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The Role of MAP Kinases, Phosphatidylinositol 3-Kinase, and Ceramide in LPS-induced Signaling in Macrophages
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Anthony L. DeFranco, Alexander J. Finn, Julie Hambleton, Mary T. Crowley, Mary Lee MacKichan, Steven L. Weinstein
Another signaling pathway activated by LPS includes the lipid kinase phosphatidylinositol 3-kinase (PI 3-kinase) and two downstream serine/threonine protein kinases Akt/PKB and p70S6kinase. In various cell types, this signaling pathway is thought to regulate translation of certain mRNAs and also to regulate apoptotic pathways (53,54). PI 3-kinase phosphorylates various inositol-containing phospholipids, generating second messengers that may work primarily by serving as ligands for pleckstrin homology (PH) domains in signaling proteins. The interaction between PH domains and the products of PI 3-kinase often serves to recruit signaling components to the plasma membrane in an inducible fashion (55,56). LPS has recently been shown to activate PI 3-kinase in monocytes (57) and in the RAW264.7 macrophage cell line (S. L. Weinstein et al., unpublished). We have also found that LPS activates Akt/PKB (A. J. Finn and A. L. DeFranco, unpublished data) and p70S6kinase (S. L. Weinstein et al., unpublished). LPS induced approximately a threefold increase in p70S6kmase activity in an in vitro kinase assay. Two inhibitors of PI 3-kinase, wortmannin and the chemically distinct inhibitor LY294002, blocked activation of p70S6kinase in response to LPS. In addition, the activation of p70S6kinase was inhibited by the immunosuppressant rapamycin, indicating a role for the mTOR protein, the target of rapamycin, in the activation of p70S6kinase.
PI3K signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
At the plasma membrane, the class-I PI3Ks couple to the cell surface receptors, and upon activation, phosphorylate phosphatidylinositol 4,5-bisphosphate (PI [4,5] P2), which gives rise to short-lived second messenger phosphatidylinositol 3,4,5 trisphosphate (PI [3,4,5] P3) (27). PIP3 induces the recruitment of pleckstrin homology (PH) domain-containing effector proteins such as protein kinases, adaptor proteins and regulators of small GTPases, at the localized site of accumulation.
Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
IRS proteins contain an N-terminal pleckstrin homology (PH) domain adjacent to a phosphotyrosine-binding (PTB) domain, which is followed by several regulatory tyrosine and serine/threonine phosphorylation sites. Here, the PTB domain represents the binding site of IRS proteins to phosphotyrosine residues on the insulin receptor after insulin activation. The PH domain can bind phosphatidylinositol lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) as a substrate of PI3K. Furthermore, the tyrosine phosphorylation sites coordinate downstream signaling cascades by also binding effector proteins like the above-mentioned PI3K or growth factor receptor-bound protein 2 (GRB2). By contrast, the specific serine phosphorylation sites, phosphorylated by the c-Jun N-terminal kinase (JNK1, also known as MAPK8) and other protein kinases, inhibit insulin-stimulated tyrosine phosphorylation. First, this is a negative feedback loop to limit over-stimulation of downstream pathways by insulin (33); second, it also represents one mechanism of insulin resistance if it persists. Upon recruitment of IRS-1 to the insulin receptor by binding of the PTB domain to phosphorylated IR tyrosine residue Tyr999 (note: original publications refer to this tyrosine residue as Tyr960 which shifted due to subsequent sequence updates), the kinase domain of the IR can then phosphorylate tyrosine residues on IRS-1 (34, 35). While the human and murine IRS-1 amino acid sequences are well conserved, the exact position of the tyrosine (Y) residues differ slightly, denoted by either hY or mY for the human or mouse residue, respectively. Thus, the phosphorylated tyrosine residues on IRS-1 are hY465/mY460, hY612/mY608, hY632/mY628, hY662/mY658, hY896/mY891, hY941/mY935, hY989/mY983, hY1179/mY1173, and hY1229/mY1220 (36–39). From here the downstream signaling branches out to either engage the PI3K-AKT or the MAPK pathways.
