The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1.
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.
Mu
Dezhi
D
Department of Pathology, University of California at San Francisco/Mt. Zion Cancer Center, San Francisco, CA 94143, USA.
Cambier
Stephanie
S
Fjellbirkeland
Lars
L
Baron
Jody L
JL
Munger
John S
JS
Kawakatsu
Hisaaki
H
Sheppard
Dean
D
Broaddus
V Courtney
VC
Nishimura
Stephen L
SL
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D006706:Homeostasis; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008175:Lung Neoplasms; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
D016023:Integrins; C507096:Mmp14 protein, mouse; D009842:Oligopeptides; D011506:Proteins; C508960:TGFB1 protein, human; D047992:TNF Receptor-Associated Factor 2; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C403414:integrin alphavbeta8; C047981:arginyl-glycyl-aspartic acid; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14