Neuroprotection
Glenn J. Jaffe, Paul Ashton, P. Andrew Pearson in Intraocular Drug Delivery, 2006
Several lines of evidence suggest that an additional, finer level of control over Bcl-2–Bax interaction may be achieved by the participation of related family members such as Bad. In the retina, Bad is expressed predominantly by ganglion cells (42). Normally, Bad is sequestered in the cytoplasm by the 14-3-3 class of proteins. Extracellular growth or survival factors appear to affect survival, in part, through activation of a pathway involving phosphoinositide 3 kinase (PI3-K) (43,44). PI3-K, in turn, activates a serine–threonine protein kinase, Akt, that phosphorylates Bad (45–47) and promotes its association with the 14-3-3 protein family (29). Thus sequestered, Bad is unable to prevent the heterodimerization of Bcl-XL with Bax, favoring cell survival.
Molecular Mechanisms of Brain Insulin Signaling 1
André Kleinridders in Physiological Consequences of Brain Insulin Action, 2023
To exert its effects in the CNS, insulin is transported across the blood-brain barrier by saturable insulin transporters (8–10) and is released into the cerebrospinal fluid (CSF) where it is distributed to insulin-sensitive brain regions. Upon insulin binding to the IR, the IR changes its conformation to bring kinase domains of the IR in proximity to tyrosine phosphorylation sites on the β-chain, allowing the autophosphorylation of at least eight tyrosine residues (11). This then leads to the activation of insulin receptor substrate (IRS) proteins and subsequently of two general downstream signaling arms through (i) the phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB, also called AKT) axis, and (ii) the mitogen-activated protein kinase (MAPK), discussed in detail below (Figure 1.1)
Increasing the Sensitivity of Adipocytes and Skeletal Muscle Cells to Insulin
Christophe Wiart in Medicinal Plants in Asia for Metabolic Syndrome, 2017
Binding of insulin to its receptor activates phosphoinositide 3-kinase which catalyzes the formation of phosphatidylinositol-3,4,5-trisphosphate, an allosteric activator of phosphoinositide-dependent kinase.331 Targets of phosphoinositide-dependent kinase include Akt and atypical protein kinase C.331 To fully activate Akt protein ser-473 activated Akt and thr-308 must be sequentially phosphorylated commands glucose transporter-4 translocation.331 Homoisoflavones fraction of Liriope platyphylla F.T. Wang and T. Tang at a concentration of 1 μg/mL enhanced glucose uptake induced by insulin in 3T3-L1 adipocytes via increased tyrosine phosphorylation of insulin receptor substrate-1, increased phosphorylation of Akt on ser-473 and increased glucose transporter-4 membrane translocation.332 Homoisoflavones present in this plant induce methylophiopogonone A, ophiopogonone A, methyophiopogonanone A, and ophiopogonanone A.332
Novel insights into the pathogenesis of molecular subtypes of diffuse large B-cell lymphoma and their clinical implications
Published in Expert Review of Clinical Pharmacology, 2019
In C5 (MCD) ABC DLBCLs, genetic alterations of components of the BCR signal cascade can be identified as a source of constitutive NF-кB-signaling (Figure 1). BCRs typically form immobile clusters in ABC lymphomas [29]. The BCR is associated with CD79A and CD79B [30]. Upon antigen stimulation, SRC-family kinases (SFK) phosphorylate the immunoreceptor tyrosine-based activation motifs (ITAM) of CD79A/B and the kinase SYK can be recruited [31,32]. The downstream activation of phosphoinositide 3-kinases (PI3K) will be further described below. Bruton’s tyrosine kinase (BTK), B-cell linker protein and phospholipase Cγ2 (PLCγ2) are located to the plasma membrane [33]. PLCγ2 creates inositol-1,4,5-trisphophate (IP3) and diacylglycerol (DAG) whereas DAG activates protein kinase Cβ (PKCβ) finally leading to the assembly of the so called CBM-complex at the plasma membrane consisting of CARD11, BCL10, and MALT1 [34,35]. The CBM-complex activates the NF-κB pathway via IKK.
(−)-4-O-(4-O-β-D-glucopyranosylcaffeoyl) quinic acid exerts anti-tumour effects against uveal melanoma through PI3K/AKT pathway
Published in Cutaneous and Ocular Toxicology, 2021
Hao Kang, Feng Ling, Xiangyang Xin, Li Ping
Phosphoinositide 3-kinases (PI3K) signalling pathway involves in the cellular growth, metabolism and survival6. Uveal melanoma is characterised by activation of signalling pathways including the PI3K and mitogen-activated protein kinase (MAPK). The PI3K pathway activation has been implicated in the pathogenesis of uveal melanoma7–9. PI3K activation catalyses the conversion of phosphatidyl inositol-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3), which activates protein kinase B (AKT) and its downstream targets. Studies showed that the expression of phospho-AKT was reported in about 55% of uveal melanoma cases7. Phosphatase and tensin homolog (PTEN) antagonises PI3K signalling pathway by converting PIP3 back to PIP2. PTEN expression loss has also been associated with a less favourable prognosis in uveal melanoma. Thereafter inhibitors of PI3K/AKT pathway provides a potential strategy to treat uveal melanoma. Pre-clinical studies in uveal melanoma have indicated that inhibiting the PI3K pathway resulted in enhanced anti-tumour effects in cell lines and xenograft tumour models10.
Regulation of hematopoietic cell signaling by SHIP-1 inositol phosphatase: growth factors and beyond
Published in Growth Factors, 2018
Margaret L. Hibbs, April L. Raftery, Evelyn Tsantikos
The Src homology-2 domain-containing inositol phosphatase SHIP-1 was initially identified more than two decades ago as a tyrosine phosphorylated protein that arose after stimulation of hematopoietic cells with various cytokines, growth factors or colony-stimulating factors (CSFs) (reviewed in Rohrschneider et al., 2000). Subsequent studies have shown that its key role is to moderate signaling initiated by phosphoinositide 3-kinase (PI3K). Consistent with this inhibitory role, knockout mouse studies have revealed that SHIP-1-deficient immune cells are hyper-responsive, which leads to a plethora of immune system defects in the mice. More recent studies have verified that SHIP-1 expression and/or activity is altered in human disease. In this review, we will discuss the contributions of SHIP-1 to hematopoietic cell signaling, the phenotypes of SHIP-1-deficient immune cells and SHIP-1–/– mice, and the consequence of dysregulation of this signaling pathway in human disease. Readers are also directed to a recent comprehensive review on SHIP-1 that discusses the role of SHIP-1 in immune cell signaling and its potential as a therapeutic target (Pauls & Marshall, 2017).
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