Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling

Chaussade, Claire; Rewcastle, Gordon W.; Kendall, Jackie D.; Denny, William A.; Cho, Kitty; Grønning, Line M.; Chong, Mei Ling; Anagnostou, Sasha H.; Jackson, Shaun P.; Danièle, Nathalie; Shepherd, Peter R.

doi:10.1042/bj20070003

Cited by 190 publications

(188 citation statements)

References 42 publications

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“…Also, experiments in vivo using specific pharmacological inhibitors showed that inhibition of p110α, but not p110β, blocks the acute effects of insulin (2). However, another report found that although p110α is required for insulin-stimulated phosphorylation of Akt in several cultured cell lines, the p110β and p110δ subunits are also necessary for insulin signaling in HepG2 hepatoma cells (48). In accordance, Jia and cols.…”

Section: The Catalytic Subunits Of Class Ia Pi3kssupporting

confidence: 55%

The PI3K signaling pathway mediates the biological effects of leptin

Donato

Frazão

Elias

2010

Arq Bras Endocrinol Metab

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SUMMARYThe activation of the leptin receptor recruits several intracellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway. While some of the leptin-induced signaling pathways, such as the JAK2/STAT3 pathway, induce cellular responses primarily through changes in gene expression, the PI3K pathway affects cellular properties more rapidly, through post-translational changes such as protein phosphorylation. Accordingly, several studies have shown that the PI3K pathway is required for the acute effects of leptin, such as a leptin-induced decrease in food intake. Leptin signaling through PI3K also affects the electrophysiological properties of neurons, including changes in their membrane potential and firing rates. In this review, we summarize the recent advances in our understanding of the role played by the PI3K signaling pathway in controlling food intake and energy balance. In particular, we focus on the importance of the PI3K signaling pathway as a mediator of the effects of leptin on hypothalamic neurons. Arq Bras Endocrinol Metab. 2010;54(7):591-602 Keywords Phosphatidylinositol; phosphatidylinositol 3-kinases; energy balance; insulin; Akt; hypothalamus SUMÁRIO A ativação do receptor de leptina recruta diversas vias de sinalização intracelular, entre elas a via da fosfatidilinositol 3-quinase (PI3K). Enquanto algumas dessas vias, como a sinalização pelo JAK2/ STAT3, induzem respostas celulares por meio de mudanças na transcrição gênica, a via da PI3K altera propriedades celulares de forma rápida, via fosforilação de proteínas. Em concordância, estudos mostraram que a via da PI3K é necessária para que a leptina induza seus efeitos agudos, como redução da ingestão alimentar, após administração de leptina. A ativação da PI3K pela leptina também afeta as propriedades fisiológicas de neurônios, incluindo mudanças no potencial de membrana e no potencial de ação. Nesta revisão, resumimos os recentes avanços na compreensão do papel desempenhado pela via de sinalização da PI3K no controle da ingestão alimentar e do balanço energético. Discutimos, principalmente, como a via da PI3K é importante para mediar os efeitos da leptina sobre os neurônios hipotalâmicos. Arq Bras Endocrinol Metab. 2010;54(7):591-602 Descritores Fosfatidilinositol; fosfatidilinositol 3-quinase; balanço energético; insulina; Akt; hipotálamo review

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Section: The Catalytic Subunits Of Class Ia Pi3kssupporting

confidence: 55%

The PI3K signaling pathway mediates the biological effects of leptin

Donato

Frazão

Elias

2010

Arq Bras Endocrinol Metab

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“…The potent p110-b inhibitor TGX-221 (IC 50 in vitro ¼ 8.5 AE 0.9 nmol/L; ref. 18) only partially impaired the proliferation of SCLC cell lines, but at high concentrations (Fig. 2B).…”

Section: Resultsmentioning

confidence: 99%

Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer

Wojtalla

Fischer

Kotelevets

et al. 2013

Clinical Cancer Research

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Purpose: The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study, we investigated the potential of targeting the catalytic class I A PI3K isoforms in small cell lung cancer (SCLC), which is the most aggressive of all lung cancer types.Experimental Design: The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival and downstream signaling were determined following PI3K isoform inhibition by selective inhibitors or downregulation by siRNA.Results: Overexpression of the PI3K isoforms p110-a and p110-b and the antiapoptotic protein Bcl-2 was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110-a with RNA interference or selective pharmacologic inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo, whereas targeting p110-b was less effective. Inhibition of p110-a also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mTOR pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1. A DNA microarray analysis revealed that p110-a inhibition profoundly affected the balance of pro-and antiapoptotic Bcl-2 family proteins. Finally, p110-a inhibition led to impaired SCLC tumor formation and vascularization in vivo.Conclusion: Together our data show the key involvement of the PI3K isoform p110-a in the regulation of multiple tumor-promoting processes in SCLC.

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“…MLN1117, originally described by Intellikine as INK1117 (24), is currently in phase I trials for patients with advanced solid tumors (clinical trials identifier NCT01449370). To inhibit p110␤ we used TGX-221 (25,26). This compound has some activity against p110␦ (IC 50 100 versus 5 nM for p110␤; Table 1).…”

Section: Pi3kmentioning

confidence: 99%

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

Yea

Oak

et al. 2013

Journal of Biological Chemistry

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Background:The class IA PI3K isoform p110␣ is a promising drug target in cancer therapy yet its role in lymphocytes is not known. Results: Lymphocyte function was minimally affected by p110␣ inhibition both in vitro and in vivo. Conclusion: Selective inhibition of p110␣ preserves lymphocyte function. Significance: The study raises confidence that selective p110␣ inhibitors in cancer therapy will not be immunosuppressive.

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Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling

Cited by 190 publications

References 42 publications

The PI3K signaling pathway mediates the biological effects of leptin

The PI3K signaling pathway mediates the biological effects of leptin

Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

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