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 ([Gill MB, 2015]) show that rather than functioning as a thymidine kinase, the KSHV ‐ TK homolog has evolved a unique function as a tyrosine kinase that is autophosphorylated. KSHV ‐ TK autophosphorylation of three SH 2 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.