Activation of the Lck tyrosine-protein kinase by the binding of the tip protein of herpesvirus Saimiri in the absence of regulatory tyrosine phosphorylation

The Tip protein of herpesvirus saimiri 484 binds to the Lck tyrosine-protei n kinase at two sites and activates it dramatically. Lck has been shown pre viously to be activated by either phosphorylation of Tyr(394) or dephosphor ylation of Tyr(505). We examined here whether a change in the phosphorylati on of either site was required for the activation of Lck by Tip. Remarkably , mutation of both regulatory sites of tyrosine phosphorylation did not pre vent activation of Lck by Tip either in vivo or in a cell free in vitro sys tem. Tip therefore appears to be able to activate Lck through an induced co nformational change that does not necessarily involve altered phosphorylati on of the kinase. Tip may represent the prototype of a novel type of regula tor of tyrosine-protein kinases.