Roles of phosphatidylinositol 3-kinase in interferon-gamma-dependent phosphorylation of STAT1 on serine 727 and activation of gene expression

STAT1 must be phosphorylated on serine 727 to be fully active in transcript ion. We show that phosphatidylinositol 3-kinase (PI3K) and its effector kin ase Akt play an important role in the serine phosphorylation of STAT1 and i n the activation of gene expression in response to interferon-gamma (IFN ga mma). IFN gamma activates PI3K as well as Akt in a variety of cell lines. S pecific inhibition of PI3K abrogates IFN gamma -induced, but not interleuki n-1- or tumor necrosis factor-a-induced, phosphorylation of STAT1. on serin e and reduces STAT1-dependent transcription and gene expression by similar to7-fold. Constitutively active forms of P13K or Akt activate and their dom inant-negative derivatives inhibit STAT1-driven transactivation in response to IFN gamma. In addition to PI3K and Akt, JAK1, JAK2, and the tyrosine 44 0 STAT1 docking residue of IFNGR1 are required for STAT1 to be phospho. ryl ated on serine. Taken together, these results suggest that the following ev ents lead to the activation of STAT1 upon IFN gamma stimulation: 1) P13K an d Akt are activated by the occupied receptor and Tyr-440 is phosphorylated by the activated JAKs; 2) STAT1 docks to Tyr-440; and 3) Tyr-701 is phospho rylated by the JAKs and Ser-727 is phosphorylated by a kinase downstream of Akt.