China
Africa
Explore chapters and articles related to this topic
Hypothalamic Neuronal Circuits Are Modulated by Insulin and Impact Metabolism 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Tadeu de Oliveira Diz, Sabela Casado, Rubén Nogueiras, Sulay Tovar
The mammalian target of rapamycin (mTOR) is a serine-threonine-kinase that, when activated, generates that is able to activate an important cascade pathway found in different cell types and involved in different roles, from cell growth to energy homeostasis (131). The mTOR is characterized by having two complexes, mTORC1 and mTORC2, which have different constitutions and act in different ways and in different locations (132). The activity of the mTORC1 complex in the hypothalamus depends on insulin binding with its receptor in the plasma membrane. Upon activation of IRS1, PI3K is stimulated and consequently phosphorylates PDK1 and AKT. Then, AKT is responsible for phosphorylating the TSC1-TSC2 (Tuberous sclerosis proteins 1 and 2) complex, leading to its inactivation and thus enabling the Rheb-GTP (Ras homolog enriched in brain) activity on mTORC1 (133, 134). With mTORC1 activated, the S6K1 (Ribosomal protein S6 kinase β-1) protein becomes a target for phosphorylation to generate a cellular response.
1,3-Diphenyl-2-Propene-1-One-Based Natural Product Antidiabetic Molecules as Inhibitors of Protein Tyrosine Phosphatase-1B (PTP-1B)
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Vivek Asati
The kinase enzyme, phosphoinositide 3-kinases (PI3K) downstream the metabolic signaling by phosphorylating the substrate PI to phosphatidylinositol biphosphate (PIP2), thereby activates the protein 3-phosphoinositide-dependent protein kinase-1 (PDK1).16 This cascade activates protein kinase-B (PKB) which is a sole component in the enrichment of glucose uptake by stimulating insulin-dependent GLUT4 translocation (Fig. 7.1).17
CLOVES Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The PI3K heterodimer is activated by receptors with protein tyrosine kinase activity (RTK), and which then phosphorylates inositol ring 3′-OH group in inositol phospholipids, thus converting phosphatidylinositol-4,4-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). This leads to the translocation and phosphorylation of protein serine/threonine kinase-3′-phosphoinositide-dependent kinase 1 (PDK1) to the cell membrane. PDK1 then phosphorylates Akt/PKB to initiate downstream processes involved in cell survival and cell cycle progression, including activation of mTOR, glycogen synthase kinase-3 (GSK3), p53, and IκB kinase (IKK), which is a positive regulator of survival factor NFκB, and inactivation of pro-apoptotic factors such as Bad and Procaspase-9 (Figure 88.1) [11,12].
BCG-induced trained immunity in macrophage: reprograming of glucose metabolism
Published in International Reviews of Immunology, 2020
Yuntong Liu, Shu Liang, Ru Ding, Yuyang Hou, Feier Deng, Xiaohui Ma, Tiantian Song, Dongmei Yan
The pyruvate dehydrogenase complex (PDC) decarboxylates pyruvate into acetyl-CoA for use by the TCA cycle, pyruvate dehydrogenase kinase (PDK) phosphorylates three serine residues of PDH to inhibit its activity.64 One study have shown that HIF-1α-PDK1-mediated metabolic changes in mild hypoxia is essential for the migration of macrophages in the inflammatory areas.63 And the knockdown of PDK1 diminishes macrophage responses to LPS and TLR2 stimulation, but has little effect on LPS activated cytokine production in GM-BMMs(GM-CSF induced macrophages).65 However, another study reveals that although LPS induces HIF-1α, the expression of PDK1 is attenuated. M(LPS) macrophages depend on the PDH flux to induce cytokine expression and synthesis of itaconate, which is explained that an additional regulator specifically prevents PDK1 expression.64 In summary, PDK1 plays a subtle regulatory role in the immune function of macrophages. Inhibiting PDK can switch fatty acid fueling of immune tolerance to glucose fueling of immune resistance.66
Myeloid deletion of phosphoinositide-dependent kinase-1 enhances NK cell-mediated antitumor immunity by mediating macrophage polarization
Published in OncoImmunology, 2020
Yuexi He, Juan Du, Zhongjun Dong
Mammalian target of rapamycin (mTOR) signaling is a key nutrient/energy sensor that links nutrient availability to downstream metabolic processes such as protein synthesis, glycolysis and de novo lipogenesis.39 Phosphoinositide-dependent kinase-1 (PDK1) is considered to be a major regulator of mTOR signaling through phosphorylating Akt, which indirectly activates mTOR complex1 (mTORC1) as a serine/threonine kinase. PDK1 is an important signaling molecule downstream of PI3Ks. Overexpression of PDK1 relates to the occurrence and development of tumors.40–43 PDK1 is ubiquitously expressed in all normal cells. Although many chemical inhibitors targeting PDK1 are developed, clinical use of these potential drugs has the risk of lethal toxicity, which hinders further use of these inhibitors. Moreover, PDK1 is also expressed in all immune cells and is essential for the regulation of the immune system. This kinase is indispensable for T lymphocyte activation.44,45 Cell-type specific PDK1 deletion revealed that the absence of PDK1 leads to stunted development of all lymphocytes, including T cells, B cells or NK cells. Therefore, targeting PDK1 very likely causes significant side effects from an immune perspective.
Aberrant upregulation of PDK1 in ovarian cancer cells impairs CD8+ T cell function and survival through elevation of PD-L1
Published in OncoImmunology, 2019
Jing-Jing Wang, Michelle K. Siu, Yu-Xin Jiang, Thomas H. Leung, David W. Chan, Ran-Ran Cheng, Annie N. Cheung, Hextan Y. Ngan, Karen K. Chan
PDK1 is a crucial glycolytic gene involved in several cancer cell processes, such as proliferation, apoptosis and invasion.17,40 In this study, we showed that PDK1 expressed in ovarian cancer regulates PD-L1 through the JNK-c-Jun pathway, consequently influencing CD8+ T cell function and survival. While its oncogenic function has been broadly documented, JNK also participates in the regulation of immune responses.41 For instance, in melanoma cells, c-Jun is reported to directly regulate PD-L1 as an inducible transcription factor, which may be enhanced by cooperation with STAT3. Inhibition of JNK upstream kinase or knockdown of JNK led to reduced PD-L1 expression in melanoma cells,27,42 while after treatment with the JNK inhibitor, SP600125, PD-L1 expression was attenuated in bladder cancer,28 clearly indicating that JNK influences PD-L1 expression. In our experiments, phosphorylation of JNK and c-Jun was inhibited in ovarian cancer cells with knockdown of PDK1 and, conversely, enhanced with PDK1 overexpression. Furthermore, upon siRNA-induced JNK1 knockdown in OVCAR3 cells overexpressing PDK1, PD-L1 overexpression was partially inhibited, supporting the theory that PDK1 influences PD-L1 expression through the JNK-c-Jun pathway.