BETACELLULIN ACTIVATES THE EPIDERMAL GROWTH-FACTOR RECEPTOR AND ERBB-4, AND INDUCES CELLULAR-RESPONSE PATTERNS DISTINCT FROM THOSE STIMULATED BY EPIDERMAL GROWTH-FACTOR OR NEUREGULIN-BETA

Betacellulin is a member of the epidermal growth factor (EGF) family. These soluble proteins are ligands for one or more of the four recepto r tyrosine kinases encoded by the erbB gene family (erbB-1/epidermal g rowth factor receptor (EGFR), neu/erbB-2/HER2, erbB-3/HER3 and erbB-4/ HER4). While evidence suggests that betacellulin is a ligand for the E GFR, the ability of betacellulin to regulate other erbB family recepto rs has not been analysed. Previously we engineered derivatives of the mouse Ba/F3 hematopoietic cell line to ectopically express erbB family receptors, singly and in pairwise combinations. We have stimulated th is panel of cell lines with betacellulin and two other EGF family memb ers, EGF itself and neuregulin-beta (NRG-beta). In the cell lines expr essing a single erbB family receptor, betacellulin not only stimulated EGFR tyrosine phosphorylation, but it activated erbB-4 as well. Furth ermore, in the double recombinant Ba/F3 derivatives, betacellulin stim ulated a complex pattern of receptor phosphorylation distinct from the patterns activated by NRG-beta and EGF. Moreover, betacellulin stimul ated a complex pattern of interleukin-3 independence in the Ba/F3 deri vatives distinct from those activated by NRG-beta and EGF. These data identify a novel receptor for betacellulin and establish that differen t EGF family ligands activate distinct patterns of receptor phosphoryl ation and coupling to cellular signaling pathways.