A point mutation in the neu oncogene mimics ligand induction of receptor aggregation

Abstract

The rat neu gene, which encodes a protein closely related to the epidermal growth factor receptor, is a proto-oncogene that can be converted into an oncogene by a point mutation. Both genes encode proteins with a relative molecular mass of 185,000 but the question of why the neu gene product, p185neu, is oncogenic, whereas the product of c-neu, p185c-neu, is not, remains unanswered. The proteins have several features common to the family of tyrosine kinase growth-factor receptors, including cysteine-rich external domains, a hydrophobic transmembrane region and a cytoplasmic tyrosine kinase domain. The oncogenic p185neu differs from p185c-neu by an amino-acid substitution in the transmembrane region of the glycoprotein: this replacement of valine by glutamic acid at position 664 induces increased intrinsic tyrosine kinase activity which is associated with transformation. Many glycoproteins with charged amino acids in the transmembrane region exist as multimeric complexes at the plasma membrane. We have therefore investigated the association state of both products of the neu gene and show that the oncoprotein p185neu is organized at the plasma membrane primarily in an aggregated form, but that p185c-neu is not. Induction of an aggregated state may mimic aspects of ligand-induced receptor aggregation resulting in enzymatic activation that leads to cellular transformation.

Absence of autophosphorylation site Y882 in the p185neu oncogene product correlates with a reduction of transforming potential

“…It is thought that contacts in the ectodomain in erbB family receptors initiate the formation of dimers thereby bringing the kinase domains in proximity with one another, which is required for catalytic activation (Weiner et al, 1989;Ullrich and Schlessinger, 1990). The use of dominant-negative mutant receptors has established that ectodomain interactions alone are su cient for erbB family homo-and heterodimerization O'Rourke et al, 1997), although cytoplasmic interactions determine receptor signaling outcome (Qian et al, 1995).…”

“…Mutation and overexpression of erbB family receptors has been found to lead to receptor activation by inducing the formation of dimeric and oligomeric forms (Weiner et al, 1989;Samanta et al, 1994). The net e ects of oligomerization are both enhanced kinase activity and subsequent signal transduction .…”

The Ron oncogenic activity induced by the MEN2B-like substitution overcomes the requirement for the multifunctional docking site

“…Constitutive activation of a tyrosine kinase receptor can occur also by alteration of the sequence of the transmembrane domain. This is the case of p185 neu* , an oncogenic form of Neu, where a V?E substitution at position 664 induces constitutive dimerization, tyrosine kinase autophosphorylation and cell transformation (Weiner et al, 1989;Sternberg and Gullick, 1989).…”

Overexpression of activated neu/erbB2 initiates immortalization and malignant transformation of immature Schwann cells in vitro

“…In particular, immature cells of the rat Schwann cell lineage exposed transplacentally or at early neonatal stages to N-ethyl-N-nitrosourea (ENU) reproducibly have a speci®c activating transversion mutation at the transmembrane region of neu (Bargmann and Weinberg, 1988;Weiner et al, 1989;Nikitin et al, 1991). Schwann cells are the major supportive cell population in the peripheral nervous system and ensheath all peripheral axons.…”