblasts
Am. J. Pathol.
(2006) - et al.
Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins
Cell
(1998) - et al.
Adhesion-mediated mechanosensitivity: a time to experiment, and a time to theorize
Curr. Opin. Cell Biol.
(2006) - et al.
Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3
Cell
(1996) - et al.
Integrin alpha(v)beta8-mediated activation of transforming growth factor-beta by perivascular astrocytes: an angiogenic control switch
Am. J. Pathol.
(2005) - et al.
Upregulation of TGF-beta1 expression may be necessary but is not sufficient for excessive scarring
J. Investig. Dermatol.
(2006) - et al.
Plasmin, substilisin-like [sic!] endoproteases, tissue plasminogen activator, and urokinase plasminogen activator are involved in activation of latent TGF-beta 1 in human seminal plasma
Biochem. Biophys. Res. Commun.
(1998) - et al.
Authentic matrix vesicles contain active metalloproteases (MMP). A role for matrix vesicle-associated MMP-13 in activation of transforming growth factor-beta
J. Biol. Chem.
(2001) - et al.
Characterization and autoregulation of latent transforming growth factor beta (TGF beta) complexes in osteoblast-like cell lines. Production of a latent complex lacking the latent TGF beta-binding protein
J. Biol. Chem.
(1994)
Integrin and ECM functions: roles in vertebrate development
Trends Genet.
Processing of transforming growth factor beta 1 precursor by human furin convertase
J. Biol. Chem.
Substrate rigidity and force define form through tyrosine phosphatase and kinase pathways
Trends Cell Biol.
Integrin regulation
Curr. Opin. Cell Biol.
Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse
Am. J. Pathol.
Formation and function of the myofibroblast during tissue repair
J. Investig. Dermatol.
Mechanisms of force generation and transmission by myofibroblasts
Curr. Opin. Biotechnol.
Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation
Am. J. Pathol.
The myofibroblast: one function, multiple origins
Am. J. Pathol.
Anti-latent TGF-beta binding protein-1 antibody or synthetic oligopeptides inhibit extracellular matrix expression induced by stretch in cultured rat mesangial cells
Kidney Int.
Integrins: bidirectional, allosteric signaling machines
Cell
TGF-beta activation by traction?
Trends Cell Biol.
Sequential deposition of latent TGF-beta binding proteins (LTBPs) during formation of the extracellular matrix in human lung fibroblasts
Exp. Cell Res.
Definition of an unexpected ligand recognition motif for alphav beta6 integrin
J. Biol. Chem.
The logic of TGFbeta signaling
FEBS Lett.
The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis
Cell
Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology
Cytokine Growth Factor Rev.
Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer
Biochim. Biophys. Acta
The fibrillins
Int. J. Biochem. Cell Biol.
Alpha(v)beta(3) integrin interacts with the transforming growth factor beta (TGFbeta) type II receptor to potentiate the proliferative effects of TGFbeta1 in living human lung fibroblasts
J. Biol. Chem.
Molecular interactions and functional interference between vitronectin and transforming growth factor-beta
Lab. Invest.
Integrin signaling revisited
Trends Cell Biol.
In vivo functions of integrins: lessons from null mutations in mice
Matrix Biol.
Release of transforming growth factor-beta 1 from the pericellular matrix of cultured fibroblasts and fibrosarcoma cells by plasmin and thrombin
J. Biol. Chem.
Extracellular matrix-associated transforming growth factor-beta: role in cancer cell growth and invasion
Adv. Cancer Res.
Latent TGF-beta binding proteins
Int. J. Biochem. Cell Biol.
Distinct endocytic responses of heteromeric and homomeric transforming growth factor beta receptors
Mol. Biol. Cell
Making sense of latent TGFbeta activation
J. Cell Sci.
Integrin {alpha}V{beta}6-mediated activation of latent TGF-{beta} requires the latent TGF-{beta} binding protein-1
J. Cell Biol.
Increased expression of integrin alpha(v)beta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts
J. Immunol.
Involvement of alphavbeta5 integrin-mediated activation of latent transforming growth factor beta1 in autocrine transforming growth factor beta signaling in systemic sclerosis fibroblasts
Arthritis Rheum.
Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer
Nat. Rev. Cancer
Latent TGF-beta1 activation by platelets
J. Cell Physiol.
Role of transforming growth factor beta in human disease
N. Engl. J. Med.
Integrins as targets in therapy
Expert Opin. Ther. Patents
Functional consequences of integrin gene mutations in mice
Circ. Res.
Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling
J. Cell Sci.
Integrin activation
J. Cell Sci.
Fibrillin-1 regulates the bioavailability of TGFbeta1
J. Cell Biol.
Integrins in regulation of tissue development and function
J. Pathol.
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