Interactions between growth factors and integrins: latent forms of transforming growth factor-beta are ligands for the integrin alphavbeta1.
The multipotential cytokine transforming growth factor-beta (TGF-beta) is secreted in a latent form. Latency results from the noncovalent association of TGF-beta with its processed propeptide dimer, called the latency-associated peptide (LAP); the complex of the two proteins is termed the small latent complex. Disulfide bonding between LAP and latent TGF-beta-binding protein (LTBP) produces the most common form of latent TGF-beta, the large latent complex. The extracellular matrix (ECM) modulates the activity of TGF-beta. LTBP and the LAP propeptides of TGF-beta (isoforms 1 and 3), like many ECM proteins, contain the common integrin-binding sequence RGD. To increase our understanding of latent TGF-beta function in the ECM, we determined whether latent TGF-beta1 interacts with integrins. A549 cells adhered and spread on plastic coated with LAP, small latent complex, and large latent complex but not on LTBP-coated plastic. Adhesion was blocked by an RGD peptide, and cells were unable to attach to a mutant form of recombinant LAP lacking the RGD sequence. Adhesion was also blocked by mAbs to integrin subunits alphav and beta1. We purified LAP-binding integrins from extracts of A549 cells using LAP bound to Sepharose. alphavbeta1 eluted with EDTA. After purification in the presence of Mn2+, a small amount of alphavbeta5 was also detected. A549 cells migrated equally on fibronectin- and LAP-coated surfaces; migration on LAP was alphavbeta1 dependent. These results establish alphavbeta1 as a LAP-beta1 receptor. Interactions between latent TGF-beta and alphavbeta1 may localize latent TGF-beta to the surface of specific cells and may allow the TGF-beta1 gene product to initiate signals by both TGF-beta receptor and integrin pathways.
Munger
J S
JS
Department of Medicine, New York University School of Medicine, New York, New York 10016, USA. mungej01@popmail
Harpel
J G
JG
Giancotti
F G
FG
Rifkin
D B
DB
D002448:Cell Adhesion; D002465:Cell Movement; D002846:Chromatography, Affinity; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins / Q000378:metabolism*; D019030:Receptors, Vitronectin; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
D016023:Integrins; D008024:Ligands; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins; D019030:Receptors, Vitronectin; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C064660:integrin alphaVbeta5; C094340:integrin alphavbeta1