A Mechanism for Regulating Pulmonary Inflammation and Fibrosis: The Integrin αvβ6 Binds and Activates Latent TGF β1

Munger, John S.; Huang, Xiaozhu; Kawakatsu, Hisaaki; Griffiths, Mark; Dalton, Stephen; Wu, Jianfeng; Pittet, Jean–François; Kaminski, Naftali; Garat, Chrystelle; Matthay, Michael A.; Rifkin, Daniel B.; Sheppard, Dean

doi:10.1016/s0092-8674(00)80545-0

Cited by 1,775 publications

(610 citation statements)

References 40 publications

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“…The bioassay and ELISA for TGF-b and the immunoblot analysis analysis using antibodies to TGFb1 and b1-LAP demonstrated that this activation of the TGF-b pathway was due to an accelerated conversion of latent TGF-b to an active form in the HOXD3-overexpressing cells. It has been proposed that TGF-b activation occurs in vivo through the pathways of plasminogen/plasmin, TSP-1/CD36, integrin avb3/MMP-2 (or MMP-9) or integrin avb6 (Khalil, 1999;Lyons et al, 1988;Schultz-Cherry et al, 1995;Yehualaeshet et al, 1999;Munger et al, 1999;Yu and Stamenkovic, 2000). To examine whether the After 6 h-incubation, migrated cells were counted by using a microscope.…”

Section: Discussionmentioning

confidence: 99%

HOXD3 enhances motility and invasiveness through the TGF-β-dependent and -independent pathways in A549 cells

et al. 2002

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Homeobox genes regulate sets of genes that determine cellular fates in embryonic morphogenesis and maintenance of adult tissue architecture by regulating cellular motility and cell-cell interactions. Our previous studies showed that a speci®c member, HOXD3, when overexpressed, upregulates integrin b3 expression in human erythroleukemia HEL cells and lung cancer A549 cells, and enhances their motility and invasiveness. We performed a microarray study of over 7075 genes to determine the mechanisms underlying the HOXD3-enhanced motility and invasiveness in A549 cells. RT ± PCR-based tracking gene analyses highlighted a set of TGF-b-upregulated genes, which included matrix metalloproteinase-2, syndecan-1, CD44, and TGF-b-induced 68 kDa protein. Exogenous TGF-b also caused this pattern of upregulation in A549 cells and enhanced their migratory and invasive activity, con®rming the involvement of TGF-b signaling. However, HOXD3 reduced the expression of TGF-b-independent genes coding for desmosomal components such as desmoglein, desmoplakin and plakoglobin which are known to suppress tumor invasion and metastasis. These results suggest that HOXD3 enhances the invasive and metastatic potential of cancer cells through the TGF-b-dependent and -independent pathways.

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Section: Discussionmentioning

confidence: 99%

HOXD3 enhances motility and invasiveness through the TGF-β-dependent and -independent pathways in A549 cells

et al. 2002

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“…Although a role for LTBP-1 in latent TGF-␤ activation was suggested (34), the size of the antibody used in these experiments may have interfered nonspecifically with the activation process. Moreover, the fact that activation by the integrin ␣v␤6 requires the Arg-Gly-Asp within the LAP sequences of TGF-␤1 or ␤3 (TGF-␤2 LAP does not have an Arg-Gly-Asp) (40) suggested that LTBP is not part of that activation pathway. However, LTBP-1 is required for latent TGF-␤ activation by ␣v␤6 (19).…”

Section: Minireview: Latent Tgf-␤ Binding Proteins 7410mentioning

confidence: 99%

Latent Transforming Growth Factor-β (TGF-β) Binding Proteins: Orchestrators of TGF-β Availability

Rifkin

2005

Journal of Biological Chemistry

384

313

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“…Several new and biologically important integrin ligands have been identified based on the presence of this sequence (4,5). Drugs modeled on the structure of the RGD sequence are being used or tested to inhibit integrin function for treatment of thrombosis, inflammation, atherosclerosis, osteoporosis, and cancer (5).…”

