BioAssay record AID 743310 submitted by Burnham Center for Chemical Genomics: SAR confirmation of uHTS small molecule inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase, LMPTP, in a fluorescence-based, VHR-1 (dual specificity phosphatase 3) selectivity assay.
TY - JOUR. T1 - Haemophilus ducreyi targets Src family protein tyrosine kinases to inhibit phagocytic signaling. AU - Mock, Jason R.. AU - Vakevainen, Merja. AU - Deng, Kaiping. AU - Latimer, Jo L.. AU - Young, Jennifer A.. AU - Van Oers, Nicolai S C. AU - Greenberg, Steven. AU - Hansen, Eric J.. PY - 2005/12. Y1 - 2005/12. N2 - Haemophilus ducreyi, the etiologic agent of the sexually transmitted disease chancroid, has been shown to inhibit phagocytosis of both itself and secondary targets in vitro. Immunodepletion of LspA proteins from H. ducreyi culture supernatant fluid abolished this inhibitory effect, indicating that the LspA proteins are necessary for the inhibition of phagocytosis by H. ducreyi. Fluorescence microscopy revealed that macrophages incubated with wild-type H. ducreyi, but not with a lspA1 lspA2 mutant, were unable to complete development of the phagocytic cup around immunoglobulin G-opsonized targets. Examination of the phosphotyrosine protein profiles of these two sets of ...
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T-Cell Protein Tyrosine Phosphatase (TC PTP) is a phospho tyrosine-specific protein phosphatase. It is a truncated form of the human T-Cell protein tyrosine phosphatase (residues 1-317) which lacks a C-terminal regulatory domain (1
Ludwig, L.M.; Weihrauch, D.; Kersten, J.R.; Pagel, P.S.; Warltier, D.C., 2004: Protein kinase C translocation and Src protein tyrosine kinase activation mediate isoflurane-induced preconditioning in vivo: potential downstream targets of mitochondrial adenosine triphosphate-sensitive potassium channels and reactive oxygen species
Protein tyrosine phosphatases (PTPs) play an important role in regulating cell signaling events in coordination with tyrosine kinases to control cell proliferation, apoptosis, survival, migration, and invasion. Receptor-type protein tyrosine phosphatases (PTPRs) are a subgroup of PTPs that share a transmembrane domain with resulting similarities in function and target specificity. In this review, we summarize genetic and epigenetic alterations including mutation, deletion, amplification, and promoter methylation of PTPRs in cancer and consider the consequences of PTPR alterations in different types of cancers. We also summarize recent developments using PTPRs as prognostic or predictive biomarkers and/or direct targets. Increased understanding of the role of PTPRs in cancer may provide opportunities to improve therapeutic approaches.
Activation of T lymphocytes constitutes a central event in adaptive immune responses against infectious pathogens or tumor cells. Antigen recognition by T cells is performed through the T cell receptor (TCR) which triggers a cascade of intracellular signals leading to T cell activation and development of effector functions. Proper TCR signaling requires the sequential activities of lymphocyte-specific protein tyrosine kinase (Lck) and zeta-chain-associated protein kinase 70 (ZAP-70) kinases, resulting in the phosphorylation of tyrosine residues located in the CD3 immunoreceptor tyrosine-based activation motifs (ITAMs) and the linker for activation of T cells (LAT) adaptor, respectively. Phosphorylation of LAT causes the recruitment of many proteins to the membrane, allowing their phosphorylation and activation of downstream signaling pathways. Although there has been a huge increase in knowledge on early intracellular signaling in recent years, much less is known about the molecular mechanisms
Assignment of the human gene for receptor-type protein tyrosine phosphatase IA-2 (PTPRN) to chromosome region 2q35-q36.1 and identification of an intragenic genetic ...
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Looking for online definition of Bruton tyrosine kinase in the Medical Dictionary? Bruton tyrosine kinase explanation free. What is Bruton tyrosine kinase? Meaning of Bruton tyrosine kinase medical term. What does Bruton tyrosine kinase mean?
Malignant mesothelioma is an aggressive tumor arising from mesothelial cells of serous membranes. Src family kinases (SFKs) have a pivotal role in cell adhesion, proliferation, survival and apoptosis. Here, we examined the effect of SFK inhibitors in NCI-H2052, ACC-MESO-4 and NCI-H28 cells, mesothelioma cell lines and Met5A, a human non-malignant mesothelial cell line. We found that PP2, a selective SFK inhibitor, inhibited SFK activity and induced apoptosis mediated by caspase-8 in NCI-H28 but not Met5A, NCI-H2052 and ACC-MESO-4 cells. Src, Yes, Fyn and Lyn protein, which are members of the SFK, were expressed in these cell lines, whereas NCI-H28 cells were deficient in Fyn protein. Small interfering RNA (siRNA) targeting Fyn facilitated PP2-induced apoptosis mediated by caspase-8 in NCI-H2052 and ACC-MESO-4 cells. PP2 reduced Lyn protein levels and suppressed SFK activity in all mesothelioma cell lines. Lyn siRNA induced caspase-8 activation and apoptosis in NCI-H28 cells but not in NCI-H2052 ...
