Receptor Protein-Tyrosine Kinases

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Role of receptor and non-receptor protein tyrosine kinases in vasoactive peptide-induced signaling

Role of receptor and non-receptor protein tyrosine kinases in vasoactive peptide-induced signaling

Abstract Endothelin-1 (ET-1) and angiotensin II (Ang II) play important roles in maintaining blood pressure and vascular homeostasis, and a heightened activity of these vasoactive peptides is thought to contribute to the development of vascular pathologies, such as hypertension, atherosclerosis, hypertrophy and restenosis. This is caused by an excessive activation of several growth and proliferative signaling pathways, which include members of the mitogen-activated protein kinase (MAPK) family, as well as the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) pathway. While the activation of these signaling pathways is well elucidated, the upstream elements responsible for ET-1 and Ang II- induced MAPK and PI3-K/PKB activation remain poorly understood. During the last several years, the concept of transactivation of receptor and/or non-receptor protein tyrosine kinases (PTK) in triggering vasoactive peptide-induced signaling events has gained much recognition. We have recently demonstrated that insulin-like growth factor-1 receptor (IGF-1R) plays a role in tranducing the effect of H 2 O 2, leading to PKB phosphorylation.
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Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers

Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers

1. Introduction To be able to play their physiological role (intra- and inter-cellular signal transmission, adaptation to changes in the microenvironment), cells must be able to receive, integrate and respond to numerous extracellular messengers. These communications between cells and their environment are made possible through the attachment of molecules considered as messengers to their receptors, identified as effectors (cytokines, growth factors, etc). As proposed by Ehrlich in 1910, “to act, a substance must be fixed." These receptors are essentially located at the cell membrane, although there are also intra-cytoplasmic receptors such as steroid hormone that can be translocated into the nucleus to regulate expression of numerous genes. Membrane receptors possess: (i) an extracellular hydrophilic domain, often glycosylated, which recognises the ligand; (ii) a hydrophobic trans-membrane domain that makes embedding possible within the lipid bilayer of the plasma membrane; and (iii) an intra- cytoplasmic domain dedicated to signal transduction within the cell. The binding of a ligand to its receptor is specific, reversible and involves a large number of low-energy bonds (hydrogen, ionic, hydrophobic, Van der Waals). Thus, at equilibrium, the dissociation rate is equal to the rate of association. Among the receptors of cytokine/growth factors, six types of receptor have intrinsic enzymatic activity (kinase or phosphatase receptors, and guanylyl cyclase-coupled receptors) or not (the G protein-coupled receptors, the receptor-type "channel", and cytokine receptors).
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Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

2. Tyrosine Kinase (TK) Group 2.1. Tropomyosin-Related Kinases (Trks) Tropomyosin-related kinases (Trks) are frequently cited as targets for pain application. The tropomyosin-related kinases (Trks) are cell surface receptor tyrosine kinases divided into three homologous isoforms: TrkA, TrkB and TrkC. TrkA was initially identified as an oncoprotein, leading to numerous works dealing with Trk inhibitors with anticancer application. However, the involvement of nerve growth factor (NGF) and its receptor TrkA in chronic pain management is now well established [ 9 ]. Therapies that target NGF–TrkA signaling demonstrated significant analgesic activity, showing that small molecule Trk inhibitors would be relevant as new therapeutic approaches to manage several types of chronic pain. Other growth factors of the neurotrophin family (BDNF and NT4 interacting with TrkB; NT3 interacting with TrkC) are also involved in chronic pain. For example, Wang et al., using the cyclic peptide cyclotraxin B, a noncompetitive highly potent and selective TrkB inhibitor (IC 50 TrkB = 0.3 nM) [ 10 ], demonstrated the implication of BDNF/TrkB in
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The role of RICTOR downstream of receptor tyrosine kinase in cancers

