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J Biol Chem. 1998 Dec 18;273(51):34335-40.

Release of the neuregulin functional polypeptide requires its cytoplasmic tail.

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Victor Chang Cardiac Research Institute, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.


Based on both in vivo and in vitro studies, we have shown previously that the intracellular domain of a membrane-bound isoform of the growth factor, neuregulin, regulates proteolytic release of its extracellular domain ErbB receptor-activating ligand. To investigate the mechanism(s) involved in this regulation, a series of intracellular domain mutants were constructed and tested for susceptibility to proteolytic processing after transient transfection in COS-7 cells. These studies revealed that regulation of extracellular domain cleavage by the intracellular domain is sequence-specific and involves three distinct 30-60-residue segments. The presence of any two of these three segments is both necessary and sufficient for proteolytic processing, and resistance to proteolysis is not due to an alteration in cellular localization or transport. Evidence was also obtained that regulation of extracellular domain processing involves initial intracellular domain dimerization. Thus, with expression of a construct encoding only the intracellular domain, dimerization could be demonstrated in cross-linking experiments. Furthermore, resistance to proteolytic processing of a construct lacking a large portion of the intracellular domain was rescued with a chimera, in which the intracellular domain was replaced with a spontaneously dimerizing Fc fragment. Taken together these studies indicate that intracellular domain interactions are critically involved in the spacial and temporal control of growth and development by membrane-bound neuregulin isoforms.

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