TY - JOUR. T1 - Cross-linking of tyrosine-containing peptides by hydrogen peroxide-activated Coprinus Cinereus peroxidase. AU - Steffensen, C.L.. AU - Mattinen, Maija-Liisa. AU - Andersen, Henrik Jørgen. AU - Kruus, Kristiina. AU - Buchert, Johanna. AU - Holm Nielsen, Jacob. PY - 2008. Y1 - 2008. N2 - Hydrogen peroxide-activated Coprinus Cinereus peroxidase (CIP) can initiate polymerization of tyrosine-containing peptides via initial formation of an intermediate tyrosyl radical, which for the first time has been identified by spin trap electron spin resonance spectroscopy as located on carbon 1 in the aromatic ring, and subsequent formation of either dityrosine or isodityrosine bonds through a net elimination of two hydrogen atoms between peptides. The rate and degree of polymerization were found to depend on peptide size and the amino acid adjacent to tyrosine, as longer peptides and amino acids with bulky side groups were less reactive. In the forwarded hypothesis for the reaction mechanism ...
Aims: The human cardiac transient outward K + current Ito (encoded by Kv4.3 or KCND3) plays an important role in phase 1 rapid repolarization of cardiac action potentials in the heart. However, modulation of I to by intracellular signal transduction is not fully understood. The present study was therefore designed to determine whether/how human atrial I to and hKv4.3 channels stably expressed in HEK 293 cells are regulated by protein tyrosine kinases (PTKs). Methods and results: Whole-cell patch voltage-clamp, immunoprecipitation, western blotting, and site-directed mutagenesis approaches were employed in the present study. We found that human atrial I to was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2. The inhibitory effect was countered by the protein tyrosine phosphatase inhibitor orthovanadate. In HEK 293 cells stably expressing human KCND3, genistein, AG556, ...
TY - JOUR. T1 - Docking-based substrate recognition by the catalytic domain of a protein tyrosine kinase, C-terminal Src kinase (Csk). AU - Lee, Sungsoo. AU - Ayrapetov, Marina K.. AU - Kemble, David J.. AU - Parang, Keykavous. AU - Sun, Gongqin. PY - 2006/3/24. Y1 - 2006/3/24. N2 - Protein tyrosine kinases are key enzymes of mammalian signal transduction. Substrate specificity is a fundamental property that determines the specificity and fidelity of signaling by protein tyrosine kinases. However, how protein tyrosine kinases recognize the protein substrates is not well understood. C-terminal Src kinase (Csk) specifically phosphorylates Src family kinases on a C-terminal Tyr residue, which down-regulates their activities. We have previously determined that Csk recognizes Src using a substrate-docking site away from the active site. In the current study, we identified the docking determinants in Src recognized by the Csk substrate-docking site and demonstrated an interaction between the docking ...
T cell development in the thymus produces multiple lineages of cells, including conventional naïve CD4+ and CD8+ T cells, regulatory T cells, and innate T cells. Innate T cells encompass γδ T cells, invariant natural killer (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and H2-M3-restricted cells (Berg, 2007). Although they are a minor subset of all thymocytes, innate T cells develop in the thymus and share characteristics of the innate and adaptive immune systems (Berg, 2007). These lymphocytes undergo antigen receptor rearrangement and are able to exert their effector function immediately upon ex vivo stimulation (Berg, 2007). However, in several strains of mice harboring mutations in T cell signaling proteins or transcriptional regulators, conventional CD8+ T cells develop as innate cells that share characteristics with memory T cells (Atherly et al., 2006b; Broussard et al., 2006; Fukuyama et al., 2009; Gordon et al., 2011; Verykokakis et al., 2010b; Weinreich et al., 2010). One of
The protein kinase activity associated with pp60src, the transforming protein of RSV, phosphorylates tyrosine when assayed in an immunoprecipitate. This observation is surprising because protein modification by way of phosphorylation of tyrosine is unprecedented (28, 29). It is nonetheless real. We have found that chicken cells (Table 1) and mouse, rat, and hamster cells (data not shown) all contain readily detectable amounts of Tyr(P). This modified amino acid appears to have escaped detection before because it is rare (phosphoserine and phosphothreonine together being about 3000 times more abundant) and because it and phosphothreonine are difficult to separate by traditional electrophoretic procedures. Because there is a 7-fold increase in the abundance of Tyr(P) in proteins in cells transformed by RSV and because pp60src itself contains Tyr(P), it seems likely that pp60src phosphorylates tyrosine in vivo as well as in vitro. We suggest that pp60src is a protein kinase and that the ...
