Cloning and Characterization of a G Protein-Activated Human Phosphoinositide-3 Kinase

Stoyanov, Borislav; Volinia, Stefano; Hanck, Theodor; Rubio, Ignacio; Loubtchenkov, Michael; Malek, Daria; Stoyanova, Stefka; Vanhaesebroeck, Bart; Dhand, Ritu; Nürnberg, Bernd; Gierschik, Peter; Seedorf, Klaus; Hsuan, J. Justin; Waterfield, Michael D.; Wetzker, Reinhard

doi:10.1126/science.7624799

Cited by 651 publications

(518 citation statements)

References 30 publications

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“…After preliminary screening with phospho-specific antibodies against different signal molecules, we found that the phosphorylation of Akt (Ser473) was consistently elevated in the LNCaP-R273H subline (Figure 1). The data are in agreement with the ability of the Gbg subunits of GPCR to activate PI3K/Akt (Stoyanov et al, 1995;Murga et al, 1998). We noted that a basal level of phospho-Akt was detected in parental LNCaP, presumably due to the inactivating mutation of PTEN in this cell line (Vlietstra et al, 1998).…”

Section: H2-relaxin Induces Activation Of Akt and The Phosphorylationsupporting

confidence: 83%

Inappropriate activation of androgen receptor by relaxin via β-catenin pathway

Liu¹,

Vinall²,

Tepper³

et al. 2007

Oncogene

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We have previously demonstrated that human H2-relaxin can mediate androgen-independent growth of LNCaP through a mechanism that involves the activation of the androgen receptor (AR) signaling pathway. The goal of the current study is to elucidate the mechanism(s) by which H2-relaxin causes activation of the AR pathway. Our data indicate that there is cross-talk between AR and components of the Wnt signaling pathway. Addition of H2-relaxin to LNCaP cells resulted in increased phosphorylation of protein kinase B (Akt) and inhibitory phosphorylation of glycogen synthase kinase-3b (GSK-3b) with subsequent cytoplasmic accumulation of b-catenin. Immunoprecipitation and immunocytochemical studies demonstrated that the stabilized b-catenin formed a complex with AR, which was then translocated into the nucleus. Chromatin immunoprecipitation analysis determined that the AR/b-catenin complex binds to the proximal region of the prostatespecific antigen promoter. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, using LY294002, prevented both H2-relaxin-mediated phosphorylation of Akt and GSK-3b and translocation of b-catenin/AR into the nucleus. Knockdown of b-catenin levels using a b-cateninspecific small interfering RNA inhibited H2-relaxin-induced AR activity. The combined data demonstrate that PI3K/ Akt and components of the Wnt pathway can facilitate H2-relaxin-mediated activation of the AR pathway.

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Section: H2-relaxin Induces Activation Of Akt and The Phosphorylationsupporting

confidence: 83%

Inappropriate activation of androgen receptor by relaxin via β-catenin pathway

Liu¹,

Vinall²,

Tepper³

et al. 2007

Oncogene

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“…There is a growing awareness that wortmannin inhibits also other types of enzymes apart from PI3-kinase. Elevated levels of phosphatidyl inositol 3,4,5 trisphosphate (PIP 3 ) is seen both as a result of activation of PI3-kinase, and of the G-protein-coupled p110g (Stoyanov et al, 1995). It cannot be excluded that FGFR-1 communicates with G-protein-coupled signal transduction pathways to induce p110g activity, and that wortmannin in our model inhibits p110g and in consequence, cellular migration.…”

Section: Discussionmentioning

confidence: 84%

Fibroblast growth factor receptor-1 mediates chemotaxis independently of direct SH2-domain protein binding

et al. 1998

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Endothelial cells expressing ®broblast growth factor receptor-1 (FGFR-1) migrate and proliferate in response to treatment with FGF. We analysed ligand-induced migration and proliferation of porcine aortic endothelial cells expressing wild-type FGFR-1, point-mutated Y766F FGFR-1, unable to activate phospholipase C-g1 (PLCg1), or carboxyl-terminally truncated FGFR-1, lacking either 48 (from amino acid 774 in the FGFR-1 sequence) or 63 (from amino acid 759) amino acid residues of the C-terminal tail. The truncated CT63 FGFR-1 mutant failed to mediate chemotaxis, but was in response to ligand stimulation capable of mediating proliferation of the cells, stimulation of MAP kinase activity and tyrosine phosphorylation of FRS2, an FGFR-1 speci®c signaling molecule. The defect in migration-capacity of CT63 was not due to loss of Y766, and thereby PLC-g1 activation, since cells expressing the mutant Y766F FGFR-1 migrated as e ciently as the wild-type receptor cells. Induction of phospholipase A 2 (PLA 2 ) activity by the activated FGFR-1 was dependent on the presence of Y766, and was therefore also not critical for the chemotactic response. Although the FGFR-1 only very ine ciently mediates activation of phosphatidylinositol 3' kinase (PI 3-kinase), the PI 3-kinase inhibitor wortmannin suppressed wild-type FGFR-1 mediated migration. We conclude that the signal transduction pathway for FGFR-1 mediated migration is independent of phosphotyrosine residues in the receptor and requires activation of a wortmannin-sensitive enzyme.

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“…The observed stimulation of the PI-3 kinase and Akt signalling pathway is not necessarily contradictory to the proposed G-protein involvement. Stimulation of G i / G o -protein-coupled receptors may result in activation of PI-3 kinase-γ via its association with the dissociated βγ subunits of the G-protein complex [33,34]. Notably, PI-3 kinase-γ is highly expressed in kidney proximal tubular cells [35].…”

Section: Discussionmentioning

confidence: 99%