The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP–dependent activation of TGF-β1

By D. Mu, S. Cambier, L. Fjellbirkeland, J. Baron, J. Munger, H. Kawakatsu, D. Sheppard, V. Broaddus, S. Nishimura. Journal of Cell Biology, 2002

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Întegrins, matrix metalloproteases (MMPs), and the cytokine TGF-β have each been implicated in homeostatic cell behaviors such as cell growth and matrix remodeling. TGF-β exists mainly in a latent state, and a major point of homeostatic control is the activation of TGF-β. Because the latent domain of TGF-β1 possesses an integrin binding motif (RGD), integrins have the potential to sequester latent TGF-β (SLC) to the cell surface where TGF-β activation could be locally controlled. Here, we show that SLC binds to αvβ8, an integrin expressed by normal epithelial and neuronal cells in vivo. This binding results in the membrane type 1 (MT1)-MMP–dependent release of active TGF-β, which leads to autocrine and paracrine effects on cell growth and matrix production. These data elucidate a novel mechanism of cellular homeostasis achieved through the coordination of the activities of members of three major gene families involved in cell–matrix interactions.

Subfields: Cancer Research, Immunology and Allergy, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1f40b912db388f21d1f9e9d11b2d3194e05d5287

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Citations in the corpus

Making sense of latent TGFβ activation (2003, background): “Recently, Mu et al., reported that the integrin αvβ8 can activate latent TGFβ1 (Mu et al., 2002).”
Extracellular Matrix Communication and Turnover in Cardiac Physiology and Pathology (2015, neutral): “For instance, transforming growth factor-β (TGF β ) is secreted and sequestered the ECM by binding to latent TGF β -binding peptide ), an ECM protein (416), and is released in response proteolytic (273,485) or mechanical triggers (465).”
TGF-β1 Signaling and Tissue Fibrosis. (2018, background): “Cell culture studies with epithelial cells showed that the closely related integrin, avb8, can also potently activate TGF-b (Mu et al. 2002).”
Role of tissue stroma in cancer cell invasion (2003, background): “Membrane type (MT)1-MMP-dependent activation of TGF-β requires an interaction of the LAP domain of TGF-β with the integrin αVβ8 [71].”
TGF-β signaling in fibrosis (2011, background): “On the other hand, aVb8 integrin was shown to activate TGF-b1 through a membrane type 1 matrix metalloproteinase (MT1-MMP)-dependent mechanism (Mu et al. 2002).”
Signaling mechanisms of the epithelial-mesenchymal transition (2014, background): “The binding of latent TGF-β to integrins aVb6 and aVb8 induces the proteolytic release of the latency-associated peptide (LAP), hence activating TGF-β at the cell membrane; aVb8 mediates this activation through the protease activity of membrane type 1 MMP (also known as MMP-14) (217, 218).”
Matrix Metalloproteinases: Regulators of the Tumor Microenvironment (2010, background): “…studies describing MMP-mediated regulation of cell growth signals, such as the activation of TGF-β by MMP-2, -9, and -14 (Dallas et al., 2002; Mu et al., 2002), the proteolytic release of soluble EGFR ligands, or the degradation of E-cadherin by MMP-3 or -9 (Cowden Dahl et al., 2008;…”