The cDNAs encoding human prostatic acid phosphatase were cloned and characterized. The mRNAs contain 3' noncoding regions of heterogeneous sizes 646, 1887 or 1913 nucleotides. A dimer and a monomer of the conserved Alu-repeats are present in the longer 3' noncoding sequences. The complete sequence of 354 amino acids for the mature enzyme was determined by sequencing both cDNA and protein. Human prostatic and lysosomal acid phosphatases exhibit 50% sequence homology, including five Cys residues and two putative N-linked glycosylation sites. The Acp-3 gene coding for human prostatic acid phosphatase was mapped onto chromosome 3 in this investigation. The Acp-2 gene coding for lysosomal acid phosphatase has previously been located on chromosome 11, while the Acp-1 gene coding for red blood cell acid phosphatase is on chromosome 2.
Nuclear extracts from pre-B and B cell lines contain a nuclear DNA binding protein (kappa locus protein, KLP) that specifically recognizes a DNA sequence in the immunoglobulin kappa light chain joining (J) segment gene region. KLP is not observed in mature B cells, T cells, or nonlymphoid cell types. Two tandem binding sites for KLP designated KI and KII have been identified by methylation interference analysis to be immediately proximal to the J-kappa-1 nonamer-heptamer recognition sequences and separated by 38 base pairs from each other. Fragments of DNA containing KI and KII sites compete for binding to KLP, and both protein-DNA complexes have the same electrophoretic mobility. Other flanking sequences of immunoglobulin gene fragments do not bind to KLP. The position of KLP-DNA binding and its tissue-specific expression suggest that it may be involved in the regulation of lymphoid gene DNA rearrangements by targeting recombinase to the kappa-chain gene region. ...
Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that modulates key signaling molecules involved in synaptic plasticity and neuronal function. Targets include extracellular-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase p38 (p38), the Src family tyrosine kinase Fyn, N-methyl-d-aspartate receptors (NMDARs), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). STEP-mediated dephosphorylation of ERK1/2, p38, and Fyn leads to inactivation of these enzymes, whereas STEP-mediated dephosphorylation of surface NMDARs and AMPARs promotes their endocytosis. Accordingly, the current model of STEP function posits that it opposes long-term potentiation and promotes long-term depression. Phosphorylation, cleavage, dimerization, ubiquitination, and local translation all converge to maintain an appropriate balance of STEP in the central nervous system. Accumulating evidence over the past decade indicates that STEP dysregulation ...
TY - JOUR. T1 - The Influence of Thyroxine and Thiouracil on Rats Fed Excess Tyrosine (34572). AU - Boctor, Amal M.. AU - Rogers, Quinton. AU - Harper, A. E.. PY - 1970/1/1. Y1 - 1970/1/1. N2 - Addition of thiouracil to a high tyrosine diet alleviated signs of tyrosine toxicity in the rat, whereas, daily injections of thyroxine aggravated them. Plasma tyrosine concentration and liver tyrosine transaminase activity were high in rats fed a high tyrosine diet; thyroxine administration increased them further, but depressed slightly the activity of liver p-hydroxyphenylpyruvate hydroxylase.. AB - Addition of thiouracil to a high tyrosine diet alleviated signs of tyrosine toxicity in the rat, whereas, daily injections of thyroxine aggravated them. Plasma tyrosine concentration and liver tyrosine transaminase activity were high in rats fed a high tyrosine diet; thyroxine administration increased them further, but depressed slightly the activity of liver p-hydroxyphenylpyruvate hydroxylase.. UR - ...
Tyrosine is derived from the diet, from metabolism of phenylalanine, and from the body's proteins during catabolic stress. Tyrosine degradation is catalyzed by a series of five enzymatic reactions, with end products being acetoacetate and fumarate. The hepatocyte and renal proximal tubules are the only two cell types that express the complete pathway and contain sufficient quantities of all enzymes required for tyrosine catabolism (Figure 17-1). Normal plasma tyrosine concentrations are between 30 and 120 μmol/L. Increased concentrations of tyrosine in plasma are common and may be the result of a primary inherited metabolic disorder, but they may also be secondary. The most common causes are listed in Table 17-1. The primary disorders are all defects in the tyrosine degradation pathway. The first is tyrosine aminotransferase deficiency (tyrosinemia type 2) and the second is 4-hydroxy-phenylpyruvate dioxygenase deficiency (tyrosinemia type 3). The most common disorder in the pathway, however, is ...