The role of RICTOR downstream of receptor tyrosine kinase in cancers

Abbreviations AJCC: American joint committee on cancer; CRC: Colorectal cancer; EGFR: Epidermal growth factor receptor; ESCC: Esophageal squamous cell carcinoma; FGFR: Fibroblast growth factor receptor; GBM: Glioblastoma; GC: Gastric cancer; GDP: Guanosine diphosphate; GIST: Gastrointestinal stromal cancer; GTP: Guanosine triphosphate; HER2: Human epidermal growth factor receptor 2; HGFR: Hepatocyte growth factor receptor; HIF- 1 α: Hypoxia-induced factor-1α; IGFR: Insulin-like growth factor receptor; IR: Insulin receptor; MAPK: Mitogen-activated protein kinases; mTOR: Mammalian target of rapamycin; mTORC1: Mammalian target of rapamycin complex 1; mTORC2: Mammalian target of rapamycin complex 2; PDAC: Pancreatic ductal adenocarcinoma; PDGFR: Platelet-derived growth factor receptor; PDK1: Phosphoinositol-dependent kinase-1; PH: Pleckstrin homology; PI3K: Phosphoinositide 3-kinase (mTOR); PIP2: Phosphatidylinositol 4,5 phosphate; PIP3: Phosphatidylinositol 3,4,5 phosphate;
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Regulation of the hepatocyte cell cycle: signaling pathways and protein kinases.

Regulation of the hepatocyte cell cycle: signaling pathways and protein kinases.

rats. They further demonstrate that the cell cycle activity is partially restored by the adenosine derivate IFC-305 and suggest that the preservation of mitochondrial function may contribute to the recovery of proliferation in cirrhotic livers. The second and major theme of this issue is dedicated to the activation of intracellular signaling pathways and gene profile modifications controlling the priming of hepatocytes and progression in early G1 phase of the cell cycle. T. Garcin and T. Tordjmann “Calcium signalling and liver regeneration” reviewed the latest knowledge regarding the calcium sig- naling in liver regeneration following stimulation of the hepatocytes by calcium mobilizing agonists and activation of tyrosine kinase receptors, receptor channels, and G-protein- coupled receptors. This review emphasizes that calcium movement both in the cytoplasm and nucleus are clearly important events in the proliferative signaling through the transcriptional activation of immediate early genes and the control of the G1/S and G2/M transitions. Four other reviews develop distinct aspects of the signaling pathways especially phosphorylation events regulating the progression throughout the G1 phase and the commitment to DNA replication. The G1 phase of the cell cycle is per se under the control of extracellular growth factors activating a cascade of phosphorylation/dephosphorylation events that ultimately lead to the commitment to DNA replication. Beyond the G1/S transition, committed cells will proceed to DNA replication and mitosis regardless of the presence of growth factors in the extracellular microenvironment. The review by A. C. de l’Hortet and co-workers “EGFR: A
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Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology

Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology

EGFR signaling is complex because EGFR can be activated indirectly by various compounds known to participate in the pathogenesis of CCA, such as bile acids (BAs). BAs increased cellular myeloid cell leuke- mia sequence 1 (Mcl-1) protein levels, a potent antia- poptotic protein from the B-cell lymphoma 2 (Bcl-2) family, by inhibiting Mcl-1 degradation through the EGFR/Raf-1 signaling pathway (47) and the production of cyclooxygenase-2 (COX-2) through the EGFR/ mitogen-activated protein kinase (MAPK) signaling pathway. (47) EGFR activation by BAs occurred through a TGFa-dependent mechanism involving MMP activity as a requisite for TGFa membrane release (48) (Fig. 2). More recently, it was reported that conjugated BAs promoted the invasive growth of CCA through activation of sphingosine 1-phosphate receptor 2 (S1PR2; Fig. 2) followed by activation of the EGFR/extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway. (49) Finally, it was shown, in BDL mice, that BAs trigger cholangiocyte proliferation after binding to their G-protein-coupled
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Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

2. Tyrosine Kinase (TK) Group 2.1. Tropomyosin-Related Kinases (Trks) Tropomyosin-related kinases (Trks) are frequently cited as targets for pain application. The tropomyosin-related kinases (Trks) are cell surface receptor tyrosine kinases divided into three homologous isoforms: TrkA, TrkB and TrkC. TrkA was initially identified as an oncoprotein, leading to numerous works dealing with Trk inhibitors with anticancer application. However, the involvement of nerve growth factor (NGF) and its receptor TrkA in chronic pain management is now well established [ 9 ]. Therapies that target NGF–TrkA signaling demonstrated significant analgesic activity, showing that small molecule Trk inhibitors would be relevant as new therapeutic approaches to manage several types of chronic pain. Other growth factors of the neurotrophin family (BDNF and NT4 interacting with TrkB; NT3 interacting with TrkC) are also involved in chronic pain. For example, Wang et al., using the cyclic peptide cyclotraxin B, a noncompetitive highly potent and selective TrkB inhibitor (IC 50 TrkB = 0.3 nM) [ 10 ], demonstrated the implication of BDNF/TrkB in
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Quantitative phosphoproteomics reveals a cluster of tyrosine kinases that mediates SRC invasive activity in advanced colon carcinoma cells.

