THE CYTOPLASMIC CARBOXY-TERMINAL AMINO-ACID SPECIFIES CLEAVAGE OF MEMBRANE TGF-ALPHA INTO SOLUBLE GROWTH-FACTOR

Membrane-anchored transforming growth factor a (proTGFalpha) belongs to a group of transmembrane proteins whose extracellular domains are selectively cleaved and released into the medium. We demonstrate that the carboxy-terminal valine in the cytoplasmic tail of proTGFalpha is required for cleavage of the growth factor ectodomain in response to various activators. This cleavage process occurs outside Golgi or lysosomal locations, affects cell surface proTGFalpha, and requires little or no membrane traffic. We propose that cleavage and release of proTGFalpha ectodomain involve a specialized proteolytic system and depend on the recognition of a simple and specific determinant located in the proTGFalpha cytoplasmic tail.