Looking for online definition of tyrosinemia type I in the Medical Dictionary? tyrosinemia type I explanation free. What is tyrosinemia type I? Meaning of tyrosinemia type I medical term. What does tyrosinemia type I mean?
Increasing evidence supports the hypothesis that tannic acid, a plant polyphenol, exerts anticarcinogenic activity in chemically induced cancers. In the present study, tannic acid was found to strongly inhibit tyrosine kinase activity of epidermal growth factor receptor (EGFr) in vitro (IC50 = 323 nM). In contrast, the inhibition by tannic acid of p60c-src tyrosine kinase (IC50 = 14 μM) and insulin receptor tyrosine kinase (IC50 = 5 μM) was much weaker. The inhibition of EGFr tyrosine kinase by tannic acid was competitive with respect to ATP and non-competitive with respect to peptide substrate. In cultured cells, growth factor-induced tyrosine phosphorylation of growth factor receptors, including EGFr, platelet-derived growth factor receptor, and basic fibroblast growth factor receptor, was inhibited by tannic acid. No inhibition of insulin-induced tyrosine phosphorylation of insulin receptor and insulin-receptor substrate-1 was observed. EGF-stimulated growth of HepG2 cells was inhibited in ...
TY - JOUR. T1 - The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors. AU - Rho, Jin Kyung. AU - Choi, Yun Jung. AU - Lee, Jin Kyung. AU - Ryoo, Baek Yeol. AU - Na, Im Il. AU - Yang, Sung Hyun. AU - Lee, Seung Sook. AU - Kim, Cheol Hyeon. AU - Yoo, Young Do. AU - Lee, Jae Cheol. PY - 2009/10. Y1 - 2009/10. N2 - The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) seems almost inevitable, even in patients with lung cancer that initially respond well to EGFR-TKIs. MET amplification was recently found to be a mechanism of escape from the anticancer effect of EGFR inhibitors. In the present study, we investigated the means whereby MET affects sensitivity to EGFR-TKIs in PC-9 cells. Gefitinib- or erlotinib-resistant sublines were established by exposing the parental PC-9 cell line to chronic, repeated treatments with these drugs. These resistant sublines showed more than 100-fold more ...
TY - GEN. T1 - The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism. AU - Eun, Ju Lee. AU - Jin, Ha Whang. AU - Nam, Kyeong Jeon. AU - Kim, Jin. PY - 2007/1. Y1 - 2007/1. N2 - Oral squamous cell carcinomas (OSCCs) are characterized by a marked propensity for local invasion and dissemination to cervical lymph nodes. Overexpression of the epidermal growth factor receptor (EGFR) and high levels of certain matrix metalloproteinases (MMPs) have been implicated in the development of squamous cell carcinoma of oral cancer. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is clinically used for cancer patients. This article attempted to determine the mechanisms underlying the effects of ZD1839 on the cellular level, and to characterize the effects of ZD1839 with regard to human OSCC cell ...
Infections are thought to be important in the pathogenesis of many heart diseases. Coxsackievirus B3 (CVB3) has been linked to chronic dilated cardiomyopathy, a common cause of progressive heart disease, heart failure and sudden death. We show here that the sarcoma (Src) family kinase Lck (p56lck) i …
TY - JOUR. T1 - Use of 3-aminotyrosine to examine the pathway dependence of radical propagation in Escherichia coli ribonucleotide reductase. AU - Minnihan, Ellen C.. AU - Seyedsayamdost, Mohammad R.. AU - Stubbe, Joanne. PY - 2009/12/29. Y1 - 2009/12/29. N2 - Escherichia coli ribonucleotide reductase (RNR), an α2β2 complex, catalyzes the conversion of nucleoside 5′-diphosphate substrates (S) to 2′-deoxynucleoside 50-diphosphates. α2 houses the active site for nucleotide reduction and the binding sites for allosteric effectors (E). β2 contains the essential diferric tyrosyl radical (Y122 •) cofactor which, in the presence of S and E, oxidizes C 439 in α to a thiyl radical, C439•, to initiate nucleotide reduction. This oxidation occurs over 35 Å and is proposed to involve a specific pathway: Y122• → W48 → Y356 in β2 to Y731 → Y730 → C439 in α2. 3-Aminotyrosine (NH2Y) has been sitespecifically incorporated at residues 730 and 731, and formation of the aminotyrosyl radical ...
