DNA tumor viruses and Src family tyrosine kinases, an intimate relationship.

the Src family of tyrosine kinases are membrane-associReplication of viruses depends on a plethora of ated and act as transducers of signals emanating from highly specific interactions with the host cell resulting plasma membrane receptors, like, e.g., the PDGF recepin the subversion of multiple cellular signal transductor (Kypta et al., 1990) or the B and T cell receptors tion pathways. Cell cycle progression, intracellular (reviewed in Rudd et al., 1993). The activity of Src kinases protein transport, and protein and nucleotide metabois regulated by intramolecular interaction between a carlism are among the many cellular processes dereguboxy-terminal phosphorylated tyrosine residue and the lated by viral proteins in order to establish a cellular SH2 (Src homology 2) domain located in the amino-termienvironment favorable for virus replication. Viruses nal half of the molecule (Liu et al., 1993) (Fig. 1). When the also modulate a host’s immune response to escape SH2 domain is engaged in binding the carboxy-terminal immunosurveillance. Many of the pathways controlling phosphotyrosine, the kinase is inactive. The SH3 (Src cell behavior are tightly regulated by cellular tyrosine homology 3) domain immediately adjacent to the SH2 kinases. One particular family of these enzymes, Src domain is capable of binding proline-rich peptides and family kinases, are involved in processing signals emaseems to further stabilize the closed conformation of Srcnating from the plasma membrane. Two families of related kinases perhaps upon binding to the catalytic or DNA viruses, polyomaand herpesviruses, encode SH1 (Src homology 1) domain (Abrams and Zhao, 1995; proteins targeted at tyrosine kinases. Middle-T antiSeidel-Dugan et al., 1992). Alternatively, the SH3, togens expressed by mouse and hamster polyomavirus gether with the SH2 domain and the tail, might be inassociate with and activate Src family tyrosine kinases, volved in dimerization of Src kinases. This model was while two members of the herpes family of DNA visuggested by a crystal structure of the covalently linked ruses, Epstein – Barr virus (EBV) and herpesvirus saimSH3 and SH2 domains of Lck complexed with the tail iri (HVS), encode proteins, LMP2A and Tip, respecpeptide (Eck et al., 1994). Src-related tyrosine kinases are tively, that associate with cellular tyrosine kinases of activated by upstream signaling molecules that appear the Src and Syk/Zap family. All four viral proteins tightly to weaken the intramolecular interaction between the bind these kinases resulting in altered enzymatic activregulatory tyrosine residue and the SH2 domain. Dephosity and changes in downstream signaling. In this rephorylation of this tyrosine residue by cellular phosphaview we focus on the mechanisms involved in the detases might stabilize the open, active conformation. Actiregulation of tyrosine kinases by viral proteins and vation results in the phosphorylation of substrates downdiscuss their possible function in virus replication and stream in the signaling cascade, triggering interactions spreading and in virus-induced tumorigenesis. with a variety of cellular proteins.