PI3K signaling in spermatogenesis and male infertility
Rajender Singh in Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Protein kinase B (PKB)/Akt is a serine/threonine-specific kinase and a key class-I PI3K effector, which plays a pivotal role in the regulation of cell survival, cell cycle, glucose metabolism, protein synthesis and migration. There is no direct role of PIP3 in the activation of (PKB)/Akt. It allows recruitment of Akt/PKB to the plasma membrane and its subsequent phosphorylation on Thr308 by the phosphoinositide-dependent kinase-1 (PDK1) (22). Additionally, PDK2 phosphorylates AKT on Ser473, which results in its full activation, followed by its migration to the nucleus and regulation of various cellular functions through phosphorylation of several downstream targets (22) (see Figure 16.2). Activated AKT also leads to the activation of the mTOR complex (21,28–30).
Structure-Function Elucidation of Flavonoids by Modern Technologies
Dilip Ghosh, Pulok K. Mukherjee in Natural Medicines, 2019
Glucose uptake is an important and widely used biological assay to study glucose metabolism in muscles, adipose and liver cells (Yamamoto et al. 2011). Insulin stimulates glucose uptake by activating phosphorylation of insulin receptor substrate (IRS) which in turn instigates PI3 kinase, protein kinase B and protein kinase C isoforms. Subsequently, protein kinase B activates glucose transporter 4 (GLUT-4) translocation to the cell surface and stimulates glucose uptake in the cell (Chang et al. 2004). Various natural phytochemicals are found to be insulin mimetic and effective in increasing glucose uptake. Some of these phytochemicals reported are epigallocatechin (Daisy et al. 2010) and myricetin (Kandasamy and Ashokkumar 2014). Apart from this, AMPK-mediated translocation of GLUT-4 is another alternative mechanism by which various phytochemicals such as kaempferol (Alkhalidy et al. 2015), quercetin (Alam et al. 2014), and naringin (Jung et al. 2004; Pu et al. 2012) along with some other phytochemicals are found to be effective in increasing glucose transport into cells (Huang and Czech 2007). Thus, improved glucose uptake is one of the efficient ways that can help in improving hyperglycaemia in diabetic condition (Boucher et al. 2014). To elucidate the glucose uptake stimulatory activity of phytochemicals, the cells are incubated with test compounds in presence or absence of insulin.
REGULATORY MECHANISMS
David M. Gibson, Robert A. Harris in Metabolic Regulation in Mammals, 2001
catalyzes the phosphorylation of the 3 position of the inositol ring of 4,5 diphospho-phosphatidyl inositol. The product is phosphatidyl inositol 3,4,5-trisphosphate (PIP,) (embedded in the plasma membrane). Typically, as a signal transduction intermediate or second messenger, PIP, is only transiently elevateti during insulin signaling since it is opposed bv a phosphatase (PTEN in figure 3.8, or SIIIP2, a 5-phosphatase). Overall the PI-3-K step occupies a "nodal" point in several signal pathway outcomes depending on cell type: enhancement of transcription and translation, impairment of programmed cell death (apoptosis, figure 3.10), or the terminal dcphosphorylation state of enzymes that are instrumental in metabolic control. The next two steps of the PI 3 К pathway are two protein kinases: PDK-1 (Pi-dependent kinase) and PKB (Protein Kinase B). The latter is active in the phosphorylated state and possesses PH (pleckstrin homology) domains (Table 3.2) which bind to PI 3,4,5 trisphosphate, thus bringing PKB and PDK-1 together next to the plasma membrane.