TY - JOUR. T1 - Tgfβ mediated corneal myofibroblast transformation is dependent on tyrosine phosphorylation. AU - Jester, J. V.. AU - Huang, J.. AU - Kao, W. W.. AU - Petroll, Walter M. AU - Cavanagh, Harrison D. PY - 1997/12/1. Y1 - 1997/12/1. N2 - Recent studies of the inhibitory effects of ROD peptides on TGFβ induced keratocyte transformation and a-smooth muscle-specific actin (a-SM) expression suggest the presence of an outside-in signal transduction mechanism involving interactions between fibronectin (FN) and the FN receptors, a5βl integrin. The purpose of this study was to identify the role of integnn-dependent tyrosine phosphorylation in regulating a-SM gene expression and ultimately myofibroblast development. Methods: Since cell culture in serum containing media mimics myofibroblast transformation, all experiments were carried out on freshly isolated rabbit keratocytes plated in defined, serum-free media. Cells were exposed to TGFR (1 ng/ml), GRGDdSP (50 uM), GRADSP (100 uM) or ...
TY - JOUR. T1 - Activation of the Syk tyrosine kinase is insufficient for downstream signal transduction in B lymphocytes. AU - Hsueh, Robert C.. AU - Hammill, Adrienne M.. AU - Lee, Jamie A.. AU - Uhr, Jonathan W.. AU - Scheuermann, Richard H.. PY - 2002/12/6. Y1 - 2002/12/6. N2 - Background: Immature B lymphocytes and certain B cell lymphomas undergo apoptotic cell death following activation of the B cell antigen receptor (BCR) signal transduction pathway. Several biochemical changes occur in response to BCR engagement, including activation of the Syk tyrosine kinase. Although Syk activation appears to be necessary for some downstream biochemical and cellular responses, the signaling events that precede Syk activation remain ill defined. In addition, the requirements for complete activation of the Syk-dependent signaling step remain to be elucidated. Results: A mutant form of Syk carrying a combination of a K395A substitution in the kinase domain and substitutions of three phenylalanines (3F) ...
TY - JOUR. T1 - The myeloperoxidase-derived oxidant HOSCN inhibits protein tyrosine phosphatases and modulates cell signalling via the mitogen-activated protein kinase (MAPK) pathway in macrophages. AU - Lane, Amanda E.. AU - Tan, Joanne T.M.. AU - Hawkins, Clare L.. AU - Heather, Alison K.. AU - Davies, Michael J.. N1 - Copyright: Copyright 2010 Elsevier B.V., All rights reserved.. PY - 2010/8/15. Y1 - 2010/8/15. N2 - MPO (myeloperoxidase) catalyses the oxidation of chloride, bromide and thiocyanate by hydrogen peroxide to HOCl (hypochlorous acid), HOBr (hypobromous acid) and HOSCN (hypothiocyanous acid) respectively. Specificity constants indicate that SCN- is amajor substrate for MPO. HOSCN is also a major oxidant generated by other peroxidases including salivary, gastric and eosinophil peroxidases. While HOCl and HOBr are powerful oxidizing agents, HOSCN is a less reactive, but more specific, oxidant which targets thiols and especially low pKa species. In the present study we ...
The goal of the present studies was to determine whether fyn gene deletion altered the behavioral and functional actions of drugs that act at GABAA receptors. To this end, we obtained our own colony of fyn-null mutant and wild-type mice. Similar to the results of Miyakawa et al. (1997) using mice that were developed by a different research group, our null mutants were more sensitive to the hypnotic effects of ethanol (Boehm et al., 2003), a compound known to enhance GABAA receptor function. Moreover, although the genotypes did not differ in hypnotic sensitivity to the positive allosteric modulators pentobarbital, flurazepam, and alfaxalone, our fyn-deficient mice exhibited a shorter duration of loss of righting reflex following administration of the GABAA receptor agonist, THIP.. The above results were consistent with those of Kitazawa et al. (1998) and suggested that fyn gene deletion altered GABAA receptor function, so we next assessed the actions of THIP using a functional assay. ...
TY - JOUR. T1 - Requirement of SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 for paired immunoglobulin-like receptor B (PIR-B)-mediated inhibitory signal. AU - Maeda, Akito. AU - Kurosaki, Mari. AU - Ono, Masao. AU - Takai, Toshiyuki. AU - Kurosaki, Tomohiro. PY - 1998/4/20. Y1 - 1998/4/20. N2 - Paired immunoglobulin-like receptor B (PIR-B) (p91) molecule has been proposed to function as an inhibitory receptor in B cells and myeloid lineage cells. We demonstrate here that the cytoplasmic region of PIR-B is capable of inhibiting B cell activation. Mutational analysis of five cytoplasmic tyrosines indicate that tyrosine 771 in the motif VxYxxL plays the most crucial role in mediating the inhibitory signal. PIR-B-mediated inhibition was markedly reduced in the SH2-containing protein tyrosine phosphatases SHP- 1 and SHP-2 double-deficient DT40 B cells, whereas this inhibition was unaffected in the inositol polyphosphate 5'-phosphatase SHIP-deficient cells. These data demonstrate that ...
