Journal
JOURNAL OF CELL BIOLOGY
Volume 157, Issue 3, Pages 493-507Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200109100
Keywords
integrins; transforming growth factor beta; metalloprotease; cell cycle; homeostasis
Categories
Funding
- NCI NIH HHS [CA63143] Funding Source: Medline
- NHLBI NIH HHS [HL8985, F32 HL008985, HL63786, R01 HL053949, R01 HL063993, HL53949, R37 HL053949, HL63993, R01 HL063786] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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Integrins, matrix metalloproteases (MMPs), and the cytokine TGF-beta have each been implicated in homeostatic cell behaviors such as cell growth and matrix remodeling. TGF-beta exists mainly in a latent state, and a major point of homeostatic control is the activation of TGF-beta. Because the latent domain of TGF-beta1 possesses an integrin binding motif (RGD), integrins have the potential to sequester latent TGF-beta (SLC) to the cell surface where TGF-beta activation could be locally controlled. Here, we show that SLC binds to alphavbeta8, 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-beta, 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.
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