Cleavage of the membrane precursor for transforming growth factor alpha is a regulated process.
Transforming growth factor alpha (TGF-alpha) is generated by cleavage of a membrane-anchored precursor protein, proTGF-alpha. ProTGF-alpha is cleaved at a slow rate and accumulates on the cell surface, thereby mediating cell-cell adhesion and mitogenic stimulation. We show here that cleavage of membrane proTGF-alpha by an elastase-like enzyme constitutes an important regulatory step in the generation of soluble TGF-alpha. Cleavage is activated in response to serum factors and tumor-promoting phorbol esters, leading to depletion of cell surface proTGF-alpha, which disperses as soluble factor. Activation of proTGF-alpha cleavage is mediated by protein kinase C-dependent and -independent mechanisms. The results demonstrate the existence of mechanisms that control the switch of TGF-alpha from a juxtacrine to a paracrine growth factor.
Pandiella
A
A
Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Massagué
J
J
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology / Q000502:physiology; D010450:Endopeptidases / Q000378:metabolism*; D008954:Models, Biological; D010196:Pancreatic Elastase / Q000378:metabolism; D011487:Protein Conformation; D011498:Protein Precursors / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification
D011498:Protein Precursors; D016211:Transforming Growth Factor alpha; C052268:protransforming growth factor alpha; D010450:Endopeptidases; D010196:Pancreatic Elastase; D013755:Tetradecanoylphorbol Acetate