Quantitative phosphoproteomics reveals a cluster of tyrosine kinases that mediates SRC invasive activity in advanced colon carcinoma cells.

kinases, except Syk (Fig. 5A, left panel). Similar results were obtained from SW620-Src cells that were transiently transfected with specific siRNA targeting Met, EphA2 and Fak, indicating that these inhibitory effects were not due to off-targets and/or long-term depletion of these kinases (Supplementary Fig. S4C and S4D). In contrast, they had a low impact on the

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Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice

Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice

(Fig. 5 a), without affecting normal mechanical nociception (Supplementary Fig. 5 d). These changes were accompanied by reductions of PNP-related mRNAs (Supplementary Fig. 5 e) and protein levels, as shown by reductions in numbers of cells expressing ATF3, NPY, and GFAP in the DRG (Fig. 5 b, c). To determine whether neuronal FLT3 in DRG is necessary and sufficient to regulate PNP symptoms, we constructed an AAV9 virus vector co-expressing an Flt3 shRNA (Flt3-sh) and the green fluorescence protein (GFP). When injected intrathecally, virus- derived GFP expression in DRG was restricted to neurons (Fig. 5 d) and in DSC appeared only in fiber-like processes, most likely originating from sensory neuron projections. GFP expres- sion was not present in DSC cell bodies (Supplementary 6 a, b). Following reduction of FLT3 protein levels in the DRG after treatment with the Flt3-directed shRNA-expressing AAV9 virus (Supplementary Fig. 6 c, d), intrathecal FL injections failed to produce evoked mechanical pain hypersensitivity (Fig. 5 e), as well as increase pain score, which takes into account pain-related behaviors (Fig. 5 f), thus showing that the effect of FL is exerted directly via neuronal FLT3. Furthermore, Flt3-directed shRNA largely reduced percentage of withdrawal in CCI mice, whereas an AAV9 virus expressing a non-targeting shRNA had no effect (Fig. 5 g). Thus, inhibition of Flt3 expression reduced mechanical pain hypersensitivity produced by either FL injection or nerve injury. Altogether, these results show that PNP symptoms
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Etude du métabolisme d'inhibiteurs de tyrosine kinases, caractérisation de nouveaux métabolites réactifs du pazopanib et du sunitinib par une approche de catalyse biomimétique et implication potentielle dans leurs effets indésirables

Etude du métabolisme d'inhibiteurs de tyrosine kinases, caractérisation de nouveaux métabolites réactifs du pazopanib et du sunitinib par une approche de catalyse biomimétique et implication potentielle dans leurs effets indésirables

Page | 36 ([IC 95% : 1,56-4,82], p < 0,001)/1,66 ([IC 95% : 1,25-2,20], p = 0,001) pour l’ALAT et - /1,61 ([IC 95% : 1,21-2,14], p = 0,001) pour l’ASAT) 71,72 . L’hépatotoxicité des ITK se manifeste sous la forme d’élévation de bas grade/de haut grade des transaminases chez environ 25-35%/2% des patients, mais l’incidence est très variable selon les molécules (6-86%/<1-12%). Ces perturbations biologiques surviennent généralement au cours des deux premiers mois de traitement et sont le plus souvent spontanément résolutives ou réversibles grâce à une prise en charge adaptée. Toutefois, des manifestations sévères d’hépatotoxicité d’évolution parfois fatale ont été rapportées, bien que les cas d’insuffisance hépatique soient rares. Une surveillance régulière de la fonction hépatique est donc nécessaire afin de pouvoir faire un diagnostic précoce 42 . La prise en charge des patients repose essentiellement sur des réductions posologiques et des arrêts thérapeutiques temporaires voire définitifs 42,43 . Dans ce dernier cas, l’ITK hépatotoxique peut être substitué par un autre ITK ayant les mêmes cibles sans récidive de toxicité hépatique. L’absence de toxicité croisée au sein d’une classe d’ITK, tout comme le fait que tous les ITK soient hépatotoxiques (bien qu’à des degrés divers), indique que l’hépatotoxicité ne résulte pas d’un effet pharmacodynamique au niveau des tyrosine kinases cibles 43 .
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Purification and Identification of G Protein- coupled Receptor Protein Complexes under Native Conditions

