The Regulation and Activities of the Multifunctional Serine/Threonine Kinase Akt/PKB

doi:10.1006/excr.1999.4690

Experimental Cell Research

Volume 253, Issue 1, 25 November 1999, Pages 210-229

https://doi.org/10.1006/excr.1999.4690 Get rights and content

Abstract

The serine/threonine kinase Akt, or protein kinase B (PKB), has recently been a focus of intense research. It appears that Akt/PKB lies in the crossroads of multiple cellular signaling pathways and acts as a transducer of many functions initiated by growth factor receptors that activate phosphatidylinositol 3-kinase (PI 3-kinase). Akt/PKB is particularly important in mediating several metabolic actions of insulin. Another major activity of Akt/PKB is to mediate cell survival. In addition, the recent discovery of the tumor suppressor PTEN as an antagonist of PI 3-kinase and Akt/PKB kinase activity suggests that Akt/PKB is a critical factor in the genesis of cancer. Thus, elucidation of the mechanisms of Akt/PKB regulation and its physiological functions should be important for the understanding of cellular metabolism, apoptosis, and cancer.

References (191)

M. Andjelkovic et al.
Developmental regulation of expression and activity of multiple forms of the Drosophila RAC protein kinase
J. Biol. Chem.
(1995)
T.F. Franke et al.
The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase
Cell
(1995)
D. Brodbeck et al.
A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain
J. Biol. Chem.
(1999)
K. Nakatani et al.
Identification of a human Akt3 (protein kinase B γ) which contains the regulatory serine phosphorylation site
Biochem. Biophys. Res. Commun.
(1999)
M. Andjelkovic et al.
Role of translocation in the activation and function of protein kinase B
J. Biol. Chem.
(1997)
M.J. Aman et al.
The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells
J. Biol. Chem.
(1998)
H. Banfic et al.
A novel integrin-activated pathway forms PKB/Akt-stimulatory phosphatidylinositol 3,4-bisphosphate via phosphatidylinositol 3-phosphate in platelets
J. Biol. Chem.
(1998)
B. Tilton et al.
G-protein-coupled receptors and Fcgamma-receptors mediate activation of Akt/protein kinase B in human phagocytes
J. Biol. Chem.
(1997)
C. Murga et al.
Activation of Akt/protein kinase B by G protein-coupled receptors. A role for alpha and beta gamma subunits of heterotrimeric G proteins acting through phosphatidylinositol-3-OH kinasegamma
J. Biol. Chem.
(1998)
R.D. Polakiewicz et al.
mu-Opioid receptor activates signaling pathways implicated in cell survival and translational control
J. Biol. Chem.
(1998)

M. Ushio-Fukai et al.

Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells

J. Biol. Chem.

(1999)

D.R. Alessi et al.

Molecular basis for the substrate specificity of protein kinase B: Comparison with MAPKAP kinase-1 and p70 S6 kinase

Fed. Eur. Biochem. Soc.

(1996)

D. Alessi et al.

Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα

Curr. Biol.

(1997)

D.R. Alessi et al.

3-Phosphoinositide-dependent protein kinase-1 (PDK1): Structural and functional homology with the Drosophila DSTPK61 kinase

Curr. Biol.

(1997)

K.E. Anderson et al.

Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B

Curr. Biol.

(1998)

A. Balendran et al.

PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2

Curr. Biol.

(1999)

R. Meier et al.

Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase B beta

J. Biol. Chem.

(1997)

T. Maehama et al.

The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate

J. Biol. Chem.

(1998)

V. Stambolic et al.

Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN

Cell

(1998)

S. Ogg et al.

The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway

Mol. Cell.

(1998)

T. Habib et al.

Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein

J. Biol. Chem.

(1998)

H. Ishihara et al.

Molecular cloning of rat SH2-containing inositol phosphatase 2 (SHIP2) and its role in the regulation of insulin signaling

Biochem. Biophys. Res. Commun.

