Multiple signals activate cleavage of the membrane transforming growth factor-alpha precursor.
Cleavage of the membrane-anchored precursor for transforming growth factor-alpha (TGF-alpha), a rate-limiting step in the generation of soluble TGF-alpha, can be stimulated by phorbol esters acting via protein kinase C. In the present study, activators of other intracellular signaling pathways were tested for their ability to stimulate pro-TGF-alpha cleavage in Chinese hamster ovary cells transfected with a pro-TGF-alpha cDNA. Treatment with the Ca2+ ionophore, A23187, rapidly increased the rate of pro-TGF-alpha cleavage over 25-fold. This effect of A23187 on pro-TGF-alpha cleavage was dependent on the influx of extracellular calcium and was largely independent of protein kinase C activation. In contrast, phorbol 12-myristate 13-acetate stimulation of pro-TGF-alpha cleavage via activation of protein kinase C did not require extracellular calcium. Stimulation of pro-TGF-alpha cleavage by serum was largely independent of both protein kinase C and extracellular calcium influx, whereas activators of protein kinase A and protein kinase G did not stimulate pro-TGF-alpha cleavage. These results suggest that regulation of pro-TGF-alpha cleavage is a complex process that can be controlled by extracellular agents via at least three distinct signal transduction pathways.
Pandiella
A
A
Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Massagué
J
J
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D007700:Kinetics; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
D016211:Transforming Growth Factor alpha; D000001:Calcimycin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium