KSHV-TK: thymidine kinase or tyrosine kinase?

The thymidine kinases (TK) of alphaherpesviruses phosphorylate nucleosides, allowing viral replication in non-dividing cells. They also phosphorylate acyclovir (ACV), a specific antiviral when modified. Despite encoding a TK homolog, Kaposi’s sarcoma-associated herpesvirus (KSHV), a gammaherpesvirus, is relatively immune to the effects of ACV. In this issue, Gill et al (2015) show that rather than functioning as a thymidine kinase, the KSHVTK homolog has evolved a unique function as a tyrosine kinase that is autophosphorylated. KSHV-TK autophosphorylation of three SH2 domains leads to Crk binding and likely sequestration of Crk from focal adhesions. KSHV-TK also binds to FAK with a concurrent loss of phosphorylation in the focal adhesions, leading to a loss of cell morphology and membrane blebbing. Rather than acting to create nucleotide pools for replication, the KSHV-TK homolog may play a pivotal role in viral pathogenesis by altering focal adhesions and cell detachment.