Purification and Identification of G Protein- coupled Receptor Protein Complexes under Native Conditions

cot 姞 search engine (version 2.1.04). Up to two trypsin missed cleav- ages were allowed, and the mass tolerance for peptide and MS/MS fragment ions was 0.5 Da. Cysteine carbamidomethylation and pro- pionamide and methionine oxidation were set as variable modifica- tions. Identification was considered positive if the protein was iden- tified with at least one peptide with an ion score greater than the Mascot significance threshold of 36 (p ⬍ 0.05). For the protein with a score close to the threshold value, the identification was confirmed by manual interpretation of corresponding MS/MS data. To evaluate the false-positive rate in these large scale experiments, we repeated the searches using identical search parameters and validation criteria against a random database made of the same compilation in which the sequences have been reversed. These statistical analyses pro- vided respectively 2.1, 4.1, and 5.8% false-positive rate for MT 1 -TAP,
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Neutralizing aptamers from whole-cell SELEX inhibit the RET receptor tyrosine kinase.

Neutralizing aptamers from whole-cell SELEX inhibit the RET receptor tyrosine kinase.

We next determined whether D4 could inhibit wild-type RET. Cells from a PC12-derived cell line expressing the human wild-type RET (PC12/wt) were stimulated with a mixture containing GDNF and soluble GDNF family receptor a1 (GFRa1), and either treated with the D4 aptamer or with the starting pool of 29F-Py RNA as a negative control. As shown in Figure 4A, the D4 aptamer, but not the control RNA pool, strongly inhibited GDNF-induced phosphorylation of RET (left panel) and of the downstream effector ERK (middle panel). A similar inhibitory effect was observed in PC12-a1/wt cells, a PC12-derived cell line that stably expresses both human RET and GFRa1 (unpublished data). In contrast, D4 was inactive in inhibiting the signaling triggered by the unrelated nerve growth factor (NGF) receptor tyrosine kinase TrkA, thus indicating that D4-induced inhibition of ERK phosphorylation was specific for RET intracellular signaling (Figure 4A, right pane)
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Plant Lectins and Lectin Receptor-Like Kinases: How Do They Sense the Outside?

Plant Lectins and Lectin Receptor-Like Kinases: How Do They Sense the Outside?

2. Occurrence of Lectin Domains in Plants 2.1. Distribution of Lectin Domains through Life Kingdoms A first survey of the literature indicates that proteins having the architecture of LecRLKs belong to several lectin and CBM families, namely the G-type and L-type lectins [ 1 ], together with the LysM and malectin CBMs [ 23 , 24 ]. In order to address an overview of the domain organization of lectins among the different families, we carried out a comprehensive search using the Pfam database [ 25 ] (pfam.xfam.org; version 31, March 2017). The data mining concerned the above lectin families, but also all the CBM families [ 21 ] (available online: www.cazy.org ) and the C-type lectin and jacalin families. We summarize the results of the search in Figure 1 . First, lectins are widespread proteins and several thousand sequences were retrieved for each family. However, their expansion tremendously varied depending on the life kingdom. While G-type and L-type lectin families found large spreading in plants, LysM CBMs and C-type lectins are expanded in bacteria and in animals respectively. Malectin CBMs are referenced in two accessions, i.e., malectin domains (PF11721) and malectin-like domains (PF12819): both found large spreading in plants (Figure 1 ). Second, it appears that three domain organizations are predominant in most families: (i) the typical LecRLK architecture, i.e., from N- to C-terminus, signal peptide, lectin/CBM domain, transmembrane domain and intracellular kinase domain; (ii) the receptor-like protein (LecRLP) architecture, i.e., the same as previous except the lack of the kinase domain; (iii) the soluble protein (LecP) architecture, with only signal peptide and lectin/CBM domain.
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The protein tyrosine phosphatase interacting protein 51 (PTPIP51) is required for the differentiation of photoreceptors

