Differential Regulation by Calcium Reveals Distinct Signaling Requirements for the Activation of Akt and p70S6k

Conus, Nelly; Hemmings, Brian A.; Pearson, Richard B.

doi:10.1074/jbc.273.8.4776

Cited by 112 publications

(106 citation statements)

References 51 publications

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“…Thus PI-3K-mediated p70 S'K activation may well occur via alternative pathways. In support of this, certain agonists can differentially induce PKB and p70 S'K [94].…”

Section: Protein Synthesismentioning

confidence: 75%

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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“…Thus PI-3K-mediated p70 S'K activation may well occur via alternative pathways. In support of this, certain agonists can differentially induce PKB and p70 S'K [94].…”

Section: Protein Synthesismentioning

confidence: 75%

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

Coffer

Jin

Woodgett

1998

Biochemical Journal

990

818

View full text Add to dashboard Cite

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“…Although it seems contradictory that both EGTA and thapsigargin elicit apoptosis, the important factor may be the change in intracellular architecture caused by the depletion of intracellular stores, rather than changes in cytosolic Ca2+. Ca2+ is slowly lost from the intracellular stores of cells exposed to millimolar concentrations of EGTA (Conus et al, 1998). In addition, in preliminary experiments we found that BAPTNAM, a cell-permeant intracellular Ca2+ chelator, mediated concentration-dependent activation of caspase-3-like proteases and provided no protection against thapsigargin-mediated cell death in SH-SY5Y cells (unpublished data).…”

Section: Discussionmentioning

confidence: 89%

Alterations of Extracellular Calcium Elicit Selective Modes of Cell Death and Protease Activation in SH‐SY5Y Human Neuroblastoma Cells

McGinnis¹,

Wang²,

Gnegy³

1999

Journal of Neurochemistry

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Abstract:The role of intracellular Ca2+ homeostasis in mechanisms of neuronal cell death and cysteine protease activation was investigated in SH-SY5Y human neuroblastoma cells. Cells were incubated in 2 mM EGTA to lower intracellular Ca2+ or 5 mM CaCI, to raise it. Cell death and activation of calpain and caspase-3 were measured. Both EGTA and excess CaCI, elicited cell death. EGTA induced DNA laddering and an increase in caspase-3-like, but not calpain, activity. Pan-caspase inhibitors protected against EGTA-, but not CaCI,-, induced cell death. Conversely, excess Ca2+ elicited necrosis and activated calpain but not caspase-3. Calpain inhibitors did not preserve cell viability. Ca2+ was the death-mediating factor, because restoration of extracelMar Ca2+ protected against cell death induced by EGTA and blockade of Ca2+ channels by Ni'+ protected against that induced by high Ca2+. We conclude that the EGTA treatment lowered intracellular Ca2+ and elicited caspase-3-like protease activity, which led to apoptosis. Conversely, excess extracellular Ca2+ entered Ca2+ channels and increased intracellular Ca2+ leading to calpain activation and necrosis. The mode of cell death and protease activation in response to changing Ca2+ were selective and mutually exclusive, demonstrating that these are useful models to individually investigate apoptosis and necrosis. Key Words: Apoptosis-Necrosis-Calpain-Caspase-3-Ca2+ homeostasis-Neuronal death.

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“…This glucosestimulated activation of S6K1 is possibly mediated by increased ATP supply and reduced AMPK activation. Dominant-negative suppression of HNF1A has also been shown to reduce glucose-induced Ca 2+ signalling in INS-1 cells [21], an event that may also contribute to the early inactivation of S6K1 and its partial rescue by high glucose, as increased intracellular Ca 2+ concentrations have been shown to activate S6K1 but not AKT1 [45]. MAP kinase signalling pathways in particular are activated by increasing glucose and Ca 2+ concentrations [46,47].…”

Section: Resultsmentioning

confidence: 99%

Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-α (HNF1A) function in INS-1 insulinoma cells

et al. 2008

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Aims/hypothesis Mutations in the HNF1A (previously known as TCF1) gene encoding hepatocyte nuclear factor-1α (HNF1A) lead to the development of maturity-onset diabetes of the young, type 3 (HNF1A-MODY), characterised by impaired insulin secretion and a reduction in beta cell mass. HNF1A plays an important role in pancreatic beta cell differentiation and survival. The mammalian target of rapamycin (mTOR) is a central growth factor-and nutrientactivated protein kinase controlling cell metabolism, growth and survival. We investigated the role of mTOR inactivation in the decline in beta cell mass in a cellular model of HNF1A-MODY. Methods Previously we showed that suppression of HNF1A function via expression of a dominant-negative mutant (DN-HNF1A) decreases insulin gene transcription in insulinoma (INS-1) cells. We investigated the signalling of two distinct mTOR protein complexes, mTORC1 and mTORC2, in response to DN-HNF1A induction.Results We observed delayed inactivation of mTORC2 48 h after DN-HNF1A induction, evidenced by a reduction in serine 473 phosphorylation of thymoma viral protooncogene 1 (AKT1). We also observed an early inactivation of mTORC1 24 h after DN-HNF1A induction, which was detected by decreases in threonine 389 phosphorylation of p70 ribosomal protein S6 kinase (S6K1) and serine 65 phosphorylation of translational inhibitor eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). Flow cytometry and gene expression analysis demonstrated a preapoptotic decrease in INS-1 cell size in response to DN-HNF1A induction, and an increase in the level of the mTORC1-regulated cell-cycle inhibitor, cyclin-dependent kinase inhibitor 1B p27. Conclusions/interpretation Our data suggest that mTOR kinase and signalling through mTORC1 are highly sensitive to suppression of HNF1A function, and may contribute to disturbance of cell-size regulation and cell-cycle progression in HNF1A-MODY.

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Differential Regulation by Calcium Reveals Distinct Signaling Requirements for the Activation of Akt and p70S6k

Cited by 112 publications

References 51 publications

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

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

Alterations of Extracellular Calcium Elicit Selective Modes of Cell Death and Protease Activation in SH‐SY5Y Human Neuroblastoma Cells

Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-α (HNF1A) function in INS-1 insulinoma cells

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