Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism.
Cleavage and release of membrane protein ectodomains, a regulated process that affects many cell surface proteins, remains largely uncharacterized. To investigate whether cell surface proteins are cleaved through a shared mechanism or through multiple independent mechanisms, we mutagenized Chinese hamster ovary (CHO) cells and selected clones that were unable to cleave membrane-anchored transforming growth factor alpha (TGF-alpha). The defect in TGF-alpha cleavage in these clones is most apparent upon cell treatment with the protein kinase C (PKC) activator PMA, which stimulates TGF-alpha cleavage in wild-type cells. The mutant clones do not have defects in TFG-alpha expression, transport to the cell surface or turnover. Concomitant with the loss of TGF-alpha cleavage, these clones have lost the ability to cleave many structurally unrelated membrane proteins in response to PMA. These proteins include beta-amyloid precursor protein (beta-APP), whose cleavage into a secreted form avoids conversion into the amyloidogenic peptide A beta, and a group of cell surface proteins whose release into the medium is stimulated by PMA in wild type CHO cells but not in mutants. The mutations prevent cleavage by PKC-dependent as well as PKC-independent mechanisms, and thus affect an essential component that functions downstream of these various signaling mechanisms. We propose that regulated cleavage and secretion of membrane protein ectodomains is mediated by a common system whose components respond to multiple activators and act on susceptible proteins of diverse structure and function.
Arribas
J
J
Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York 10021.
Massagué
J
J
D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D016466:CHO Cells; D006224:Cricetinae; D006868:Hydrolysis; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D016211:Transforming Growth Factor alpha; D013755:Tetradecanoylphorbol Acetate