We previously showed the herpes simplex virus 1 (HSV-1) tegument protein VP11/12 activates the lymphocyte-specific Src family kinase (SFK) Lck and is tyrosine phosphorylated in an Lck-dependent manner during T cell illness. and main fibroblasts. VP11/12 interacts with PI3K or PI3K signaling complexes during illness suggesting that VP11/12 activates PI3K directly. SFK activity is required for tyrosine CPPHA phosphorylation of VP11/12 VP11/12-PI3K relationships FCRL5 and Akt activation in infected fibroblasts suggesting that SFK-dependent phosphorylation of VP11/12 is required for relationships with downstream signaling effectors. Akt settings many biological functions including cell survival cell motility and translation but it is currently unclear which Akt focuses on are modulated by VP11/12 during illness. Even though Akt target mTORC1 is triggered during HSV-1 illness VP11/12 is not required for this effect implying that one or more additional viral proteins regulate this pathway. Further studies are therefore required to determine which Akt focuses on and associated biological functions are distinctively modulated by VP11/12. Tegument proteins are layered between the capsid and the envelope in virions of the family including those of herpes simplex virus 1 (HSV-1). These proteins are delivered into the cytoplasm during viral access and from there they translocate to numerous subcellular locations to manipulate host cell functions. Examples include virion protein 16 (VP16) a viral transcription element that promotes immediate-early gene transcription during illness (examined in research 68) and virion sponsor shutoff protein which contributes to an early blockade of sponsor protein synthesis by destabilizing cellular mRNAs (examined in research 55). Many tegument proteins likely play important functions in virus-host relationships but the functions of most of these remain undefined. VP11/12 probably one of the most abundant proteins in the HSV-1 tegument lacks a well-established function during illness; however studies from our laboratory suggest that it serves as a substrate and an activator of the lymphocyte-specific Lck tyrosine kinase (64 72 Originally identified as two proteins VP11 and VP12 based on its mobility relative to that of additional virion proteins inside a denaturing SDS-polyacrylamide gel (at ca. 87 and ca. 93 kDa) (57) VP11/12 is CPPHA now known to be one protein encoded from the open reading framework UL46 (74). VP11/12 enhances immediate-early viral gene manifestation in transfection-based assays by augmenting the activity of the HSV-encoded transcriptional activator VP16 (19 32 However studies of VP11/12-null CPPHA viruses have shown that VP11/12 is not required for viral immediate-early gene manifestation during HSV illness (72 75 VP11/12 is present in the membrane portion of infected cells although it is not membrane connected in adult virions (36). In addition VP11/12 localizes to the plasma membrane immediately following viral access (67). These studies suggest that VP11/12 may serve a membrane-associated function that is unique from its part in virion assembly. Our previous studies raised the possibility that VP11/12 modulates one or more cellular signaling pathways (64 72 VP11/12 is definitely highly tyrosine phosphorylated in lymphocytes and in Jurkat T cells tyrosine phosphorylation is largely dependent on the lymphocyte-specific Src family kinase (SFK) Lck (72). Lck is definitely triggered during CPPHA HSV-1 illness of T cells and VP11/12 is required for this effect; moreover VP11/12 interacts with Lck or Lck signaling complexes (64). These data suggest that VP11/12 activates Lck to induce its own tyrosine phosphorylation maybe therefore inducing or modifying downstream signaling events. However effects of VP11/12 on signaling downstream of Lck or additional SFKs have not yet been recorded. Despite the well-established part of Lck in initiating signaling through the T cell receptor (TCR) (examined in research 56) VP11/12-dependent activation of Lck does not result in TCR signaling (72). Indeed HSV-1 illness inhibits TCR signaling (53) and VP11/12 is not required for this effect (72). Therefore the biological function of Lck-dependent tyrosine phosphorylation of VP11/12 offers yet to be defined. It is possible that VP11/12 also interacts with SFKs other than Lck. Robust tyrosine phosphorylation of VP11/12 is definitely observed for infected T and B cells and natural killer.