Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS

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Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS. / Molinaro, Angela; Becattini, Barbara; Mazzoli, Arianna; Bleve, Augusto; Radici, Lucia; Maxvall, Ingela; Sopasakis, Victoria Rotter; Molinaro, Antonio; Bäckhed, Fredrik; Solinas, Giovanni.

In: Cell Metabolism, Vol. 29, No. 6, 2019, p. 1400-1409.e5.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Molinaro, A, Becattini, B, Mazzoli, A, Bleve, A, Radici, L, Maxvall, I, Sopasakis, VR, Molinaro, A, Bäckhed, F & Solinas, G 2019, 'Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS', Cell Metabolism, vol. 29, no. 6, pp. 1400-1409.e5. https://doi.org/10.1016/j.cmet.2019.03.010

APA

Molinaro, A., Becattini, B., Mazzoli, A., Bleve, A., Radici, L., Maxvall, I., Sopasakis, V. R., Molinaro, A., Bäckhed, F., & Solinas, G. (2019). Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS. Cell Metabolism, 29(6), 1400-1409.e5. https://doi.org/10.1016/j.cmet.2019.03.010

Vancouver

Molinaro A, Becattini B, Mazzoli A, Bleve A, Radici L, Maxvall I et al. Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS. Cell Metabolism. 2019;29(6):1400-1409.e5. https://doi.org/10.1016/j.cmet.2019.03.010

Author

Molinaro, Angela ; Becattini, Barbara ; Mazzoli, Arianna ; Bleve, Augusto ; Radici, Lucia ; Maxvall, Ingela ; Sopasakis, Victoria Rotter ; Molinaro, Antonio ; Bäckhed, Fredrik ; Solinas, Giovanni. / Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS. In: Cell Metabolism. 2019 ; Vol. 29, No. 6. pp. 1400-1409.e5.

Bibtex

@article{9f22c805734a469ab13c60d798dec640,
title = "Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS",
abstract = "Phosphatidylinositol-3-kinase (PI3K) activity is aberrant in tumors, and PI3K inhibitors are investigated as cancer therapeutics. PI3K signaling mediates insulin action in metabolism, but the role of PI3K isoforms in insulin signaling remains unresolved. Defining the role of PI3K isoforms in insulin signaling is necessary for a mechanistic understanding of insulin action and to develop PI3K inhibitors with optimal therapeutic index. We show that insulin-driven PI3K-AKT signaling depends on redundant PI3Kα and PI3Kβ activities, whereas PI3Kδ and PI3Kγ are largely dispensable. We have also found that RAS activity promotes AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depends on PI3Kα. These findings reveal the detailed mechanism by which insulin activates AKT, providing an improved mechanistic understanding of insulin signaling. This improved model for insulin signaling predicts that isoform-selective PI3K inhibitors discriminating between PI3Kα and PI3Kβ should be dosed below their hyperglycemic threshold to achieve isoform selectivity. Insulin signaling is believed to be mediated by PI3Kα activity, which depends on RAS. Molinaro et al. show that maximal insulin-induced AKT phosphorylation, but not downstream signaling, depends on RAS. They show that insulin signaling in hepatocytes and insulin action on glycemia are mediated by redundant PI3Kα and PI3Kβ activities.",
keywords = "diabetes, glycogen, hepatic glucose production, insulin resistance, obesity, phosphoinositide 3-kinase, PROS, PTEN",
author = "Angela Molinaro and Barbara Becattini and Arianna Mazzoli and Augusto Bleve and Lucia Radici and Ingela Maxvall and Sopasakis, {Victoria Rotter} and Antonio Molinaro and Fredrik B{\"a}ckhed and Giovanni Solinas",
year = "2019",
doi = "10.1016/j.cmet.2019.03.010",
language = "English",
volume = "29",
pages = "1400--1409.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",

}

RIS

TY - JOUR

T1 - Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS

AU - Molinaro, Angela

AU - Becattini, Barbara

AU - Mazzoli, Arianna

AU - Bleve, Augusto

AU - Radici, Lucia

AU - Maxvall, Ingela

AU - Sopasakis, Victoria Rotter

AU - Molinaro, Antonio

AU - Bäckhed, Fredrik

AU - Solinas, Giovanni

PY - 2019

Y1 - 2019

N2 - Phosphatidylinositol-3-kinase (PI3K) activity is aberrant in tumors, and PI3K inhibitors are investigated as cancer therapeutics. PI3K signaling mediates insulin action in metabolism, but the role of PI3K isoforms in insulin signaling remains unresolved. Defining the role of PI3K isoforms in insulin signaling is necessary for a mechanistic understanding of insulin action and to develop PI3K inhibitors with optimal therapeutic index. We show that insulin-driven PI3K-AKT signaling depends on redundant PI3Kα and PI3Kβ activities, whereas PI3Kδ and PI3Kγ are largely dispensable. We have also found that RAS activity promotes AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depends on PI3Kα. These findings reveal the detailed mechanism by which insulin activates AKT, providing an improved mechanistic understanding of insulin signaling. This improved model for insulin signaling predicts that isoform-selective PI3K inhibitors discriminating between PI3Kα and PI3Kβ should be dosed below their hyperglycemic threshold to achieve isoform selectivity. Insulin signaling is believed to be mediated by PI3Kα activity, which depends on RAS. Molinaro et al. show that maximal insulin-induced AKT phosphorylation, but not downstream signaling, depends on RAS. They show that insulin signaling in hepatocytes and insulin action on glycemia are mediated by redundant PI3Kα and PI3Kβ activities.

AB - Phosphatidylinositol-3-kinase (PI3K) activity is aberrant in tumors, and PI3K inhibitors are investigated as cancer therapeutics. PI3K signaling mediates insulin action in metabolism, but the role of PI3K isoforms in insulin signaling remains unresolved. Defining the role of PI3K isoforms in insulin signaling is necessary for a mechanistic understanding of insulin action and to develop PI3K inhibitors with optimal therapeutic index. We show that insulin-driven PI3K-AKT signaling depends on redundant PI3Kα and PI3Kβ activities, whereas PI3Kδ and PI3Kγ are largely dispensable. We have also found that RAS activity promotes AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depends on PI3Kα. These findings reveal the detailed mechanism by which insulin activates AKT, providing an improved mechanistic understanding of insulin signaling. This improved model for insulin signaling predicts that isoform-selective PI3K inhibitors discriminating between PI3Kα and PI3Kβ should be dosed below their hyperglycemic threshold to achieve isoform selectivity. Insulin signaling is believed to be mediated by PI3Kα activity, which depends on RAS. Molinaro et al. show that maximal insulin-induced AKT phosphorylation, but not downstream signaling, depends on RAS. They show that insulin signaling in hepatocytes and insulin action on glycemia are mediated by redundant PI3Kα and PI3Kβ activities.

KW - diabetes

KW - glycogen

KW - hepatic glucose production

KW - insulin resistance

KW - obesity

KW - phosphoinositide 3-kinase

KW - PROS

KW - PTEN

U2 - 10.1016/j.cmet.2019.03.010

DO - 10.1016/j.cmet.2019.03.010

M3 - Journal article

C2 - 30982732

AN - SCOPUS:85066293946

VL - 29

SP - 1400-1409.e5

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 6

ER -

ID: 238430812