A NOVEL BRAIN-DERIVED MEMBER OF THE EPIDERMAL GROWTH-FACTOR FAMILY THAT INTERACTS WITH ERBB3 AND ERBB4

A novel member of the epidermal growth factor (EGF) family, the neural -and thymus-derived activator for ErbB kinases (NTAK), has been purifi ed and cloned. Five alternative spliced isoforms have been detected in the rat adrenal pheochromocytoma cell line, PC-12 cells. The rat NTAK alpha 2a isoform exhibits 94% identity in its primary sequence with t he human NTAK alpha isoform. In vivo, NTAK is only expressed in the br ain of rat E11.5 embryos, and in the brain and thymus of adult rats. T he soluble 46 kDa form binds directly to ErbB3 and B4, but not to ErbB 1 or B2. NTAK, however, transactivates ErbB1 and B2 via heterodimeriza tion with ErbB3 or E4. NTAK stimulates the differentiation of MDA-MB-4 53 cells and competitively inhibits the binding of [I-125] neuregulin to these cells. In addition to these neuregulin-like properties, NTAK exhibits limited structural homology to neuregulins in the immunoglobu lin (Ig)-like, EGF-like, and hydrophobic domains. Thus, NTAK appears t o be a new member of the EGF family displaying neuregulin properties.