Latent transforming growth factor-beta from human platelets. A high molecular weight complex containing precursor sequences.
Human platelets, when induced to degranulate by thrombin, secrete transforming growth factor-beta (TGF-beta) in a biologically latent form. In this form, TGF-beta cannot bind to its cellular receptor, nor can it be immunoprecipitated by polyclonal antisera to TGF-beta, suggesting that the receptor-binding site and other TGF-beta epitopes may be masked. Western blot analysis of the platelet secretate indicates that the latent form of TGF-beta is a 220-235 kDa complex, in which mature TGF-beta (25 kDa) is noncovalently associated with sequences from the remainder of the precursor (74 kDa), and a third unidentified entity (approximately 135 kDa). The third component is immunologically unrelated to other growth factor binding proteins. The complex is glycosylated, and gel filtration analysis suggests it may exist in solution as higher molecular weight aggregates. Further chromatographic analysis indicates that in its latent form, the platelet TGF-beta cannot bind to alpha 2-macroglobulin (alpha 2M), but that if the platelet latent TGF-beta is activated by transient acidification, the released active TGF-beta will bind to alpha 2M. We have previously identified the latent form of TGF-beta found in serum as an alpha 2M.TGF-beta complex (O'Connor-McCourt, M. D., and Wakefield, L. M. (1987) J. Biol. Chem. 262, 14090-14099). We now propose that the latent TGF-beta secreted by platelets may be a cellular delivery complex, whereas the latent form found in serum may represent a clearance complex. Thus alpha 2M may scavenge excess TGF-beta that is released when the platelet latent form is activated, possibly by the clotting process. Finally, we have shown that the latent form of TGF-beta secreted by a variety of cell types in culture is similar, if not identical to that secreted by platelets.
Wakefield
L M
LM
Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892.
Smith
D M
DM
Flanders
K C
KC
Sporn
M B
MB
D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000032:analysis*; D002478:Cells, Cultured; D002850:Chromatography, Gel; D006031:Glycosylation; D006801:Humans; D008970:Molecular Weight; D010455:Peptides / Q000097:blood*; D011498:Protein Precursors / Q000032:analysis*; D015291:Transforming Growth Factors
D010455:Peptides; D011498:Protein Precursors; D015291:Transforming Growth Factors