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Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1726-30.

Cleavage of the membrane precursor for transforming growth factor alpha is a regulated process.

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Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.


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.

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