PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase

Chung, Jongkyeong; Grammer, Timothy C.; Lemon, Katherine P.; Kazlauskas, Andrius; Blenis, John

doi:10.1038/370071a0

Cited by 699 publications

(560 citation statements)

References 28 publications

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“…Rapamycin and wortmannin speci®cally block the phosphorylation and subsequent activation of p70S6K induced by various agonists as shown in p70S6K immunoblot analyses (bottom panels of Figure 2b and c) and as previously reported (Chung et al, 1992(Chung et al, , 1994. Similarly, the S6 kinase activities of SRK stimulated by EGF, PMA, and cycloheximide were strongly inhibited by rapamycin and wortmannin (top panels of Figure 2b and c).…”

supporting

confidence: 80%

“…Recent studies have revealed some of the upstream regulators, which indicate at least two distinct signaling pathways in¯uence p70S6K. One pathway is regulated by PI3K and its downstream e ectors, PDKs and Akt, as revealed by a variety of molecular biological and pharmacological analyses (Chung et al, 1994;Pullen et al, 1998). A separate pathway contributing to p70S6K activation involves the FKBP12-rapamycin-associated protein (FRAP, also known as mTOR, RAFT, and RAPT) and was demonstrated using the immunosuppressant rapamycin (Chung et al, 1992).…”

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confidence: 99%

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Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); A novel nuclear target of Akt

et al. 1999

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Akt is stimulated by several growth factors, and mediates their cell survival signals. Recent studies have shown that Akt may play an intermediate role between phosphatidylinositol 3-kinase (PI3K) and p70 S6 kinase (p70S6K). Here we show that a novel nuclear p70S6K-related kinase (SRK) exists and that its in vivo function is also augmented by over-expression of Akt. Conceptual translation of the SRK cDNA revealed that the catalytic domain of SRK was highly homologous to that of p70S6K, and that the treatment of wortmannin or rapamycin strongly inhibited the phosphorylation and the activation of SRK, as in p70S6K. However, the Nand C-terminal domains of SRK were quite di erent from those of p70S6K. In immunolocalization analyses, we demonstrated a constitutive nuclear localization of SRK and the presence of a nuclear localization signal in its C-terminus. In vitro S6 phosphotransferase activities of SRK were stimulated with a slower kinetics by a variety of agonists to p70S6K. Interestingly, overexpression of the proto-oncogene Akt resulted in EGFindependent activation of SRK, while over-expression of kinase-dead Akt actually had an inhibitory e ect. This relationship between Akt and SRK suggests that SRK may be a novel target of Akt and perhaps an important downstream component in the nuclear function of Akt.

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confidence: 80%

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confidence: 99%

Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); A novel nuclear target of Akt

et al. 1999

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“…Accordingly, the 248, mutant displays lower levels of the PI(3,4,5)P 3 and PI(3,4)P 2 products when compared to wild type MT cell lines. Activation of PI3K leads to activation of pp70 s6k (an essential kinase for G1 progression) in PDGF stimulated (Chung et al, 1994) and MT-transformed cell lines (Dahl et al, 1996). High pp70 S6k activity observed in wild type and 250 MT mutants but not in 315 MT mutants, can be inhibited by wortmannin (Dahl et al, 1996) suggesting di erences in the downstream signals activated by these two MT mutants.…”

Section: Discussionmentioning

confidence: 99%

Mapping of polyomavirus middle T domain that is responsible for AP-1 activation

et al. 1998

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Cell transformation by Polyomavirus middle T (MT) oncoprotein involves binding and activation of several cytoplasmic proteins that participate in growth factorsinduced mitogenic signal transduction to the nucleus. We have previously reported that the AP-1 transcriptional complex is a target for MT during cell transformation. To analyse the interactions between MT and cellular proteins that are required for constitutive AP-1 activation, we compared wild type and transformation-defective MT mutant cell lines. High AP-1 activity, assessed by gel mobility shift assays, displayed by MT-overexpressing cells, is dependent on MT binding to phosphatidylinositol-3 kinase (P13K). Treatment with wortmannin (a speci®c P13K inhibitor) leads to decreased AP-1 activity. Supershift and Western blot analysis with speci®c antisera, indicate that JunB and cJun, but not cFos or FosB are present in the AP-1 complex. The results con®rm the AP-1 complex as a downstream MT target and indicate that AP-1 activation may not be su cient for cell transformation, since two transformation-defective MT mutants (250phe and MT322) display high AP-1 activity.

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“…The former is phosphorylated and activated by insulin in a manner that is dependent on PI 3-kinase [24], whereas the ERK MAP kinases are largely considered to be activated in a process that is independent of PI 3-kinase [25]. Despite a marked increase in the total content of p70S6 kinase in nelfinavir-treated cells, insulin-mediated phosphorylation of this protein on Thr421/Ser424 was blunted (Fig.…”

Section: Nelfinavir Impairs Propagation Of the Insulin Signal Downstrmentioning

confidence: 97%

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

et al. 2004

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Aims/hypothesis. Chronic exposure of 3T3-L1 adipocytes to the HIV protease inhibitor nelfinavir induces insulin resistance, recapitulating key metabolic alterations of adipose tissue in the lipodystrophy syndrome induced by these agents. Our goal was to identify the defect in the insulin signal transduction cascade leading to nelfinavir-induced insulin resistance. Methods. Fully differentiated 3T3-L1 adipocytes were exposed to 30 µmol/l nelfinavir for 18 h, after which the amount, the phosphorylation and the localisation of key proteins in the insulin signalling cascade were evaluated.Results. Insulin-induced interaction of phosphatidylinositol 3′-kinase (PI 3-kinase) with IRS proteins was normal in cells treated with nelfinavir, as was IRS-1-associated PI 3-kinase activity. Yet insulin-induced phosphorylation of Akt/protein kinase B (PKB), p70S6 kinase and extracellular signal-regulated kinase 1/2 was significantly impaired. This could not be attributed to increased protein phosphatase 2A activity or to increased expression of phosphoinositide phosphatases (SHIP2 or PTEN). However, insulin failed to induce translocation of the PI 3-kinase effectors Akt/PKB and protein kinase C-ζ (PKC-ζ) to plasma membrane fractions of nelfinavir-treated adipocytes. Conclusions/interpretation. We therefore conclude that nelfinavir induces a defect in the insulin signalling cascade downstream of the activation of PI 3-kinase. This defect manifests itself by impaired insulin-mediated recruitment of Akt/PKB and PKC-ζ to the plasma membrane.

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PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase

Cited by 699 publications

References 28 publications

Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); A novel nuclear target of Akt

Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); A novel nuclear target of Akt

Mapping of polyomavirus middle T domain that is responsible for AP-1 activation

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

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