Knockdown of PHLDA2 promotes apoptosis and autophagy of glioma cells through the AKT/mTOR pathway
Published in Journal of Neurogenetics, 2022
Chengyong Guo, Shuo Liu, Tao Zhang, Jipeng Yang, Zhaohui Liang, Shengkui Lu
Pleckstrin homology like domain family A member 2 (PHLDA2), an imprinted gene expressed in placenta (Tunster, Creeth, & John, 2016), regulated birth weight (Ishida et al., 2012), and spontaneous miscarriages or fetal deaths (Dória et al., 2010). PHLDA2 was associated with cell apoptosis, and previous study showed that over-expression of PHLDA2 induced cell apoptosis of trophoblast (Jin, Qiao, Luan, & Li, 2016). PHLDA2 was dysregulated in endometrial cancer (Liu, Lin, & He, 2019) and lung cancer (Baldavira et al., 2021), and is therefore associated with the poor prognosis. PHLDA2 functioned as an oncogene in pancreatic ductal adenocarcinoma (Idichi et al., 2018), and knockdown of PHLDA2 repressed colorectal cancer cell proliferation and metastasis through promoting of apoptosis and autophagy (Ma, Lou, & Jiang, 2020). However, the role of PHLDA2 in glioma has not been reported yet.
The roles of epidermal growth factor receptor in viral infections
Published in Growth Factors, 2022
Similar to PKC, PI3K/AKT signalling cascade is responsible for cellular processes including cell survival, cell adhesion and cell migration. PI3K are heterodimeric kinases that composed of a p85 regulatory subunit and a p110 catalytic subunit. p85 subunit directly interacts with activated EGFR through the binding between its SH2 domain and phosphorylated tyrosine of the receptors (Jean and Kiger 2014). Following binding, p110 subunit catalyses phosphorylation of membrane bound PIP2 to form PIP3. Pleckstrin homology (PH) domain-containing serine-threonine kinase AKT is recruited to the plasma membrane through association with PIP3 and activated by 3-phosphoinositide-dependent kinase 1 (PDK1). Activated AKT signals to multiple downstream targets including mTOR, glycogen synthase kinase-3 (GSK3), insulin receptor substrate-1 (IRS-1) and cell cycle regulators (p21CIP1, p27KIP1, cyclin D1) (Koyama et al. 2003; Mebratu and Tesfaigzi 2009).
Overcoming challenges in developing small molecule inhibitors for GPVI and CLEC-2
Published in Platelets, 2021
Foteini-Nafsika Damaskinaki, Luis A. Moran, Angel Garcia, Barrie Kellam, Steve P. Watson
The clustering of GPVI and CLEC-2 drives intracellular signaling cascades that lead to activation of platelets. GPVI is a single transmembrane protein belonging to the immunoglobulin family of receptors that is expressed in the membrane with the dimeric Fc receptor (FcR) γ-chain, with each chain having an immunoreceptor tyrosine-based activation motif (ITAM), characterized by two conserved YxxL sequences [29]. In contrast, the single transmembrane, lectin-like receptor, CLEC-2, has one YxxL sequence in its cytosolic tail, named a hemITAM (or hemi-ITAM) [30]. Clustering of GPVI or CLEC-2 leads to phosphorylation of the conserved tyrosines in the hemITAM or ITAM sequence by Src and Syk tyrosine kinases, leading to binding of the tandem SH2 domains in Syk and initiation of a downstream signaling cascade orchestrated through the protein adapter LAT. This acts as a binding template for other proteins facilitating a phosphorylation cascade, including various adapter and effector proteins, leading to activation of PI 3-kinase and PLCγ2 (Figure 1). PI 3-kinase generates the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) which binds to pleckstrin homology and SH2 domains. PLCγ2 generates the second messenger inositol 1,4, 5-trisphosphate (IP3) and 1,2-diacylglycerol, which release Ca2+ and activate protein kinase C, respectively.