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(Received for publication, May 15, 1995; and in revised form, June 14, 1995) neu differentiation factor (NDF), also known as
heregulin, is structurally related to the epidermal growth factor
family of growth factors; it stimulates tyrosine phosphorylation of the neu/HER-2 oncogene and causes differentiation of certain human
breast cancer cell lines. Alternative splicing of a single gene gives
rise to multiple isoforms of NDF/heregulin, as well as the neuronal
homologues, designated ARIA (acetylcholine receptor inducing activity)
and GGF (glial growth factor); at least 15 structural variants are
known. All but two of the NDF/heregulin cDNAs are predicted to encode
transmembrane, glycosylated precursors of soluble NDF. In this
report we characterized the biosynthetic processing of different NDF
isoforms in stably transfected Chinese hamster ovary cells expressing
individual NDF isoforms, and in the native cell line Rat 1-EJ, which
expresses at least six different NDF isoforms. We found that the
precursors for NDF undergo typical glycosylation and trafficking. A
portion of the molecules are proteolytically cleaved intracellularly
leading to the constitutive secretion of soluble, mature NDF into the
culture media. However, a significant portion of the newly synthesized
NDF precursor molecules escape intracellular cleavage and are
transported to the cell surface of both transfected and native cells,
where they reside as full-length, transmembrane proteins. Finally we
show that these full-length, transmembrane NDF molecules can undergo
phorbol ester regulated cleavage from the membrane, releasing the
soluble growth factor into the medium.
Volume 270,
Number 32,
Issue of August 11, pp. 19188-19196, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
GLYCOSYLATION, TRAFFICKING, AND REGULATED CLEAVAGE FROM THE CELL
SURFACE
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