PURPOSE OF REVIEW: The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, are effective as first-line treatment of advanced nonsmall cell lung cancer (NSCLC) harboring activating EGFR mutations (deletions in exon 19 and exon 21 L858R mutation). EGFR T790 M resistance mutation (EGFR T790 M) ultimately emerged in most of these patients. The second and third-generation EGFR-TKIs were designed to have more potent inhibition of EGFR and to overcome EGFR T790 M. This review describes the recent developments of these novel EGFR-TKIs.. RECENT FINDINGS: The second-generation EGFR-TKIs, afatinib and dacomitinib, irreversibly bind to the tyrosine kinase of EGFR and other ErbB-family members. Afatinib has been approved as first-line treatment of advanced NSCLC harboring activating EGFR mutations. Dacomitinib is under development. Third-generation EGFR-TKIs, AZD9291, CO-1686, and HM61713, inhibit both EGFR activating and resistance mutations, ...
Title: Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and New Therapeutic Perspectives in Non Small Cell Lung Cancer. VOLUME: 12 ISSUE: 6. Author(s):Laura Bonanno, Antonio Jirillo and Adolfo Favaretto. Affiliation:Medical Oncology 2, Istituto Oncologico Veneto-IRCCS, Via Gattamelata, 64, 35128 Padova, Italy.. Keywords:EGFR, Tyrosine kinase inhibitors, resistance, mutations, amplifications, MET, VEGFR, NSCLC, Gefitinib, Erlotinib. Abstract: EGFR somatic mutations define a subset of NSCLCs that are most likely to benefit from EGFR tyrosine kinase inhibitors (TKIs). These tumors are dependent on EGFR-signaling for survival. Recently, tyrosine kinase domain somatic mutations have been approved as criterion to decide first-line therapy in this group of advanced NSCLCs. Anyway, all patients ultimately develop resistance to these drugs. Acquired resistance is linked to a secondary EGFR mutation in about a half of patients. Uncontrolled activation of ...
PAG (phosphoprotein associated with GEMs), also known as Cbp (Csk-binding protein), is a ubiquitously expressed 46 kDa transmembrane adaptor protein present in membrane rafts (glycosphingolipid-enriched microdomains), which however migrates on SDS PAGE gels anomalously as an 80 kDa molecule. Following tyrosine phosphorylation by Src family kinases, PAG binds and thereby activates the protein tyrosine kinase Csk, the major negative regulator of the Src family kinases. Signaling via the B-cell receptor in B cells or high affinity IgE receptor (FcepsilonRI) in mast cells leads to PAG increased tyrosine phosphorylation and Csk binding, while T cell receptor signaling causes PAG dephosphorylation, loss of Csk binding and increased activation of the protein tyrosine kinase Lck ...
TY - JOUR. T1 - Src family kinases negatively regulate platelet-derived growth factor α receptor-dependent signaling and disease progression. AU - Rosenkranz, Stephan. AU - Ikuno, Yasushi. AU - Leong, Fee Lai. AU - Klinghoffer, Richard A.. AU - Miyake, Sachiko. AU - Band, Hamid. AU - Kazlauskas, Andrius. PY - 2000/3/31. Y1 - 2000/3/31. N2 - We tested the hypothesis that Src family kinases (SFK) contribute to c- Cbl-mediated degradation of the platelet-derived growth factor (PDGF) α receptor (αPDGFR). Using either a receptor mutant that does not engage SFKs (F72174), or cells that that lack SFKs, we found that SFKs contributed to degradation of the αPDGFR. Overexpression of c-Cbl also reduced the receptor half-life, but only if the receptor was able to engage SFKs. In cultured cells, prolonging the half-life of the receptor correlated with enhanced signaling and more efficient S phase entry, whereas accelerating receptor degradation had the opposite effect. Consistent with these tissue ...
By means of an RT-PCR approach we isolated a specific tyrosine phosphatase (FsPTP1) induced by abscisic acid (ABA) and correlated with seed dormancy in Fagus sylvatica seeds. To provide genetic evidence of FsPTP1 function in seed dormancy and ABA signal transduction pathway, we overexpressed this gene in Cape Verde Island ecotype of Arabidopsis thaliana, which shows the deepest degree of seed dormancy among Arabidopsis accessions. As a result, 35S:FsPTP1 transgenic seeds showed a reduced dormancy and insensitivity to ABA and osmotic stress conditions accompanied by a reduction in the level of expression of RAB18 and RD29, well-known ABA-responsive genes. Taken together, all these data are consistent with a role of this tyrosine phosphatase as a negative regulator of ABA signaling. In addition, phenotypes of FsPTP1 transgenic plants resemble those observed in ethylene constitutive mutants, accompanied by an increase in the level of expression of a key gene involved in ethylene signaling such as ...
