c-erb B2 amplification and overexpression in human tumors

Abstract

c-erbB2 or HER2/neu was originally isolated because of its close homology to the epidermal growth factor receptor (EGFr) [1,2] and, together with the recently characterized c-erbB3, these molecules form the type 1 family of tyrosine kinase growth factor receptors [3, 4]. The epidermal growth factor receptor and possibly the other two molecules are activated by binding of ligand to their extracellular domain, which is thought to induce a conformational change allowing dimerization of two molecules. This in turn activates the tyrosine kinase of the cytoplasmic region, which phosphorylates both the receptor itself and a collection of intracellular secondary messenger substrates, thus transducing the mitogenic signal [5]. There are a number of molecules that have been shown to have agonism for the EGF receptor; however, only one putative ligand has been isolated for c-erbB2 — gp30 [6]. This 30-kDa protein will stimulate autophosphorylation of p185^erbB, the 185-kDa protein encoded by the c-erbB2 gene. Paradoxically this is not associated with cell growth when gp30 is added to cultured cells bearing a low to normal number of receptors. Addition of gp30 to cells with overexpression results in inhibition of growth, as is seen in EGF receptor overexpressing cells treated with EGF. In separate experiments conditioned media from ras transformed fibroblasts could induce both p185^neu phosphorylation and a proliferative response in hemopoietic cells previously transfected with the rat c-erbB2 homologue called erb. The active component of the conditioned media has not been isolated [7].