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Neuroendocrine Interactions in the Control of Glucose- and Energy Homeostasis
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Although JAK2-STAT3-SOCS3 signalling is the most well-described and thoroughly investigated signalling cascade downstream of LEPRb, other pathways that are known to mediate insulin signal transduction are also involved in leptin signal transduction. One such pathway is the IRS-PI3K-AKT signalling pathway described above. Leptin recruitment of this pathway was first suggested by a study showing that IRS2-null mice displayed elevated leptin levels, hyperphagia and decreased energy expenditure (50). Subsequently, it was demonstrated that systemic administration of leptin in rats activates PI3K in the hypothalamus and that intracerebroventricular infusion of inhibitors of this enzyme prevented the anorexigenic effects of leptin (51). Leptin-induced PI3K activation is likely mediated through SH2B1, which recruits IRS proteins to JAK2. Activated PI3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate to phosphatidylinositol-3,4,5-tris-phosphate (PIP3), whereas tumour suppressor phosphatase and tensin homolog (Pten) initiate the opposite reaction (52). PIP3 then binds to the Pleckstrin homology domain of Akt (also known as protein kinase B, PKB), allowing for the phosphorylation of Akt by its activating kinases, phosphoinositide-dependent kinase 1 (PDPK1, at threonine 308, and the mammalian target of rapamycin complex 2 (mTORC2, at serine 473) (53). Leptin signalling through this pathway is especially important for the regulation of glucose homeostasis, both through direct effects on glucose fluxes (54) and by regulating insulin sensitivity (55).
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
In addition, phosphatase and tensin homolog (PTEN) and protein phosphatase 2A (PP2A) control two crucial steps in PI3K/Akt signalling, and they can be targeted by ROS-mediated signalling (Figure 3.3). Besides the transitory inhibition of PTEN (Lee et al., 2002), ROS-mediated signalling causes phosphorylation of PTEN, triggering its degradation (Abraham and O’Neill, 2014). For PP2A, it has been demonstrated that peroxynitrite-mediated nitration resulted in inhibition of PP2A, which promotes sustained activation of PI3/Akt signalling (Low et al., 2014). Additionally, Akt alone is also a redox-sensitive protein that has a disulphide bond between Cys297 and Cys311 (Murata et al., 2003) and other two cysteine residues in the pleckstrin homology domain (Cys60 and Cys77). Thus, the net balance toward PI3K/Akt/mTORC pathways might be caused by a pro-oxidant environment after exercise and thereby sustaining the activation of an anabolic cascade to mediate hypertrophy (Figure 3.3).
Introduction to Cell Biology
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Proteins containing Src-homology (SH)2 domains or phosphotyrosine-binding (PTB) domains bind to specific phosphorylated tyrosine residues on other proteins. Examples include the adapters Shc and the catalytic protein tyrosine kinase Src. SH3 domains recognize sequences on target proteins that are rich in the amino acid proline. Src, for example, also contains SH3 domains. In addition to protein-protein interactions, other protein modules allow for recognition of certain lipids, DNA sequences, or other molecules. Examples include the pleckstrin homology domain, which recognizes specific membrane phospholipids and thus plays a key role in determining intracellular localization (e.g., Akt) and DNA-binding domains (DBD), which allow for transcription factors to recognize particular regions on DNA and thus regulate transcription.
How can we turn the PI3K/AKT/mTOR pathway down? Insights into inhibition and treatment of cancer
Published in Expert Review of Anticancer Therapy, 2021
Said M. Afify, Aung Ko Ko Oo, Ghmkin Hassan, Akimasa Seno, Masaharu Seno
AKT is a serine/threonine kinase having three isoforms, viz., AKT1, AKT2, and AKT3, encoded by the genes PKBα, PKBβ, and PKBγ, respectively (Figure 3) [2,32]. All three isoforms possess a similar structure: an N-terminal Pleckstrin homology domain, a central kinase domain, and a small C-terminal extension (EXT) containing a regulatory hydrophobic motif (HM) [33]. AKT activation is initiated by translocation to the plasma membrane mediated by docking of the PH domain in the N-terminal region of AKT to the PI(3,4,5)P3 on the membrane, resulting in a conformational change in AKT, exposing two critical amino acid residues for phosphorylation [34]. Both phosphorylation events, i.e. T308 by PDK1 and S473 by mTORC2, are required for full activation of AKT. PDK1 initially activates AKT, and a positive feedback by mTORC2 amplifies the activity of AKT [35–37]. Once phosphorylated and activated, AKT phosphorylates many other proteins, e.g. Tuberous Sclerosis Complex 2 (TSC2), glycogen synthase kinase 3 (GSK3), and the forkhead family of transcription factors (FOXOs), thereby regulating a wide range of cellular processes involved in protein synthesis, cell survival, proliferation, and metabolism (Figure 2).
Lithium-induced gene expression alterations in two peripheral cell models of bipolar disorder
Published in The World Journal of Biological Psychiatry, 2019
Sarah Kittel-Schneider, Max Hilscher, Claus-Jürgen Scholz, Heike Weber, Lena Grünewald, Ricarda Schwarz, Andreas G. Chiocchetti, Andreas Reif
PLEKHA2 codes for a protein called pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 2, which binds specifically to phosphatidylinositol 3,4-diphosphate. Phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2) is a phospholipid component of cell membranes and also plays a role as a second messenger. PLEKHA2 (synonym: TAPP2) therefore is involved in phosphoinositide signalling pathways. Lithium is known to interact with the phosphoinositide pathways by among others inhibiting myoinositol metabolism and through inositol depletion (Williams et al. 2002). The neurotrophic effect of lithium can be blocked by inhibition of phosphatidylinositol 3-kinase in primary hippocampal neurons (Park et al. 2014). Lithium treatment significantly increased PLEKHA2 expression after long-term treatment (t3) in our study. A previous study investigating platelets of bipolar patients, showed a decreased relative amount of PIP2 (phosphatidyl-inositol-4,5-bisphosphate) due to lithium treatment (Soares et al. 1999). Our results hint that lithium might also display its inhibitory effect on PIP2 production via increase in binding capacities for PtdIns(3,4)P2 and thereby reducing or modulating the activity of following enzymes.
Expression of BTK/p-BTK is different between CD5+ and CD5- B lymphocytes from Autoimmune Hemolytic Anemia/Evans syndromes
Published in Hematology, 2019
Ningning Duan, Manjun Zhao, Yi Wang, Yingying Qu, Hong Liu, Huaquan Wang, Limin Xing, Zonghong Shao
This study revealed a significant increment of BTK expression on CD5+ and CD5-B lymphocytes in AIHA/ES, but the degree of increase was significantly different. p-BTK on CD5+B cells was obviously higher than that on CD5-B cells. Many factors can regulate BTK. These include an inhibitor of BTK, which we identified as being bound to the pleckstrin-homology domain of BTK, and down-regulated the activity of BTK [14]. Protein kinase C-beta, which phosphorylates BTK at the S180 serine residue in the TH domain, which modulates BTK membrane localization [15]; and miR-185, overexpression of microRNA inhibited BTK mRNA in follicular B cells, thereby down-regulating BTK [16]. The regulation of BTK in CD5+ and CD5-B lymphocytes may be different. Further studies are needed to identify whether there are other regulatory mechanisms of BTK in CD5+ and CD5-B lymphocytes.