Augmented binding and activation of latent transforming growth factor-beta by a tryptic fragment of latency associated peptide.
Transforming growth factor-beta (TGF-beta) is secreted in a latent form; thus, activation is critical for the control of TGF-beta action. Latent TGF-beta exists in a complex in which mature TGF-beta is noncovalently linked to latency associated peptide (LAP) and latent TGF-beta binding protein (LTBP) complex. We have shown that latent TGF-beta is efficiently activated in heterotypic cultures of endothelial cells (ECs) and smooth muscle cells (SMCs). Under those conditions, LAP plays an important role in targeting latent TGF-beta to the surface of SMCs, and plasmin and calpain target it to the surface of ECs for activation. Here, we demonstrate in a homotypic culture system that fragments of LAP increase the binding of latent TGF-beta to ECs, resulting in its activation by cell-associated proteolysis. LAP fragments appear to bind to the cell surface and augment the binding of latent TGF-beta, independent of transglutaminase. These results suggest a unique mechanism for the activation of latent TGF-beta by proteolytic fragments of LAP. The mechanism may arise from degradation by elevated levels of proteases under certain conditions.
Abe
M
M
Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.
Oda
N
N
Sato
Y
Y
Shibata
K
K
Yamasaki
M
M
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism*; D013552:Swine; D016212:Transforming Growth Factor beta / Q000819:agonists / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D010447:Peptide Hydrolases