TY - JOUR. T1 - A role for cholecystokinin-stimulated protein tyrosine phosphorylation in regulated secretion by the pancreatic acinar cell. AU - Lutz, M. P.. AU - Sutor, S. L.. AU - Abraham, R. T.. AU - Miller, L. J.. PY - 1993/1/1. Y1 - 1993/1/1. N2 - Cholecystokinin (CCK) is a gastrointestinal hormone that acts through a G protein-coupled receptor to stimulate pancreatic enzyme secretion. In this work, we demonstrate that CCK stimulation of dispersed pancreatic acini results in increased tyrosine phosphorylation of several cellular proteins. This is mediated via a calcium-dependent pathway, also activated by a phenethyl ester analogue of CCK and calcium ionophores, and by a protein kinase C-dependent cascade, also activated by the phorbol ester 12-O- tetradecanoylphorbol-13-acetate. All demonstrable stimulated tyrosine phosphorylation events were inhibited by genistein, with different subsets of proteins affected by staurosporine and H-7. The importance of tyrosine phosphorylation events in ...
Summary is not available for the mouse gene. This summary is for the human ortholog.] The scaffolding protein encoded by this gene is the main component of the caveolae plasma membranes found in most cell types. The protein links integrin subunits to the tyrosine kinase FYN, an initiating step in coupling integrins to the Ras-ERK pathway and promoting cell cycle progression. The gene is a tumor suppressor gene candidate and a negative regulator of the Ras-p42/44 mitogen-activated kinase cascade. Caveolin 1 and caveolin 2 are located next to each other on chromosome 7 and express colocalizing proteins that form a stable hetero-oligomeric complex. Mutations in this gene have been associated with Berardinelli-Seip congenital lipodystrophy. Alternatively spliced transcripts encode alpha and beta isoforms of caveolin 1.[provided by RefSeq, Mar 2010 ...
The Src-family and Syk/ZAP-70 family of protein tyrosine kinases (PTK) are required for T cell receptor (TCR) functions. We provide evidence that the Src-family PTK Lck is responsible for regulating the constitutive tyrosine phosphorylation of the TCR zeta subunit in murine thymocytes. Moreover, ligation of the TCR expressed on thymocytes from Lck-deficient mice largely failed to induce the phosphorylation of TCR-zeta, CD3 epsilon, or ZAP-70. In contrast, we find that the TCR-zeta subunit is weakly constitutively tyrosine phosphorylated in peripheral T cells isolated from Lck-null mice. These data suggest that Lck has a functional role in regulation of TCR signal transduction in thymocytes. In peripheral T cells, other Src-family PTKs such as Fyn may partially compensate for the absence of Lck. ...
TY - JOUR. T1 - Identification of the src family kinases, Lck and Fgr in platelets. T2 - Their tyrosine phosphorylation status and subcellular distribution compared with other Src family members. AU - Pestina, T. I.. AU - Stenberg, P. E.. AU - Druker, B. J.. AU - Steward, S. A.. AU - Hutson, N. K.. AU - Barrie, R. J.. AU - Jackson, C. W.. PY - 1997. Y1 - 1997. N2 - We have identified the Src family members, Lck and Fgr in resting human and rodent platelets and compared their subcellular distributions and tyrosine phosphorylation status to those of the other Src family kinases to gain insights into the signal transduction pathways active in maintaining platelets in the circulation. Like Fyn, Lyn, and Yes, most of Fgr and Lck was detergent-insoluble in human and rat platelets. In comparison, Src showed higher detergent solubility than the Src-related kinases. Most all human platelet Src was detergent-soluble, while that of rodent platelets was present in all detergent fractions. We also compared ...
Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways. In addition of this role of signal transduction in T-cell activation, CD3D plays an essential role in thymocyte differentiation. Indeed, participates in correct intracellular TCR-CD3 complex assembly and surface expression. In absence of a functional TCR-CD3 complex, thymocytes are unable to differentiate properly (PubMed:10935641). Interacts with CD4 and CD8 and thus serves to establish a functional link between the TCR and coreceptors
Protein-tyrosine kinase C-terminal Src kinase (Csk) was originally purified as a kinase for phosphorylating Src and other Src family kinases. The phosphorylation of a C-terminal tyrosine residue of Src family kinases suppresses their kinase activity. Therefore, most physiological studies regarding Csk function have been focused on Csk as a negative regulator of Src family tyrosine kinases and as a potential tumor suppressor. Paradoxically, the protein levels of Csk were elevated in some human carcinomas. In this report, we show that eukaryotic elongation factor 2 (eEF2) is a new protein substrate of Csk and could locate in the nucleus ...
