Absence of integrin-mediated TGFbeta1 activation in vivo recapitulates the phenotype of TGFbeta1-null mice.
The multifunctional cytokine transforming growth factor (TGF) beta1 is secreted in a latent complex with its processed propeptide (latency-associated peptide [LAP]). TGFbeta1 must be functionally released from this complex before it can engage TGFbeta receptors. One mechanism of latent TGFbeta1 activation involves interaction of the integrins alpha v beta6 and alpha v beta8 with an RGD sequence in LAP; other putative latent TGFbeta1 activators include thrombospondin-1, oxidants, and various proteases. To assess the contribution of RGD-binding integrins to TGFbeta1 activation in vivo, we created a mutation in Tgfb1 encoding a nonfunctional variant of the RGD sequence (RGE). Mice with this mutation (Tgfb1(RGE/RGE)) display the major features of Tgfb1(-/-) mice (vasculogenesis defects, multiorgan inflammation, and lack of Langerhans cells) despite production of normal levels of latent TGFbeta1. These findings indicate that RGD-binding integrins are requisite latent TGFbeta1 activators during development and in the immune system.
Yang
Zhiwei
Z
Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
Mu
Zhenyu
Z
Dabovic
Branka
B
Jurukovski
Vladimir
V
Yu
Dawen
D
Sung
Joanne
J
Xiong
Xiaozhong
X
Munger
John S
JS
D000818:Animals; D001665:Binding Sites; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D053773:Transforming Growth Factor beta1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014652:Vascular Diseases / Q000235:genetics / Q000473:pathology; D015017:Yolk Sac / Q000098:blood supply / Q000473:pathology
D016023:Integrins; D053773:Transforming Growth Factor beta1