The protein tyrosine phosphatase interacting protein 51 (PTPIP51) is required for the differentiation of photoreceptors

Stenzinger A, Schreiner D, Koch P, Hofer H, Wimmer M (2009b) Cell and Molecular Biology of the Novel Protein Tyrosine- Phosphatase-Interacting Protein 51. Int Rev Cell Mol Biol 275:183–246. Stoica R, De Vos KJ, Paillusson S, Mueller S, Sancho RM, Lau K-F, Vizcay-Barrena G, Lin W- L, Xu Y-F, Lewis J, Dickson DW, Petrucelli L, Mitchell JC, Shaw CE, Miller CCJ (2014) ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat Commun 5:3996.

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The role of small adaptor proteins in the control of oncogenic signaling driven by tyrosine kinases in human cancer

The role of small adaptor proteins in the control of oncogenic signaling driven by tyrosine kinases in human cancer

MIG6 inhibits ERBB kinase activities by direct binding of its EBR region to ERBB catalytic domain. Mechanistically, the N-terminal portion of EBR, called segment 1 (amino acids 336-364), interacts with ERBB C-lobe that overlaps with a site critical for forming the asymmetric dimer with the N-lobe of the other ERBB subunit. As a result, MIG6 locks ERBB in a catalytically inactive conformation and hinders its dimerization required for signal transduction [127]. Recently, it has been shown that phosphorylation on Tyr394 and Tyr395, which are located in segment 2 (amino acids 365-412) of EBR C-terminus, is critical for effective interaction of MIG6 with EGFR [128, 129]. A structural analysis suggests that EBR segment 1 binds across the base of the C lobe of ERBB and segment 2 forms a β-hairpin-like element that occupies the peptide-substrate binding site, once phosphorylated. Interestingly, Tyr394 and Tyr395 are phosphorylated by EGFR and SRC respectively [130], thus creating a forward feedback loop in the control of ERBB activity by MIG6. MIG6 also plays a role in ERBB receptor trafficking. Upon EBR docking onto the receptor, the RED domain interacts with the endocytic proteins AP-2 and intersectins to induce clathrin-mediated ERBB endocytosis [131]. Moreover, MIG6 mediates ERBB receptor sorting to late endosomes by binding to syntaxin 8, thus promoting ERBB lysosomal degradation [132]. MIG6 expression also negatively regulates MET signaling [133]. This activity requires an intact CRIB motif, suggesting that MIG6 acts, at least in part, distally from MET, possibly by inhibiting Rho-like GTPases. Surprisingly, MIG6 can also activate the CTK ABL by interacting with its kinase domain via the EBR domain. MIG6-dependent ABL activation occurs only when ERBB is inactive and leads to the induction of ABL apoptotic function [134]. This sophisticated mechanism is consistent with a switch-like mechanism, whereby MIG6 interacts with and attenuates EGFR activity, while in the absence of ERBB stimulation, it activates ABL pro-apoptotic function.
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Calcium- and tyrosine phosphorylation-dependent mechanisms of amyloid precursor protein processing

Calcium- and tyrosine phosphorylation-dependent mechanisms of amyloid precursor protein processing

Calcium influx induced with ionomycin mimicked the effects of muscarinic receptor activation with carbachol on tyrosine phosphorylation and on APPs secretion.. These ef[r]

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Role of the Protein Tyrosine Kinase 7 gene in human neural tube defects

