Reference Detail

Ref Type Journal Article
PMID (25856301)
Authors Kajno E, McGraw TE, Gonzalez E
Title Development of a new model system to dissect isoform specific Akt signalling in adipocytes.
Journal The Biochemical journal
Vol 468
Issue 3
Date 2015 Jun 15
URL
Abstract Text Protein kinase B (Akt) kinases are critical signal transducers mediating insulin action. Genetic studies revealed that Akt1 and Akt2 signalling differentially contribute to sustain lipid and glucose homoeostasis; however Akt isoform-specific effectors remain elusive due to the lack of a suitable model system to mechanistically interrogate Akt isoform-specific signalling. To overcome those technical limitations we developed a novel model system that provides acute and specific control of signalling by Akt isoforms. We generated mutants of Akt1 and Akt2 resistant to the allosteric Akt inhibitor MK-2206. We then developed adipocyte cell lines, in which endogenous Akt1 or Akt2 has been replaced by their corresponding drug-resistant Akt mutant. Treatment of those cells with MK-2206 allowed for acute and specific control of either Akt1 or Akt2 function. Our data showed that Akt1(W80A) and Akt2(W80A) mutants are resistant to MK-2206, dynamically regulated by insulin and able to signal to Akt downstream effectors. Analyses of insulin action in this cellular system showed that Akt1 and Akt2 are both able to mediate insulin regulation of the transcription factor forkhead box O1 (FoxO1) and the glucose transporter 4 (GLUT4), revealing a redundant role for these Akt kinases in the control of glucose transport into fat cells. In contrast, Akt1 signalling is uniquely required for adipogenesis, by controlling the mitotic clonal expansion (MCE) of pre-adipocytes that precedes white adipose cell differentiation. Our data provide new insights into the role of Akt kinases in glucose transport and adipogenesis and support our model system as a valuable tool for the biochemical characterization of signalling by specific Akt isoforms.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
W80A missense no effect - predicted AKT1 W80A lies within the PH domain of the Akt1 protein (UniProt.org). Akt1 demonstrates phosphorylation and downstream signaling similar to wild-type Akt1 in cell culture (PMID: 25856301), however, is associated with Akt inhibitor resistance (PMID: 18669636, PMID: 25856301). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
AKT1 W80A Advanced Solid Tumor resistant MK2206 Preclinical - Cell culture Actionable In a preclinical study, transformed mouse adipocytes expressing human Akt1 W80A were resistant to the AKT inhibitor, MK-2206 (PMID: 25856301). 25856301