Gnetum montanum extract induces apoptosis by inhibiting the activation of AKT in SW480 human colon cancer cells
Published in Pharmaceutical Biology, 2022
Xianglong Pan, Xiaotao Hou, Fan Zhang, Peiling Tang, Wanruo Wan, Zixia Su, Yeguo Yang, Wei Wei, Zhengcai Du, Jiagang Deng, Erwei Hao
Apoptosis refers to the physiological death process of cells mediated by genes in accordance with their own pathway under a specific physiological or pathological condition to maintain the homeostasis (An et al. 2019; Ismail et al. 2019). According to Shariati and Meric-Bernstam (2019), AKT signalling pathway is closely related to cell apoptosis. AKT, also known as protein kinase B (PKB), is a serine/threonine kinase that mediates cell metabolism, proliferation, protein synthesis, survival and apoptosis (Liu et al. 2014; Manning and Toker 2017). It can be phosphorylated over 9000 proteins and it is an attractive therapeutic target in cancer (Mundi et al. 2016). Its kinase activity is positively mediated by the phosphorylation of the two key residues Thr308 and Ser473 (Liu et al. 2019). The activation of AKT signalling pathway can be governed by mainly phosphorylated AKT, glycogen synthase kinase-3β (GSK-3β), phosphoinositide dependent kinase-1 (PDK1) and Raf-1 proto-oncogene, serine/threonine kinase (c-Raf; Bamodu et al. 2020; Jiang et al. 2020). During cell cycle progression, AKT is phosphorylated and inhibits GSK-3β to prevent cyclin D1 degradation. Besides, PDK1, the 66-kD protein kinase phosphorylates AKT at Thr308. Phosphorylation of AKT negatively associated with the regulation of Raf-1 (Jun et al. 2012; Shorning et al. 2020). Numerous studies demonstrated that activation of AKT cascade often results in tumour aggressiveness and drug resistance in various types of human cancer (Chan et al. 2014; Neophytou et al. 2021).
The role of mammalian target of rapamycin pathway in the pathogenesis of pauci-immune glomerulonephritis
Published in Renal Failure, 2019
Zeki Soypacaci, Ozlem Cakmak, Fulya Cakalagoglu, Onay Gercik, Ibrahim Ertekin, Atilla Uzum, Rifki Ersoy, Servet Akar
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and plays role in the regulation of cell growth and proliferation. It also regulates cell survival and is stimulated by growth factors, nutrients, stress signals, phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K), mitogen-activated protein kinase(MAPK), 5' adenosine monophosphate(AMP), and 5' adenosine monophosphate-activated protein kinase (AMPK). mTOR complex includes two multiprotein complexes; mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [3]. mTORC1 activates a number of substrates like ribosomal subunit-6 kinase-1 (S6K1) and eucaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1), which are responsible for mRNA translation [4]. mTORC2 regulates actin cytoskeleton and activates protein kinase C-α (PKC-α) and AKT (protein kinase B; PKB). mTOR multiprotein complexes have a positive effect on fibrotic interleukins (IL). Liang et al. [3] showed that IL-4, IL-6, IL-17, and TGF-β were decreased after mTOR inhibition with rapamycin. Phosphatase and tensin homolog (PTEN) is the negative regulator of the AKT/mTOR pathway [5]. It usually inhibits mTOR by inhibiting AKT. Decreased intracellular levels of PTEN cause PI3K/AKT/mTOR pathway activation and increased cell proliferation, survival, adhesion, migration, and angiogenesis [6].
The MAP kinase-interacting kinases (MNKs) as targets in oncology
Published in Expert Opinion on Therapeutic Targets, 2019
Jianling Xie, James E. Merrett, Kirk B. Jensen, Christopher G. Proud
Since eIF4G brings MNKs and eIF4E into proximity and enhances MNK-mediated phosphorylation of eIF4E, mTORC1 activity can in principle promote eIF4E phosphorylation (Figure 1). Thus, the signalling connections to eIF4E via 4E-BP1 and MNKs mean that eIF4E phosphorylation lies at the nexus of two major oncogenic signalling pathways, ERK and mTORC1. eIF4E’s position at this signalling junction, and the many findings linking eIF4E and its phosphorylation to oncogenesis and tumour progression, motivates work aimed both at a fuller understanding of MNK/eIF4E biology and at developing and testing small molecule inhibitors of the MNKs [29]. mTORC1 is activated by the Ras/Raf/MEK/ERK and phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways [30]. Thus, mTORC1 is constitutively active in many tumours (recently reviewed in [31,32]).
Related Knowledge Centers
- Akt1
- Akt2
- Akt3
- Carbohydrate Metabolism
- Cell Migration
- Cell Proliferation
- Apoptosis
- Serine/Threonine-Specific Protein Kinase
- Transcription
- Protein Biosynthesis