Cell transformation by the middle T-antigen of polyoma virus

Abstract

The polyoma virus region expressed early in the lytic cycle encodes three proteins, or T-antigens, that together cause the infected cell to enter the cell cycle and so provide a suitable cellular environment for replication of the viral genome. Under some circumstances infection does not kill the cell, but the T-antigens are still produced, resulting in the cell becoming transformed and tumorigenic. Most of this transforming action is exerted by the middle T-antigen, which has the ability to convert established cell lines to an oncogenic state. Middle T is a membrane bound polypeptide that interacts with a number of the proteins used by tyrosine kinase associated receptors to stimulate mitogenesis, so MT can be considered as a permanently active analogue of a receptor. Through a defined series of interactions, MT assembles a large multi-protein complex at the cell membrane, consisting of MT, the core dimer of protein phosphatase 2A, an src-family tyrosine kinase, and via phosphotyrosines, ShcA, phosphatidylinositol (3′) kinase, and phospholipase Cγ-1. Tyrosine phosphorylation stimulates PI3K and PLCγ-1 enzymatic activity, and on ShcA creates binding sites for Grb2 with its associated Sos1 and Gab1. This activates p21^ras, and hence, the MAP kinase cascade. Consequently, MT can be used as a model for studying cell transformation and growth factor receptor signalling pathways.