The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain

Two neuregulin-1 isoforms highly expressed in the nervous system are the ty pe III neuregulin III-beta 1a and the type I neuregulin I-beta 1a The seque nce of these two isoforms differs only in the region that is N-terminal of the bioactive epidermal growth factor-like domain. While the biosynthetic p rocessing of the I-beta 1a isoform has been well characterized, the process ing of III-beta 1a has not been reported. In this study, we compared III-be ta 1a and I-beta 1a processing. Both III-beta 1a and I-beta 1a were synthes ized as transmembrane proproteins that were proteolytically cleaved to prod uce an N-terminal fragment containing the bioactive epidermal growth factor -like domain. For I-beta 1a, this product was released into the medium. How ever, for III-beta 1a, this product was a transmembrane protein. In culture s of cells expressing III-beta 1a, the amount of neuregulin at the cell sur face was much greater, and the amount in the medium was much less than in c ultures expressing I-beta 1a Phorbol eater treatment and truncation of the cytoplasmic tail had markedly different effects on III-beta 1a and I-beta 1 a processing. These results demonstrate an important role for the N-termina l region in determining neuregulin biosynthetic processing and show that a major product of III-beta 1a processing is a tethered ligand that may act a s a cell surface signaling molecule.