Role of the Protein Tyrosine Kinase 7 gene in human neural tube defects

i Abstract Neural tube defects (NTDs) are among the most common congenital defects with a high incidence of 1-2 per 1000 births, causing a heavy burden to both the families and society. Various types of NTDs result from defects happening in the neurulation process during vertebrate embryonic development. In order to prevent the occurrence of NTDs, understanding the underlying mechanism is a prerequisite. The etiology of NTDs is complex involving environmental and genetic factors. Folic acid supplementation was proven to efficiently decrease the frequency of NTDs by 50-70% depending on the time point of this supplementation and demographic background. Gene identification studies in NTDs have adopted mainly a candidate gene approach investigating folate-related genes and genes derived from animal models. In particular, studies in mouse models have demonstrated a strong association between the non canonical Wnt/Planar Cell Polarity (PCP) pathway and NTDs. Protein Tyrosine Kinase 7 (PTK7) is a member of the PCP pathway and was shown to cause a very severe form of NTDs called craniorachischisis in a mouse model. Ptk7 genetically interacts with a core PCP member Vangl2 where double heterozygotes suffer from spina bifida. These data make PTK7 a strong candidate for NTDs in humans. We sequenced the coding region and the exon-intron junctions of PTK7 in a cohort of 473 patients affected with various forms of open and closed NTDs. Novel and rare variants (<1%) were genotyped in a cohort of 473 individuals. Their pathogenic effect was predicted in silico and functionally in an overexpression assay in a well established zebrafish model. We identified in our cohort 6 novel rare mutations, 3 of which are absent in all public databases, in 1.1% of our NTD cohort. One variant, p.Gly348Ser, acted as a hypermorph when overexpressed in the zebrafish model. Our findings implicate mutation of PTK7 as a risk factor for NTDs and provide additional evidence for a pathogenic role of PCP signaling in these malformations.
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Mutations d’AIP (Aryl hydrocarbon receptor-Interacting Protein)
dans les adénomes hypophysaires sporadiques

Mutations d’AIP (Aryl hydrocarbon receptor-Interacting Protein) dans les adénomes hypophysaires sporadiques

Des adénomes somatotropes sont ainsi trouvés chez des patients porteurs d’un complexe de Carney, lié dans plus de 60% des cas à une mutation germinale inactivatrice du gène PRKAR1A ([r]

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Gene Expression of Protein Tyrosine Phosphatase 1B and Endoplasmic Reticulum Stress During Septic Shock

Gene Expression of Protein Tyrosine Phosphatase 1B and Endoplasmic Reticulum Stress During Septic Shock

Inflammation can directly contribute to insulin resistance by disrupting the insulin signaling pathway, in part via PTP1B activation. In a previous experimental study, we demonstrated that PTP1B gene deletion significantly limited CLP-induced insulin resistance, improved AMP-activated protein kinase signaling pathway and Glucose Transporter 4 translocation, and decreased inflammation ( 9 ). In the present work, we did not find any link between PTPN1 levels and HOMA-IR index, glycemia, glycemia variation or insulin consumption. A previous work described a strong correlation between insulin resistance evaluated through HOMA-IR index and plasma PTP1B level in a population of patients with polycystic ovarian syndrome ( 26 ).
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Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote.

Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote.

CamK group The main branch of the tree that contains the human CamKs also contains 13 PfePKs, which underlines the importance of calcium signalling in the parasite [23]. A tight cluster is formed by five of these enzymes, which share the overall structure of the calcium-dependent pro- tein kinases (CDPKs) found in plants and ciliates but not in Metazoans. CDPKs are characterised by the presence of a kinase catalytic domain located on the same polypep- tide as four EF-hand calcium-binding domains. Four of these enzymes have been described previously: PfCDPK1 [PFB0815w] [24], PfCDPK2 [MAL6P1.108] [25], PfCDKP3 [PFC0420w] [26] and more recently PfCDPK4 [PF07_0072]. The latter enzyme is expressed in sexual stages and was shown to be essential for development of the parasite in the mosquito, through mediating cell cycle resumption during male gametocyte exflagellation [27]. A fifth CDPK [PF13_0211], which like the four cited above possesses four EF-hand motifs, has been discovered in the present study. PF11_0242 appears to be related to CDPKs, but contains only one EF-hand motif. PfPK2 [Pfl1885c] constitutes a sister branch to the CDPK group. This enzyme was previously characterized as being related to the CamK family [28], and has no EF-hand domain. No malarial kinase clusters closely with the mammalian CamKs used to anchor the tree. Six other sequences, how- ever, form a sister branch to the cluster that contains the CDPKs; only one of these six sequences (PF11_0239) pos- sesses an EF-hand domain. The CamK activity described [29] as crucial for ookinete development in the mosquito vector (see below) is likely to be associated with one of the enzymes in this group.
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