PATHOGENIC POXVIRUSES REVEAL VIRAL STRATEGIES TO EXPLOIT THE ERBB SIGNALING NETWORK

Virulence of poxviruses, the causative agents of smallpox, depends on virus-encoded growth factors related to the mammalian epidermal growth factor (EGF), Here we report that the growth factors of Shope fibroma virus, Myxoma virus and vaccinia virus (SFGF, MGF and VGF) display un ique patterns of specificity to ErbB receptor tyrosine kinases; wherea s SFGF is a broad-specificity ligand, VGF binds primarily to ErbB-1 ho modimers, and the exclusive receptor for MGF is a heterodimer comprise d of ErbB-2 and ErbB3. In spite of 10- to 1000-fold lower binding affi nity to their respective receptors, the viral ligands are mitogenicall y equivalent or even more potent than their mammalian counterparts. Th is remarkable enhancement of cell growth is due to attenuation of rece ptor degradation and ubiquitination, which leads to sustained signal t ransduction, Our results imply that signal potentiation and precise ta rgeting to specific receptor combinations contribute to cell transform ation at sites of poxvirus infection, and they underscore the importan ce of the often ignored low-affinity ligand-receptor interactions.