Agonists cause nuclear translocation of phosphatidylinositol 3-kinase gamma. A Gbetagamma-dependent pathway that requires the p110gamma 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 p110gamma (or PI3Kgamma) is associated with the regulatory subunit, p101, and is stimulated by G protein betagamma heterodimers. We performed immunolocalization of transfected p110gamma in HepG2 cells and found that, under resting conditions, p110gamma was present in a diffuse cytoplasmic pattern, but translocated to the cell nucleus after serum stimulation. Serum-stimulated p110gamma translocation was inhibited by pertussis toxin and could also be induced by overexpression of Gbetagamma in the absence of serum. In addition, we found that deletion of the amino-terminal 33 residues of p110gamma had no effect on association with p101 or on its agonist-regulated translocation, but truncation of the amino-terminal 82 residues yielded a p110gamma variant that did not associate with p101 and was constitutively localized in the nucleus. This finding implies that the intracellular localization of p110gamma is regulated by p101 as well as Gbetagamma. The effect of PI3Kgamma in the nucleus is an area of active investigation.
Metjian
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Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D006528:Carcinoma, Hepatocellular; D002467:Cell Nucleus / Q000201:enzymology*; D003001:Cloning, Molecular; D016895:Culture Media, Serum-Free; D000939:Epitopes / Q000737:chemistry; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D016895:Culture Media, Serum-Free; D000939:Epitopes; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins