Lessons from polyoma middle T antigen on signaling and transformation: A DNA tumor virus contribution to the war on cancer

Abstract

Middle T antigen (MT) is the principal oncogene of murine polyomavirus. Its study has led to the discovery of the roles of tyrosine kinase and phosphoinositide 3-kinase (PI3K) signaling in mammalian growth control and transformation. MT is necessary for viral transformation in tissue culture cells and tumorigenesis in animals. When expressed alone as a transgene, MT causes tumors in a wide variety of tissues. It has no known catalytic activity, but rather acts by assembling cellular signal transduction molecules. Protein phosphatase 2A, protein tyrosine kinases of the src family, PI3K, phospholipase Cgamma1 as well as the Shc/Grb2 adaptors are all assembled on MT. Their activation sets off a series of signaling cascades. Analyses of virus mutants as well as transgenic animals have demonstrated that the effects of a given signal depend not only tissue type, but on the genetic background of the host animal. There remain many opportunities as we seek a full molecular understanding of MT and apply some of its lessons to human cancer.

Figure 1. Landmarks on MT

Sites of interaction of MT with cellular proteins are shown. Each of the signal transducers shown below the middle T sequence is known to be important for transformation. PP2A = protein phosphatase 2A, PTK = src family tyrosine kinase (src, yes, fyn), PI3K = phosphatidylinositide 3-kinase, PLCγ = phospholipase Cγ1. There can also be interaction between Gab1 and PI3K. PPP represents the proline rich/E349K sequence important for transformation. Simple versions of signaling pathways downstream of Y250, Y315 and Y322 are shown. The light blue area represents the hydrophobic membrane attachment site.

Figure 2. MT and PP 2A: PP2A exists as heterotrimeric ABC complexes

A: There are two different A subunit scaffolds to which two different catalytic C subunits could bind. There are many different B family regulatory subunits. B: The binding of PyST (or PyMT) replaces B subunits.

Figure 3. The sequence at the C-terminus of MT is responsible for association with membranes

The hydrophobic sequence is underlined. Residue 393 that is discussed in the text and residue 384 that is the last residue found in non-transforming, cytoplasmic Py1387T are indicated.