Polypeptide growth factors regulate cellular growth by stimulating the intrinsic protein tyrosine kinase activities of their specific cell surface receptors. The receptor for epidermal growth factor (EGF) is the prototype for a subfamily of structurally related proteins (termed the class I receptors; Ullrich and Schlessinger, 1990) that mediate the proliferation and differentiation of normal cells. Members of this subfamily, which include the products of the erbB2heu, erbB3, and erbB4 genes, are often found overexpressed in various human tumor cells. It has been suggested that the aberrant activation of their kinase activities contributes to tumorigenesis or progression (see Peles and Yarden, 1993). Therefore, an understanding of the mechanisms by which class I receptors become activated may yield insights into how these receptors might mediate oncogenic processes. Several recent and unexpected discoveries pertaining to receptor activation by the EGF-like growth factor heregulin (HRG) point to a possible general mechanism for signaling through the class I receptor family.

HRGs The second member of the EGF receptor subfamily to be discovered, pl 85erb821neu, was originally identified about ten years ago as the product of the transforming gene from neuroblastomas of chemically treated rats. Its homology with the EGF receptor suggested that it might be a receptor for an unidentified growth factor ligand, prompting an extensive search for soluble, secreted factors that stimulate pl 85erbB21neu autophosphorylation. Two years ago, the purification, cloning and expression of a candidate ligand for Pl 85erbs2/neu was reported independently by two groups (Peles et al., 1992; Wen et al., 1992; Holmes et al., 1992). This ligand, termed HRG or neu differentiation factor (NDF), stimulates the tyrosine phosphorylation of~ 185 erbsZlneu in some human mammary cancer cells. Moreover, iodinated HRGlNDF can be covalently cross-linked to pl 85erb82/neu in those cells. It was subsequently discovered that acetylcholine receptor-inducing activity (ARIA), a factor that stimulates the synthesis of acetylcholine receptor in muscle cells, and the glial growth factors, which promote the proliferation of cultured Schwann cells, are identical to HRGlNDF (Falls et al., 1993; Marchionni et al., 1993). These observations suggest a role for HRGl NDF in nervous system development and regeneration. Analysis of the cDNAs encoding HRGlNDF suggests that many splice variants arise from a single gene, resulting in a variety of possible expressed growth factors (Marchionni et al., 1993). The products appear to be mosa-