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PMID: 11970960 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1.

The Journal of cell biology ·Vol. 157 ·No. 3 ·2002-04-29 ·Pages 493-507

Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, Sheppard D, Broaddus VC, Nishimura SL

Abstract

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 alpha(v)beta8, 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.

MeSH Terms
Animals Cell Division/physiology Cell Line Homeostasis Humans Integrins/metabolism Lung Neoplasms Matrix Metalloproteinase 14 Matrix Metalloproteinases, Membrane-Associated Metalloendopeptidases/metabolism Mice Mice, Inbred BALB C Oligopeptides/metabolism Protein Binding Protein Structure, Tertiary Proteins/metabolism TNF Receptor-Associated Factor 2 Transfection Transforming Growth Factor beta/metabolism Transforming Growth Factor beta1 Tumor Cells, Cultured
Chemicals
Integrins Mmp14 protein, mouse Oligopeptides Proteins TGFB1 protein, human TNF Receptor-Associated Factor 2 Tgfb1 protein, mouse Transforming Growth Factor beta Transforming Growth Factor beta1 integrin alphavbeta8 arginyl-glycyl-aspartic acid Matrix Metalloproteinases, Membrane-Associated Metalloendopeptidases Matrix Metalloproteinase 14
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Mu Dezhi
Department of Pathology, University of California at San Francisco/Mt. Zion Cancer Center, San Francisco, CA 94143, USA.
Cambier Stephanie
Fjellbirkeland Lars
Baron Jody L
Munger John S
Kawakatsu Hisaaki
Sheppard Dean
Broaddus V Courtney
Nishimura Stephen L
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200109100
Published
2002-04-29
Epub
2002-00-22
Pages
493-507
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2173277
Subset
IM
Grants
NCI NIH HHS · CA63143 · United States
NHLBI NIH HHS · R01 HL063786 · United States
NHLBI NIH HHS · HL63993 · United States
NHLBI NIH HHS · R37 HL053949 · United States
NHLBI NIH HHS · HL53949 · United States
NHLBI NIH HHS · R01 HL063993 · United States
NHLBI NIH HHS · R01 HL053949 · United States
NHLBI NIH HHS · HL63786 · United States
NHLBI NIH HHS · F32 HL008985 · United States
NHLBI NIH HHS · HL8985 · United States
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1083/jcb.200109100 PMC Full Text View journal details
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