Phosphorylation and Activation of p70
            <sup>s6k</sup>
            by PDK1

Pullen, Nick; Dennis, Patrick B.; Andjelković, Mirjana; Dufner, Almut; Kozma, Sara C.; Hemmings, Brian A.; Thomas, George

doi:10.1126/science.279.5351.707

Cited by 767 publications

(561 citation statements)

References 13 publications

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“…However, our data indicate that expression of Tcl1 does not increase the Akt1-mediated phosphorylation of Bad, p70 S6 kinase, or I B (11,16,17) (not shown).…”

Section: Resultsmentioning

confidence: 45%

Tcl1 enhances Akt kinase activity and mediates its nuclear translocation

Pekarsky

Koval

Hallas

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

304

255

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The TCL1 oncogene at 14q32.1 is involved in the development of human mature T-cell leukemia. The mechanism of action of Tcl1 is unknown. Because the virus containing the v-akt oncogene causes T-cell lymphoma in mice and Akt is a key player in transduction of antiapoptotic and proliferative signals in T-cells, we investigated whether Akt and Tcl1 function in the same pathway. Coimmunoprecipitation experiments showed that endogenous Akt1 and Tcl1 physically interact in the T-cell leukemia cell line SupT11; both proteins also interact when cotransfected into 293 cells. Using several AKT1 constructs in cotransfection experiments, we determined that this interaction occurs through the pleckstrin homology domain of the Akt1 protein. We further demonstrated that, in 293 cells transfected with TCL1, the endogenous Akt1 bound to Tcl1 is 5-10 times more active compared with Akt1 not bound to Tcl1. The intracellular localization of Tcl1 and Akt1 in mouse fibroblasts was investigated by immunofluorescence. When transfected alone, Akt1 was found only in cytoplasm whereas Tcl1 was localized in the cytoplasm and in the nucleus. Interestingly, Akt1 was also found in the nucleus when AKT1 was cotransfected with TCL1, suggesting that Tcl1 promotes the transport of Akt1 to the nucleus. These findings were supported by the intracellular localization of Akt1 or Tcl1 when Tcl1 or Akt1, respectively, were confined to the specific cellular compartments. Thus, we demonstrate that Tcl1 is a cofactor of Akt1 that enhances Akt1 kinase activity and promotes its nuclear transport.

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“…However, our data indicate that expression of Tcl1 does not increase the Akt1-mediated phosphorylation of Bad, p70 S6 kinase, or I B (11,16,17) (not shown).…”

Section: Resultsmentioning

confidence: 45%

Tcl1 enhances Akt kinase activity and mediates its nuclear translocation

Pekarsky

Koval

Hallas

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

304

255

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“…Finally, the PDK1-S6K1 interaction is competed by an H-motif surrogate phosphopeptide, suggesting that PDK1 interacts with the phosphorylated H-motif of S6K1 and that this event increases the efficiency with which PDK1 phosphorylates the T-loop of S6K1. Given that the kinase activity of PDK1 is not increased by growth factors or stimuli that induce PI3K activation (24,41), and given that PDK1 and S6K1 are constitutively associated when expressed in cells (42), it is plausible that loss of Tsc1 or Tsc2, through activation of Rheb, induces H-motif phosphorylation. The phosphorylated H-motif is then recognized by PDK1, which facilitates T-loop phosphorylation of S6K1.…”

Section: Discussionmentioning

confidence: 99%

“…23). In mitogen-stimulated cells, S6K1 is phosphorylated at the T-loop site, Thr-229, by PDK1 (24,25). A phosphopeptide modeled after the phosphorylated H-motif of S6K1 binds much more efficiently to PDK1 than the unphosphorylated peptide (26), potentially explaining the strongly synergistic nature of H-motif and T-loop phosphorylation of S6K1.…”

mentioning

confidence: 99%

Critical Role of T-Loop and H-Motif Phosphorylation in the Regulation of S6 Kinase 1 by the Tuberous Sclerosis Complex

Shah¹,

Hunter

2004

Journal of Biological Chemistry

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The tuberous sclerosis gene products Tsc1 and Tsc2 behave as tumor suppressors by restricting cell growth, a function conserved among metazoans. Recent evidence has indicated that hyperactivation of S6 kinase 1 (S6K1) may represent an important biochemical change in the development of tuberous sclerosis-associated lesions. We show here that deletion of either Tsc1 or Tsc2 or expression of the Rheb (Ras homolog enriched in brain) GTPase leads to hyperphosphorylation of S6K1 at a subset of regulatory sites, particularly those of two essential residues functionally conserved among AGC superfamily serine/threonine kinases, i.e. the activation loop (T-loop; Thr-229) and the hydrophobic motif (Hmotif; Thr-389). These sites are reciprocally and dose-dependently regulated when S6K1 is coexpressed with the Tsc1-Tsc2 complex. Mutations that render S6K1 mTOR (mammalian target of rapamycin)-resistant also protect S6K1 activity and phosphorylation from down-regulation by Tsc1/2. We demonstrate that two disease-associated mutations in Tsc2 fail to negatively regulate S6K1 activity concomitant with a failure to modify T-loop and H-motif phosphorylation. Finally, we identify one pathological Tsc2 mutation that retains its ability to negatively regulate S6K1, suggesting that, in some cases, tuberous sclerosis may develop independently of S6K1 hyperactivation. These results also highlight the importance of dual control of T-loop and H-motif phosphorylation of S6K1 by the Tsc1-Tsc2 complex.

