Agonists cause nuclear translocation of phosphatidylinositol 3-kinase γ -: A Gβγ-dependent pathway that requires the p110-γ amino terminus

In hematopoietic cells, the signals initiated by activation of the phosphoinositide 3-kinase (PI3K) family have been implicated in cell proliferation and survival, membrane and cytoskeletal reorganization, chemotaxis, and the neutrophil respiratory burst. Of the four isoforms of human PI3K that phosphorylate phosphatidylinositol 4,5-bisphosphate, only p110 gamma (or PI3K gamma) is associated with the regulatory subunit, p101, and is stimulated by G protein beta gamma heterodimers. We performed immunolocalization of transfected p110 gamma in HepG2 cells and found that, under resting conditions, p110 gamma was present in a diffuse cytoplasmic pattern, but translocated to the cell nucleus after serum stimulation. Serum-stimulated p110 gamma translocation was inhibited by pertussis toxin and could also be induced by overexpression of G beta gamma in the absence of serum. In addition, we found that deletion of the amino-terminal 33 residues of p110 gamma had no effect on association with p101 or on its agonist-regulated translocation, but truncation of the amino-terminal 82 residues yielded a p110 gamma variant that did not associate with p101 and was constitutively localized in the nucleus. This finding implies that the intracellular localization of p110 gamma is regulated by p101 as well as G beta gamma. The effect of PI3K gamma in the nucleus is an area of active investigation.