title: Regulation of Akt-dependent cell survival by Syk and Rac.
abstract: Interleukin-2 (IL-2) prevents cell apoptosis and promotes survival, but the involved mechanisms have not been completely defined. Although phosphatidylinositide 3-kinase (PI 3-kinase) has been implicated in IL-2-mediated survival mechanisms, none of the 3 chains of the IL-2 receptor (IL-2R) expresses a binding site for PI 3-kinase. However, IL-2Rbeta does express a Syk-binding motif. By using an IL-2-dependent natural killer (NK) cell line, followed by validation of the results in fresh human NK cells, we identified Syk as a critical effector essential for IL-2-mediated prosurvival signaling in NK cells. Down-regulation of Syk by piceatannol treatment impaired NK cellular viability and induced prominent apoptosis as effectively as suppression of PI 3-kinase function by LY294002. Expression of kinase-deficient Syk or pretreatment with piceatannol markedly suppressed IL-2-stimulated activation of PI 3-kinase and Akt, demonstrating that Syk is upstream of PI 3-kinase and Akt. However, constitutively active PI 3-kinase reversed this loss of Akt function caused by kinase-deficient Syk or piceatannol. Thus, Syk appears to regulate PI 3-kinase, which controls Akt activity during IL-2 stimulation. More important, we observed Rac1 activation by IL-2 and found that it mediated PI 3-kinase activation of Akt. This conclusion came from experiments in which dominant-negative Rac1 significantly decreased IL-2-induced Akt activation, whereas constitutively active Rac1 reelevated Akt activity not only in Syk-impaired but also in PI 3-kinase-impaired NK cells. These results constitute the first report of a Syk --> PI3K --> Rac1 --> Akt signal cascade controlled by IL-2 that mediates NK cell survival.
authors.affiliation: Immunology Program, H. Lee Moffitt Cancer Center, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa 33612, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Jiang
authors.forename: Bin
authors.initials: B
authors.lastname: Zhong
authors.forename: Connie
authors.initials: C
authors.lastname: Ritchey
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Gilvary
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hong-Geller
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
authors.forename: Julie Y
authors.initials: JY
authors.lastname: Djeu
mesh_terms: D001773:Blood Cells; D002460:Cell Line; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D000072377:Syk Kinase
chemical_list: D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000072377:Syk Kinase; C000606896:SYK protein, human; C494918:AKT1 protein, human