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“…The situation is likely to be more complicated, however, since PDK1 has recently been shown to be capable of inducing p70 S'K activation independently of PKB [92,93]. Thus PI-3K-mediated p70 S'K activation may well occur via alternative pathways.…”

Section: Protein Synthesismentioning

confidence: 99%

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

Coffer

Jin

Woodgett

1998

Biochemical Journal

990

818

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While a plethora of extracellular molecules exist that modulate cellular functions via binding to membrane receptors inside the cell, their actions are mediated by relatively few signalling mechanisms. One of these is activation of phosphatidylinositol 3-kinase (PI-3K), which results in the generation of a membranerestricted second messenger, polyphosphatidylinositides containing a 3h-phosphate. How these molecules transduced the effects of agonists of PI-3K was unclear until the recent discovery that several protein kinases become activated upon exposure to 3h-phosphorylated inositol lipids. These enzymes include protein kinase B (PKB)\AKT and PtdIns(3,4,5)P $ -dependent kinases 1 and 2, the first two of which interact with 3h-phosphorylated ORIGINS OF AKTThe AKR strain of mice exhibit a high incidence of leukaemias and lymphomas from spontaneous thymoma [1]. A retrovirus termed AKT8 was isolated from one of these lines derived from a spontaneous thymoma. This virus was demonstrated to uniquely transform only mink lung cells (CCL64) in culture, while virus inoculated into newborn mice was shown to be tumorigenic [2]. The non-viral DNA component transduced from the mouse genome was subsequently identified, and two human homologues, AKT1 and AKT2, cloned [3]. The location of the human AKT locus was mapped to chromosome 14q32, proximal to the immunoglobulin-heavy-chain locus [4], a region frequently affected by translocations and inversions in human Tcell leukaemia\lymphoma, mixed-lineage childhood leukaemia and clonal T-cell proliferations in ataxia telangiectasia, supporting a role for this oncogene in formation of a variety of tumours [5]. Analysis of a panel of human tumours revealed a 20-fold amplification of AKT1 in a primary gastric adenocarcinoma. AKT2, on the other hand, was mapped to chromosome region 19q13.1-q13.2 and shown to be amplified and overexpressed in several ovarian carcinoma and pancreatic cancer cell lines [6,7]. A recent large-scale study of AKT2 alterations in ovarian and breast tumours revealed amplification in 12.1 % ovarian and 2.8 % breast carcinomas [8]. Furthermore, amplification of AKT2 was especially frequent in undifferentiated tumours, suggesting that AKT2 alterations may be associated with tumour aggressiveness.Abbreviations used : PI-3K, phosphatidylinositol 3-kinase ; PKB, protein kinase B ; PKA, protein kinase A ; PKC, protein kinase C ; RAC-PK, related to A-and C-kinase ; PH, pleckstrin homology ; PtdIns, phosphoinositide ; PDGF, platelet-derived growth factor ; EGF, epidermal growth factor ; bFGF, basic fibroblast growth factor ; IL, interleukin ; ERK, extracellular-signal-regulated kinase ; Btk, Bruton tyrosine kinase ; PDK, PtdIns(3,4,5)P 3 -dependent kinase ; MAPKAP, mitogen-activated protein kinase-activated protein ; SH2, Src homology 2 ; gag, group-specific antigen ; GLUT, glucose transporter ; GSK, glycogen synthase kinase ; PFK2, 6-phosphofructose-2-kinase ; IGF, insulin-like growth factor ; 4E-BP1, 4E-binding protein ; PHAS, pH-and acid-stable ; BCR-ABL, breakpoint...

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Phosphorylation and Activation of p70 ^s6k by PDK1

Cited by 767 publications

References 13 publications

Tcl1 enhances Akt kinase activity and mediates its nuclear translocation

Tcl1 enhances Akt kinase activity and mediates its nuclear translocation

Critical Role of T-Loop and H-Motif Phosphorylation in the Regulation of S6 Kinase 1 by the Tuberous Sclerosis Complex

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

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Phosphorylation and Activation of p70 s6k by PDK1

Cited by 767 publications

References 13 publications

Tcl1 enhances Akt kinase activity and mediates its nuclear translocation

Tcl1 enhances Akt kinase activity and mediates its nuclear translocation

Critical Role of T-Loop and H-Motif Phosphorylation in the Regulation of S6 Kinase 1 by the Tuberous Sclerosis Complex

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

Contact Info

Product

Resources

About

Phosphorylation and Activation of p70 ^s6k by PDK1