Ten years of protein kinase B signalling: a hard Akt to follow

Brazil, Derek P.; Hemmings, Brian A.

doi:10.1016/s0968-0004(01)01958-2

Cited by 1,102 publications

(954 citation statements)

References 65 publications

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“…Phosphorylated Akt (P-Akt) then dissociates from the plasma membrane and translocates to nucleus and other subcellular compartments to phosphorylate and regulate the function of many cellular proteins involved in cell proliferation, survival, motility and angiogenesis processes that are critical for tumorigenesis and metastasis. 3,5,9,10 The primary consequence of PI3-K activation is the generation of phospholipids at the membrane, which function as second messengers to activate downstream kinases, including PDK1 and ILK. It is not clear whether ILK is an immediate upstream kinase of Akt.…”

Section: Mechanisms Of Akt Regulationmentioning

confidence: 99%

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Ittmann

Ayala

et al. 2005

Prostate Cancer Prostatic Dis

112

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The PI3-K-Akt pathway plays a central role in the development and progression of prostate cancer and other malignancies. We review original studies and summarize relevant sections of previous reviews concerning the relationships between abnormalities in the PI3-K-Akt pathway and prostate cancer progression. We discuss laboratory and clinical data that indicate gene perturbation and dysregulation of PI3-K-Akt pathway is common in prostate cancer and other malignancies. We further discuss the critical role of the PI3-K-Akt pathway in the oncogenic signaling network and provide examples that establish the PI3-K-Akt pathway as a focal point for the future development of informative biomarkers and effective therapies for prostate cancer.

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Section: Mechanisms Of Akt Regulationmentioning

confidence: 99%

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Ittmann

Ayala

et al. 2005

Prostate Cancer Prostatic Dis

112

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“…This interaction induces conformational changes and facilitates autophosphorylation of tyrosine residues on the intracellular part of membrane-spanning β-subunits. These phosphotyrosines then attract a family of adaptor molecules, the insulin receptor substrates (IRSs Refs 12,24,25) (Fig. 1).…”

mentioning

confidence: 99%

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

Schultze

Hemmings

Nießen

et al. 2012

Expert Rev. Mol. Med.

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408

300

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New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications.

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“…These observations raise the important question of what are the downstream targets of histamine H 1 receptor-induced PKB activation? PKB is known to phosphorylate a wide variety of number of substrates including I-kB kinase a leading to enhanced transcriptional activity of NF-kB and endothelial nitric oxide synthase (eNOS) resulting in increased production of NO (Brazil & Hemmings, 2001). Interestingly, Bakker et al (2001) have shown that the histamine H 1 receptor mediates NF-kB activation in COS-7 cells.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of protein kinase B and p70 S6 kinase by the histamine H₁ receptor in DDT₁MF‐2 smooth muscle cells

Dickenson

2002

British J Pharmacology

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1 Previous studies have shown that the histamine H 1 receptor activates p42/p44 mitogen-activated protein kinases (MAPK) in DDT 1 MF-2 smooth muscle cells via a phosphatidylinositol 3-kinase (PI-3K)-dependent pathway. In this study the e ect of histamine H 1 receptor stimulation on protein kinase B (PKB) and p70 S6 kinase, both of which are downstream targets of PI-3K, has been investigated. Increases in PKB and p70 S6 kinase activation were monitored by Western blotting using phospho-speci®c PKB (Ser 473 ) and p70 S6 kinase (Thr 421 /Ser 424 ) antibodies. 2 Histamine stimulated time and concentration-dependent increases in the phosphorylation of PKB and p70 S6 kinase in DDT 1 MF-2 cells. Both responses were completely inhibited by the histamine H 1 receptor antagonist mepyramine and following pre-treatment with pertussis toxin, to block G i /G o protein dependent pathways. 3 The PI-3K inhibitors wortmannin (IC 50 5.9+0.5 nM) and LY 294002 (IC 50 6.9+0.8 mM) attenuated the increase in PKB phosphorylation induced by histamine (100 mM) in a concentration-dependent manner. 4 Histamine-induced increases in p70 S6 kinase phosphorylation were partially sensitive to rapamycin (20 nM; 68% inhibition) but completely blocked by wortmannin (100 nM), LY 294002 (30 mM) and the MAPK kinase inhibitor PD 98059 (50 mM). 5 In summary, these data demonstrate that the histamine H 1 receptor stimulates PKB and p70 S6 kinase phosphorylation in DDT 1 MF-2 smooth muscle cells. However, functional studies revealed that histamine does not stimulate DDT 1 MF-2 cell proliferation or attenuate staurosporine-induced caspase-3 activity. The challenge for future research will be to link the stimulation of these kinase pathways with the physiological and pathophysiological roles of the histamine H 1 receptor.

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Ten years of protein kinase B signalling: a hard Akt to follow

Cited by 1,102 publications

References 65 publications

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

Stimulation of protein kinase B and p70 S6 kinase by the histamine H₁ receptor in DDT₁MF‐2 smooth muscle cells

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Ten years of protein kinase B signalling: a hard Akt to follow

Cited by 1,102 publications

References 65 publications

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis

Stimulation of protein kinase B and p70 S6 kinase by the histamine H1 receptor in DDT1MF‐2 smooth muscle cells

Contact Info

Product

Resources

About

Stimulation of protein kinase B and p70 S6 kinase by the histamine H₁ receptor in DDT₁MF‐2 smooth muscle cells