Cell transformation by the middle T-antigen of polyoma virus

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 Cgamma-1. Tyrosine phosphorylation stimulates PI3K and PLCgamma-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.