(1999)

C.L. Sable et al.

cAMP stimulates protein kinase B in a Wortmannin-insensitive manner

FEBS Lett.

(1997)

H. Konishi et al.

Activation of protein kinase B (Akt/RAC-protein kinase) by cellular stress and its association with heat shock protein Hsp27

FEBS Lett.

(1997)

S.K. Moule et al.

Regulation of protein kinase B and glycogen synthase kinase-3 by insulin and beta-adrenergic agonists in rat epididymal fat cells. Activation of protein kinase B by wortmannin-sensitive and -insensitive mechanisms

J. Biol. Chem.

(1997)

P. Carmeliet et al.

Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis

Cell

(1999)

J. Deprez et al.

Phosphorylation and activation of heart 6-phosphofucto-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades

J. Biol. Chem.

(1997)

N. Sonenberg et al.

The mRNA 5′ cap-binding protein eIF4E and control of cell growth

Curr. Opin. Cell Biol.

(1998)

S.P. Staal et al.

Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma

Proc. Natl. Acad. Sci. USA

(1977)

A. Bellacosa et al.

A retroviral oncogene, akt, encoding a serine/threonine kinase containing an SH2-like region

Science

(1991)

P.J. Coffer et al.

Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families

Eur. J. Biochem.

(1991)

P.F. Jones et al.

Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily

Proc. Natl. Acad. Sci. USA

(1991)

P. Chen et al.

A pair of putative protein kinase genes (YPK1 and YPK2) is required for cell growth in Saccharomyces cerevisiae

Mol. Gen. Genet.

(1993)

T.F. Franke et al.

The SH2-like Akt homology (AH) domain of c-akt is present in multiple copies of the genome of vertebrate and invertebrate eucaryotes: Cloning and characterization of the Drosophila melanogaster c-akt homolog Dakt1

Oncogene

(1994)

H.W. Chang et al.

Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase

Science

(1997)

S. Paradis et al.

Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor

Genes Dev.

(1998)

R. Meili et al.

Chemoattractant-mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium

EMBO J.

(1999)

K. Tanaka et al.

Identification of protein kinase B (PKB) as a phosphatidylinositol 3,4,5-trisphosphate binding protein in Dictyostelium discoideum

Biosci. Biotechnol. Biochem.

(1999)

B.M. Burgering et al.

Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction

Nature

(1995)

D.A. Cross et al.

Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B

Nature

(1995)

H. Dudek et al.

Regulation of neuronal survival by the serine–threonine protein kinase Akt

Science

(1997)

A. Kauffmann-Zeh et al.

Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB

Nature

(1997)

S.G. Kennedy et al.

The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal

Genes Dev.

(1997)

G. Kulik et al.

Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt

Mol. Cell. Biol.

(1997)

P.F. Jones et al.

Molecular cloning of a second form of rac protein kinase

Cell Regul.

(1991)

D.A. Altomare et al.

Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene

Oncogene

(1995)

H. Konishi et al.

Activation of RAC-protein kinase by heat shock and hyperosmolarity stress through a pathway independent of phosphatidylinositol 3-kinase

Proc. Natl. Acad. Sci. USA

(1996)

M.K. Webster et al.

Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum

Mol. Cell. Biol.

(1993)

T. Kobayashi et al.

Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2

Biochem. J.

(1999)

A. Casamayor et al.

Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast

Curr. Biol.