Noonan syndrome with multiple lentigines (NSML) which is part of a group called Ras/MAPK pathway syndromes, is a rare autosomal dominant, multisystem disease caused by a mutation in the protein tyrosine phosphatase, non-receptor type 11 gene (PTPN11). The disease is a complex of features, mostly involving the skin, skeletal and cardiovascular systems, which may or may not be present in all patients. The nature of how the mutation causes each of the condition's symptoms is not well known; however, research is ongoing. It is a RASopathy. Noonan syndrome with multiple lentigines is caused by a different missense mutation of the same gene. Noonan syndrome is fairly common (1:1,000 to 1:2,500 live births), and neurofibromatosis 1 (which was once thought to be related to NSML) is also common (1:3500); however, no epidemiological data exists for NSML. An alternative name of the condition, LEOPARD syndrome, is a mnemonic, originally coined in 1969, as the condition is characterized by some of the ...
Adaptor protein c-Abl SH3 domain-binding protein-2 (3BP2) is known to play regulatory roles in immunoreceptor-mediated signal transduction. We have previously demonstrated that Tyr{sup 174}, Tyr{sup 183} and Tyr{sup 446} in mouse 3BP2 are predominantly phosphorylated by Syk, and the phosphorylation of Tyr{sup 183} and the Src homology 2 (SH2) domain of mouse 3BP2 are critical for B cell receptor (BCR)-induced activation of nuclear factor of activated T cells (NFAT) in human B cells. In this report, we have shown that Syk, but not Abl family protein-tyrosine kinases, is critical for BCR-mediated tyrosine phosphorylation of 3BP2 in chicken DT40 cells. Mutational analysis showed that Tyr{sup 174}, Tyr{sup 183} and Tyr{sup 426} of chicken 3BP2 are the major phosphorylation sites by Syk and the SH2 domain of 3BP2 is critical for tyrosine phosphorylation. In addition, phosphorylation of Tyr{sup 426} is required for the inducible interaction with the SH2 domain of Vav3. Moreover, the expression of the ...
The microtubule-associated protein tau can associate with various other proteins in addition to tubulin, including the SH3 domains of Src family tyrosine kinases. Tau is well known to aggregate to form hyperphosphorylated filamentous deposits in several neurodegenerative diseases (tauopathies) including Alzheimer disease. We now report that tau can bind to SH3 domains derived from the p85α subunit of phosphatidylinositol 3-kinase, phospholipase Cγ1, and the N-terminal (but not the C-terminal) SH3 of Grb2 as well as to the kinases Fyn, cSrc, and Fgr. However, the short inserts found in neuron-specific isoforms of Src prevented the binding of tau. The experimentally determined binding of tau peptides is well accounted for when modeled into the peptide binding cleft in the SH3 domain of Fyn. After phosphorylation in vitro or in transfected cells, tau showed reduced binding to SH3 domains; no binding was detected with hyperphosphorylated tau isolated from Alzheimer brain, but SH3 binding was ...
Recent evidence suggests that concanavalin A modulates tyrosyl phosphorylation and activation of a type II PtdIns 4-kinase in rat splenic lymphocytes. However, the regulatory protein tyrosine kinase(s) remain to be elusive. The present manuscript provides evidence that a type II PtdIns 4-kinase associates with p56(lck) in Con A stimulated rat splenic lymphocytes. In vitro phosphorylation studies suggest that p561(lck) regulates phosphorylation and activation of type II PtdIns 4-kinase. Inhibition of p561(lck) activity in vivo has shown to reduce tyrosyl phosphorylation and activation of PtdIns 4-kinase by Con A. These results suggest that p56(lck) may be the physiological regulator of type II PtdIns 4-kinase ...
Tyrosine Protein Kinase Receptor UFO (AXL Oncogene or AXL or EC 2.7.10.1) - Pipeline Review, H2 2017 Tyrosine Protein Kinase Receptor UFO (AXL Oncogene or - Market research report and industry analysis - 11296598
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Additionally, for the majority of phosphorylation sites identified on the CD3γδζ subunits, we observed a gradual decrease in Zap-70 null/reconstituted SILAC ratios at early time points, followed by a gradual increase in Zap-70 null/reconstituted SILAC ratios at later time points (Fig. 7E2). These trends are consistent with the hypothesis of competing positive and negative feedback loops functioning at different stages of stimulation. At early time points, positive feedback mechanisms could be regulating these sites, leading to a gradual decrease in Zap-70 null/reconstituted SILAC ratios. At later time points, negative feedback mechanisms could be regulating these same sites, leading to an increase in Zap-70 null/reconstituted SILAC ratios when Zap-70 is removed (Fig. 7E1). It has previously been shown that Erk positive and SHP-1 negative feedback pathways can compete to either activate or inhibit Lck function to allow for T cells to discriminate between self and foreign ligands (47).. To ...