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Exercise Redox Signalling
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Ruy A. Louzada, Jessica Bouviere, Rodrigo S. Fortunato, Denise P. Carvalho
Exercise is one of the best strategies to control glucose blood levels, mostly because of the capacity of contracting muscle to stimulate glucose uptake. Exercise can increase glucose transport to about 50-fold in humans (Katz, 2007). Despite the direct stimulatory effect of exercise-induced ROS on muscle glucose uptake via PI3K (Higaki et al., 2008), other studies showed that Akt2 deficiency did not affect the exercise-stimulated glucose uptake (Sakamoto et al., 2006), supporting the idea that insulin-stimulated glucose uptake pathways might be dissociated from the exercise-stimulated glucose uptake. Several signalling pathways are simultaneously activated following contraction and evoke glucose uptake. Among them, Ca2+/calmodulin-dependent kinase II (CaMKII) and AMPK are the most studied candidates for playing a role in exercise-stimulated glucose uptake (Figure 3.2).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The serine/threonine kinase Akt, named after a strain of mice and also known as Protein Kinase B (PKB), has a critical role in the PI3K-Akt signaling pathway (Figure 6.87) which is involved in a number of cellular processes including proliferation, survival, glucose metabolism, genome stability, transcription, protein synthesis, and neovascularization. Inhibition of Akt results in a reduction in cell-cycle progression and tumor growth. Akt has three isoforms, Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ), all of which share high sequence homology and are composed of similar structural domains. The catalytic structural domain has highly homology with Protein Kinases A (PKA) and C (PKC), and other cAMP-dependent protein kinases.
Protein Phosphorylation
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The genes of two serine/threonine kinases, Rac-α and Rac-β, have been cloned from human cell lines.489,490 The Rac-α protein is encoded by the AKT1 gene, which is the human homolog of the viral oncogene v-akt. The β form of Rac is a 60-kDa protein that has a carboxyl-terminal extension of 40 amino acids in comparison to the α form. A third human gene, AKT2, closely related to those encoding Rac-α and Rac-β, codes for a 56-kDa protein, Akt-2, which has serine/threonine kinase activity and contains an SH2 domain.491 The AKT2 gene is localized on human chromosome 19, at region 19q.13.1-q13.2 and was found to be amplified in some human ovarian carcinoma cell lines and primary ovarian carcinomas. The Rac/Akt kinases show a high degree of homology to both the protein kinase C and cAMP-dependent families, and may be universally expressed in human cells. These kinases are most probably involved in intracellular signal transduction. The gene encoding another serine/threonine kinase, Mak, is expressed almost exclusively in testicular meiotic cells. The mak gene is not expressed in ovarian cells, including oocytes after the dictyotene stage.492 DNA sequences homologous to the mak gene are highly conserved in mammals and may play an important role in spermatogenesis.
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca
AKT is a class of serine/threonine kinase that belongs to the AGC kinase family, also widely recognised as PKB244. The Akt family consists of three members: Akt1 (PKB α), Akt2 (PKB β), and Akt3 (PKB γ). The three AKT isotypes have similar structures, including the PH domain, the central kinase domain, and the carboxyl-terminal regulatory domain containing hydrophobic motifs245. Although the three subtypes have similar structures, they can perform different functions in cancer and physiology. AKT1, as a growth inducer, promotes tumour cell growth but damages metastasis, while AKT2 can increase tumour cell invasion and metastasis246. Thus, AKT1 is hypothesised to act as an invasion suppressor in the early stages of the disease, while AKT2 promotes invasion in the advanced stages of the disease247. AKT3 is the least studied and has been proven to be closely linked to the progression of triple-negative breast cancer (TNBC)248. The subtype-specific function of AKT remains controversial, and the mechanisms by which it impacts cancer progression require further investigation. Nonetheless, AKT remains a key target for the treatment of cancer.
Bioactivity and mechanisms of flavonoids in decreasing insulin resistance
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Min Zhou, William H. Konigsberg, Canhua Hao, Yinbo Pan, Jie Sun, Xiaojing Wang
PI3K is a heterodimer with serine kinase activity capable of inducing the production of a second messenger phosphatidylinositol trisphosphate (PIP3), which interacts with other signalling proteins. As an important effector molecule, PI3K is a key regulatory node in converting extracellular signals activated by insulin and/or growth factors into intracellular activities13. The serine/threonine protein kinase Akt (Protein Kinase B, PKB) is composed of three isoforms, Akt1, Akt2, and Akt3. Among all isoforms of Akt, Akt2 is the most important isoform in insulin-mediated glucose uptake and lipid metabolism4. Phosphoinositide-dependent protein kinase-1 (PDK1) activates Akt by phosphorylating the threonine residue of Akt; subsequently, mammalian target of rapamycin complex 2 (mTORC2) completes the activation process of Akt by phosphorylating the serine residue of Akt3. Akt inhibits lipid breakdown by activating mTORC1 and promotes lipid synthesis by regulating sterol regulatory element-binding protein (SREBP) substrates. Activation of S6K1 by mTORC1 not only increases mRNA production and translation, but also participates in negative feedback regulation of insulin signalling through serine/threonine phosphorylation of IRS14. Targeting mTOR can disable the negative feedback loop, thereby reversing IR and helping to prevent and/or treat diabetes.
AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis
Published in Hematology, 2023
Yunjian Li, Liang Du, Kaiqin Ye, Xiao Sun, Lei Hu, Shan Gao, Haiming Dai
PI3K/AKT signaling plays important role in regulating cellular functions. Moreover, activation of PI3K/AKT/mTOR signaling contributes to the pathogenesis of many cancer types. For example, PI3Ks have been reported to be involved in cell growth, proliferation, differentiation and intracellular trafficking, which in turn contribute to cancer development [58]. AKT is functionally activated or deactivated through phosphorylation or dephosphorylation, resulting in different consequences in controlling cell metabolism, growth, proliferation, and survival [59]. The activated AKTs affect cellular proliferation or survival through multiple downstream signaling pathways, such as activating the pathway for the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), or suppression of the p53 pathway [60]. Gsk690690 and MK-2206 are AKT inhibitors that effectively inhibit AKT1, AKT2, and AKT3. In particular, MK-2206 is an allosteric inhibitor of AKT with activity against all three AKT isoforms but has more inhibition against AKT1 and AKT2 [61]. MK-2206 has been under clinical trials for endometrial cancer [62], uterine serous carcinoma [63], and breast cancer [64].