title: Absence of integrin-mediated TGFbeta1 activation in vivo recapitulates the phenotype of TGFbeta1-null mice.
abstract: 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.
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yang
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Mu
authors.forename: Branka
authors.initials: B
authors.lastname: Dabovic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Jurukovski
authors.forename: Dawen
authors.initials: D
authors.lastname: Yu
authors.forename: Joanne
authors.initials: J
authors.lastname: Sung
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Xiong
authors.forename: John S
authors.initials: JS
authors.lastname: Munger
mesh_terms: 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
chemical_list: D016023:Integrins; D053773:Transforming Growth Factor beta1