(1999)

Cited by (807)

Possible role of miRNAs in pheochromocytoma pathology - Signaling pathways interaction
2023, Pathology Research and Practice
Pheochromocytoma (PCC) is a type of neuroendocrine tumor that originates from adrenal medulla or extra-adrenal chromaffin cells and results in the production of catecholamine. Paroxysmal hypertension and cardiovascular crises were among the clinical signs experienced by people with PCC. Five-year survival of advanced-stage PCC is just around 40% despite the identification of various molecular-level fundamentals implicated in these pathogenic pathways. MicroRNAs (miRNAs, miRs) are a type of short, non-coding RNA (ncRNA) that attach to the 3′-UTR of a target mRNA, causing translational inhibition or mRNA degradation. Evidence is mounting that miRNA dysregulation plays a role in the development, progression, and treatment of cancers like PCC. Hence, this study employs a comprehensive and expedited survey to elucidate the potential role of miRNAs in the development of PCC, surpassing their association with survival rates and treatment options in this particular malignancy.
Phosphoinositide 3-kinase as a therapeutic target in angiogenic disease
2023, Experimental Eye Research
Phosphoinositide 3-kinases (PI3Ks) generate lipids that control multitudinous intracellular cell signaling events which participate in cell survival and proliferation. In addition, PI3K signaling also contributes to metabolism, immunity, angiogenesis and cardiovascular homeostasis, and many diseases. The diverse actions of PI3K stem from the existence of their various isoforms and a variety of protein effectors. Hence, PI3K isoform-specific inhibitors have already achieved a wonderful effect on treating cancer. Herein, we summarize the molecular mechanism of PI3K inhibitors in preventing the permeability of vessels and neovascularization. Additionally, we briefly illustrate how PI3K signaling modulates blood vessel growth and discuss the different roles that PI3K isoforms play in angiogenesis.
Decoding the role of miRNAs in multiple myeloma pathogenesis: A focus on signaling pathways
2023, Pathology Research and Practice
Multiple myeloma (MM) is a cancer of plasma cells that has been extensively studied in recent years, with researchers increasingly focusing on the role of microRNAs (miRNAs) in regulating gene expression in MM. Several non-coding RNAs have been demonstrated to regulate MM pathogenesis signaling pathways. These pathways might regulate MM development, apoptosis, progression, and therapeutic outcomes. They are Wnt/β-catenin, PI3K/Akt/mTOR, P53 and KRAS. This review highlights the impending role of miRNAs in MM signaling and their relationship with MM therapeutic interventions.
Mechanisms of solid lipid nanoparticles-triggered signaling pathways in eukaryotic cells
2022, Colloids and Surfaces B: Biointerfaces
Solid lipid nanoparticles (SLN) are used in various fields such as pharmaceutical, cosmetic, and biomedical research and show promising results in delivering biomolecules. SLN formulations are made with solid lipids (at room and body temperature) stabilized with surfactants and co-surfactants that may guarantee specific properties. Typically, these compounds have high stability, allow large-scale production, and are biodegradable. Since most of these SLNs are formulated with biodegradable materials, they are assumed to have low toxicity or are nontoxic. Therefore, this assumption introduced experimental bias, making SLN toxicity an often overlooked area; moreover, few studies have focused on this topic. Here, we critically review the literature, focusing on blank controls (i.e., SLN formulations without cargo) and their ability to trigger signaling pathways, cellular outcomes, and cytotoxicity. We found that SLN can trigger or disturb many cell signaling pathways; thus, we emphasize the importance of testing the biocompatibility and cytotoxicity of empty SLN. Overall, more attention should be paid to the possible cytotoxic effects of SLN, which is still an open topic, showing that this topic needs further investigation. Therefore, a detailed understanding of SLN toxicity, particularly for biomedical applications, can significantly impact the transfer of SLN formulations from the laboratory bench to the bedside.
D-aspartate and N-methyl-D-aspartate promote proliferative activity in mouse spermatocyte GC-2 cells
2022, Reproductive Biology
D-Aspartate (D-Asp) and its methylated form N-methyl-d-aspartate (NMDA) promote spermatogenesis by stimulating the biosynthesis of sex steroid hormones. d-Asp also induces spermatogonia proliferation directly by activating the ERK/Aurora B pathway. In the present study, a mouse spermatocyte-derived cell line (GC-2) which represents a stage between preleptotene spermatocyte and round spermatids was exposed to 200 μM d-Asp or 50 μM NMDA for 30 min, 2 h, and 4 h to explore the influence of these amino acids on cell proliferation and mitochondrial activities occurring during this process. By Western blotting analyses, the expressions of AMPAR (GluA1-GluA2/3 subunits), cell proliferation as well as mitochondria functionality markers were determined at different incubation times. The results revealed that d-Asp or NMDA stimulate proliferation and meiosis in the GC-2 cells via the AMPAR/ERK/Akt pathway, which led to increased levels of the PCNA, p-H3, and SYCP3 proteins. The effects of d-Asp and NMDA on the mitochondrial functionality of the GC-2 cells strongly suggested an active role of these amino acids in germ cell maturation. In both d-Asp- and NMDA-treated GC-2 cells mitochondrial biogenesis as well as mitochondrial fusion are increased while mitochondria fission is inhibited. Finally, the findings showed that NMDA significantly increased the expressions of the CII, CIII, CIV, and CV complexes of oxidative phosphorylation system (OXPHOS), whereas d-Asp induced a significant increase in the expressions only of the CIV and CV complexes. The present study provides novel insights into the mechanisms underlying the role of d-Asp and NMDA in promoting spermatogenesis.
Helicobacter pylori infection and Parkinson’s Disease: etiology, pathogenesis and levodopa bioavailability
2024, Immunity and Ageing