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confidence: 99%

The Integrin α9β1 Binds to a Novel Recognition Sequence (SVVYGLR) in the Thrombin-cleaved Amino-terminal Fragment of Osteopontin

Yokosaki¹,

Matsuura

Sasaki³

et al. 1999

Journal of Biological Chemistry

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294

289

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The integrin ␣ 9 ␤ 1 mediates cell adhesion to tenascin-C and VCAM-1 by binding to sequences distinct from the common integrin-recognition sequence, arginine-glycine-aspartic acid (RGD). A thrombin-cleaved NH 2 -terminal fragment of osteopontin containing the RGD sequence has recently been shown to also be a ligand for ␣ 9 ␤ 1 . In this report, we used site-directed mutagenesis and synthetic peptides to identify the ␣ 9 ␤ 1 recognition sequence in osteopontin. ␣ 9 -transfected SW480, Chinese hamster ovary, and L-cells adhered to a recombinant NH 2 -terminal osteopontin fragment in which the RGD site was mutated to RAA (nOPN-RAA). Adhesion was completely inhibited by anti-␣ 9 monoclonal antibody Y9A2, indicating the presence of a non-RGD ␣ 9 ␤ 1 recognition sequence within this fragment. Alanine substitution mutagenesis of 13 additional conserved negatively charged amino acid residues in this fragment had no effect on ␣ 9 ␤ 1 -mediated adhesion, but adhesion was dramatically inhibited by either alanine substitution or deletion of tyrosine 165. A synthetic peptide, SVVYGLR, corresponding to the sequence surrounding Tyr 165 , blocked ␣ 9 ␤ 1 -mediated adhesion to nOPN-RAA and exposed a ligand-binding-dependent epitope on the integrin ␤ 1 subunit on ␣ 9 -transfected, but not on mocktransfected cells. These results demonstrate that the linear sequence SVVYGLR directly binds to ␣ 9 ␤ 1 and is responsible for ␣ 9 ␤ 1 -mediated cell adhesion to the NH 2 -terminal fragment of osteopontin.Integrins are cell surface heterodimeric receptors that mediate cell-cell and cell-extracellular matrix adhesion (1, 2). Upon ligation by a wide variety of ligands, integrins can initiate signaling cascades that regulate cell growth, cell death, migration, polarization, and tissue remodeling (3). Integrins recognize a surprisingly large number of functionally diverse proteins as ligands, and the list of known integrin ligands continues to grow. New integrin ligands have been identified, and drugs targeting integrins have been developed as a consequence of the description of short linear amino acid sequences that directly bind to integrins. For example, the integrins, and ␣ v ␤ 8 bind to sequences containing the tri-peptide sequence Arg-Gly-Asp (RGD). Several new and biologically important integrin ligands have been identified based on the presence of this sequence (4, 5). Drugs modeled on the structure of the RGD sequence are being used or tested to inhibit integrin function for treatment of thrombosis, inflammation, atherosclerosis, osteoporosis, and cancer (5). The RGD sequence has also been exploited to target cell surface integrins to enhance gene delivery (6). We have previously identified the recognition sequence for the integrin ␣ 9 ␤ 1 in tenascin-C and found that this sequence did not include RGD, but was homologous to the ␣ 4 ␤ 1 recognition sequence in the inducible endothelial adhesion molecule VCAM-1 (7). This finding led to our identification of ␣ 9 ␤ 1 as a receptor for VCAM-1 (8).Osteopontin is a phosphorylated acidic gly...

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A Mechanism for Regulating Pulmonary Inflammation and Fibrosis: The Integrin αvβ6 Binds and Activates Latent TGF β1

Cited by 1,775 publications

References 40 publications

HOXD3 enhances motility and invasiveness through the TGF-β-dependent and -independent pathways in A549 cells

HOXD3 enhances motility and invasiveness through the TGF-β-dependent and -independent pathways in A549 cells

Latent Transforming Growth Factor-β (TGF-β) Binding Proteins: Orchestrators of TGF-β Availability

The Integrin α9β1 Binds to a Novel Recognition Sequence (SVVYGLR) in the Thrombin-cleaved Amino-terminal Fragment of Osteopontin

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