Disease relevance of Akt2

• Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2 [1].
• Loss of Akt2 also impaired arterial thrombus formation and stability in vivo, despite having little effect on platelet responses to collagen and ADP [2].
• In addition, Akt2/PKBbeta-deficient mice exhibit fed and fasting hyperglycemia, hyperinsulinemia, glucose intolerance, and impaired muscle glucose uptake [3].
• However, Akt2(-/-) Akt3(-/-) mice were glucose and insulin intolerant and exhibited an approximately 25% reduction in body weight compared to wild-type mice [4].
• This model is upheld in Akt2-deficient mice with insulin resistance leading to diabetes mellitus [5].

High impact information on Akt2

• The mammary gland defect in female opgl-/- mice is characterized by enhanced apoptosis and failures in proliferation and PKB activation in lobulo-alveolar buds that can be reversed by recombinant OPGL treatment [6].
• A serine/threonine kinase, named protein kinase B (PKB) for its sequence homology to both protein kinase A and C, has previously been isolated [7].
• These results suggest a role for PKB in PI(3)K-mediated signal transduction [7].
• Finally, we show that a constructed Gag-PKB fusion protein, homologous to the v-akt oncogene, displays significantly increased ligand-independent kinase activity [7].
• These early events lead to activation of the serine-threonine protein kinase Akt, also known as protein kinase B. We show that mice deficient in Akt2 are impaired in the ability of insulin to lower blood glucose because of defects in the action of the hormone on liver and skeletal muscle [8].

Chemical compound and disease context of Akt2

• We have evaluated this approach in dopamine neurons of the substantia nigra, neurons affected in Parkinson's disease, by adeno-associated virus 1 transduction with a gene encoding a myristoylated, constitutively active form of the oncoprotein Akt/PKB [9].
• To investigate whether the serine/ threonine kinase Akt/PKB, which is the proto-oncogene transduced by the transforming AKT8 retrovirus, is activated by PMT, 3T3-L1 fibroblasts were stably transfected with wild type PMT [10].

Biological context of Akt2

• These data establish Akt2 as an essential gene in the maintenance of normal glucose homeostasis [8].
• Overall, the combined deletion of Akt1 and Akt2 establishes in vivo roles for Akt in cell proliferation, growth, and differentiation [1].
• In addition, Akt1/Akt2 DKO mice display impeded adipogenesis [1].
• Deletion of the gene encoding Akt2 impaired platelet aggregation, fibrinogen binding, and granule secretion, especially in response to low concentrations of agonists that activate the G(q)-coupled receptors for thrombin and thromboxane A(2) [2].
• Here we report the application of small interfering RNA-directed gene silencing to deplete both Akt1 and Akt2 in cultured 3T3-L1 adipocytes [11].

Anatomical context of Akt2

• Specifically, Akt1 and Akt2 are required for the induced expression of PPARgamma, the master regulator of adipogenesis, establishing a new essential role for Akt in adipocyte differentiation [1].
• SH2-containing inositol phosphatase 2 predominantly regulates Akt2, and not Akt1, phosphorylation at the plasma membrane in response to insulin in 3T3-L1 adipocytes [12].
• Here we show distinct roles for Akt1 and Akt2 in mouse embryo fibroblast cell migration and regulation of the cytoskeleton [13].
• Insulin-induced Akt1 and Akt2 phosphorylation was reduced in myotubes treated with siIRS-1, but only Akt2 phosphorylation was reduced in myotubes treated with siIRS-2 [14].
• In this regard, following insulin stimulation, a proportion of Akt2, and not Akt1, appeared to redistribute from the cytosol to the PM [12].

Associations of Akt2 with chemical compounds

• The serine/threonine protein kinases Akt1 and Akt2, which have been implicated as mediators of insulin-stimulated glucose uptake, as well as glycogen, lipid, and protein synthesis, were shown to mirror this selectivity in this tissue culture system [15].
• Akt1 and Akt2 differently regulate muscle creatine kinase and myogenin gene transcription in insulin-induced differentiation of C2C12 myoblasts [16].
• We measured insulin-stimulated 2-deoxyglucose (2DG) uptake in isolated extensor digitorum longus (EDL) and soleus muscles from male and female wild-type (WT) and Akt2-null (knockout [KO]) mice after ad libitum or calorie-restricted (20 days at 60% of AL) feeding [17].
• Akt2 encodes a protein-serine/threonine kinase containing a pleckstrin homology domain characteristic of many signaling molecules [18].
• Interestingly, the phosphorylation level of Akt at Thr308 (Akt2 at Thr309), but not at Ser473 (Akt2 at Ser474), was revealed to correlate well with the accumulation of phosphatidylinositol 3,4,5-trisphosphate modified by overexpression of these PTEN proteins [19].

Regulatory relationships of Akt2

• Akt2 promoter activity and protein levels were regulated by p38 activation, thus providing a mechanism for communication [20].
• These results show that activation of Akt2 is sufficient to stimulate GLUT4 translocation in 3T3-L1 adipocytes to an extent similar to insulin [21].

Other interactions of Akt2

• Basal and ligand-induced p52 production is reduced in mouse embryo fibroblasts deficient in Akt1 and Akt2 compared with parental cells [22].
• Akt2, a novel functional link between p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in myogenesis [20].
• Each PKB isoform contributed to GSK-3alpha and GSK-3beta phosphorylation, with PKBbeta having the predominant role [23].
• Our data also suggest that Akt1 and Akt2 play distinct roles in myogenic differentiation [16].
• An analysis of two sets of multilocus crosses revealed that the Akt2 gene is closely linked to the Cyp2a locus in proximal MMU7 [24].

Analytical, diagnostic and therapeutic context of Akt2

• Endogenous PKCbetaI and -betaII mRNA levels in Akt2(+/+) and Akt2(-/-) gastrocnemius muscle tissues were compared using quantitative real time PCR [5].
• Here we report that microinjection of a PKB substrate peptide or an antibody to PKB inhibited insulin-stimulated GLUT4 translocation to the plasma membrane by 66 or 56%, respectively [25].
• Fluorescence in situ hybridization of the mouse cDNA to rodent metaphase spreads demonstrated that the Akt2 gene maps to mouse chromosome band 7B1 and rat chromosome 1q22 [26].
• The expression level of Akt1 mRNA in the affected hypoglossal nucleus increased dramatically after 48 h to 7 d following axotomy of the hypoglossal nerve, whereas no change was seen in the level of Akt2 mRNA [27].
• Analyses employing isoform-specific antibodies for immunoprecipitation suggested that all three isoforms of PKB (alpha, beta and gamma) are activated in response to NGF [28].

References