View all citing articles on Scopus

¹: To whom correspondence and reprint requests should be addressed at the Department of Molecular Genetics (M/C 669), University of Illinois in Chicago, 900 South Ashland Avenue, Chicago, IL 60607. Fax: (312) 355-2032. E-mail: [email protected].

View full text

Regular ArticleThe Regulation and Activities of the Multifunctional Serine/Threonine Kinase Akt/PKB

Abstract

J. Biol. Chem.

Cell

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Fed. Eur. Biochem. Soc.

Curr. Biol.

Curr. Biol.

Curr. Biol.

Curr. Biol.

J. Biol. Chem.

J. Biol. Chem.

Cell

Mol. Cell.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

FEBS Lett.

FEBS Lett.

J. Biol. Chem.

Cell

J. Biol. Chem.

Curr. Opin. Cell Biol.

Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma

Proc. Natl. Acad. Sci. USA

A retroviral oncogene, akt, encoding a serine/threonine kinase containing an SH2-like region

Science

Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families

Eur. J. Biochem.

Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily

Proc. Natl. Acad. Sci. USA

A pair of putative protein kinase genes (YPK1 and YPK2) is required for cell growth in Saccharomyces cerevisiae

Mol. Gen. Genet.

The SH2-like Akt homology (AH) domain of c-akt is present in multiple copies of the genome of vertebrate and invertebrate eucaryotes: Cloning and characterization of the Drosophila melanogaster c-akt homolog Dakt1

Oncogene

Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase

Science

Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor

Genes Dev.

Chemoattractant-mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium

EMBO J.

Identification of protein kinase B (PKB) as a phosphatidylinositol 3,4,5-trisphosphate binding protein in Dictyostelium discoideum

Biosci. Biotechnol. Biochem.

Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction

Nature

Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B

Nature

Regulation of neuronal survival by the serine–threonine protein kinase Akt

Science

Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB

Nature

The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal

Genes Dev.

Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt

Mol. Cell. Biol.

Molecular cloning of a second form of rac protein kinase

Cell Regul.

Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene

Oncogene

Activation of RAC-protein kinase by heat shock and hyperosmolarity stress through a pathway independent of phosphatidylinositol 3-kinase

Proc. Natl. Acad. Sci. USA

Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum

Mol. Cell. Biol.

Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2

Biochem. J.

Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast

Curr. Biol.

Regular Article
The Regulation and Activities of the Multifunctional Serine/Threonine Kinase Akt/PKB