Ligand-independent dimerization of oncogenic v-erbB products involves covalent interactions

Abstract

Mutant v-erbB products of avian c-erbB1 have previously been used to correlate structural domains of the receptor encoded by this proto-oncogene with tissue-specific transformation potential. In these studies, deletion of the ligand-binding domain of the receptor has been shown to be required for transformation of erythroblasts, fibroblasts, and endothelial cells. It has, therefore, been postulated that deletion of this domain results in an allosteric change in the receptor analogous to the ligand-bound state of the epidermal growth factor receptor; i.e., it induces a receptor conformation that is constitutively active with respect to mitogenic signaling. While oncogenic v-erbB products have been shown to be expressed on the cell surface of both fibroblasts and erythroblasts, no comprehensive analysis of the oligomeric potential of these products has been conducted. Since the first event known to follow epidermal growth factor binding to its receptor is oligomerization, and receptor dimerization has been correlated with mitogenic signaling, we have carefully analyzed the ability of several v-erbB products to oligomerize in the three target cell types transformed by these oncogenes. In this report, we demonstrate that v-erbB products can efficiently homodimerize in all three target tissues, that this dimerization is ligand independent and occurs at the cell surface, and that there is no apparent correlation between v-erbB dimerization and transformation of avian fibroblasts. Furthermore, both oncogenic and nononcogenic v-erbB products can heterodimerize with the native c-erbB1 product in chicken embryo fibroblasts, suggesting that heterodimerization between v-erbB and native c-erbB1 is not sufficient to result in c-erbB1mediated sarcomagenesis.

Viruses exploit the function of epidermal growth factor receptor

“…Most members of the poxviruses family, the largest group of DNA viruses, encode EGF‐like ligands that bind to the EGFR family and promote virulence without any influence on viral replication . In contrast, avian erythroblastosis virus (AEV) encodes a truncated form of EGFR, which carries many intracellular mutations and is constitutively active , whereas HPV encodes a protein E5, which inhibits EGFR degradation through inhibition of an endosomal proton‐ATPase . This returns internalised receptors to the plasma membrane where they may again bind ligand and stimulate proliferative pathways.…”

Oligomerization of the EGF Receptor Transmembrane Domain: A 2H NMR Study in Lipid Bilayers

“…Nevertheless, controversy surrounds the details of the proposed mechanisms, including the role of conformation, motifs, and H-bonding. Moreover, while receptor clustering is often seen as a triggering event, some workers have submitted that in fact monomers may be active forms in the same or related pathways (e.g., Biswas et al, 1985;Northwood & Davis, 1988;Carraway & Cerione, 1993;Hazan et al, 1995;Adelsman et al, 1996;Gardina & Manson, 1996;Tatsuno et al, 1996).…”

“…The epidermal growth factor receptor is an important class I receptor tyrosine kinase (RTK) that has been studied for insight into signalling mechanisms (Marchesi, 1986; Brandl et al, 1988; Yarden & Ullrich, 1988; Hollenberg, 1991; Fantl et al, 1993; van der Geer & Hunter, 1994). It is a 170 kDa species possessing an external glycosylated portion responsible for the earliest events in recognition; a single transmembrane domain believed to participate at a variety of levels in signal transduction; and an intracellular portion exhibiting phosphorylation sites, docking sites, and protein kinase activity.…”

Ανοσοθεραπεία Her2/neu όγκων με ανασυνδυασμένα βιομόρια

“…Ο ιός της ερυθροβλάστωσης των πτηνών (AEV) κωδικοποιεί µια πρωτεΐνη µε δοµή παρόµοια του υποδοχέα ErbB1, η οποία στερείται µεγάλου µέρους της εξωκυτταρικής περιοχής, ενώ φέρει ενδοκυτταρικά αρκετές µεταλλάξεις. Η ογκο-πρωτεΐνη αυτή, που ονοµάζεται v-ErbB, σχηµατίζει διµερή ανεξάρτητα της παρουσίας προσδέτη στην κυτταρική επιφάνεια (Adelsman et al 1996). Άλλα στελέχη ρετροϊών παράγουν ενεργές µορφές πρωτεϊνών καταρροϊκά των υποδοχέων ErbB, όπως µικρές πρωτεΐνες που συνδέονται σε GTP (v-Ras), πρωτεΐνες "µεταφοράς σήµατος" (v-Crk), πρωτεϊνικές κινάσες (v-Src, v-Akt, v-Raf) και µεταγραφικούς παράγοντες (v-Jun, v-Fos) .…”