Proteins encoding phosphotyrosine binding (PTB) domains function as adaptors or scaffolds to organize the signaling complexes involved in wide-ranging physiological processes including neural development, immunity, tissue homeostasis and cell growth. Due to structural differences, PTB domains are divided into three groups represented by phosphotyrosine-dependent IRS-like, phosphotyrosine-dependent Shc-like (see ,PDOC00907,), and phosphotyrosine-independent Dab-like PTBs (see ,PDOC00907,). IRS-type PTB domain has an average length of about 100 amino acids. It binds to the insulin receptor through the Asn-Pro-Xaa-Tyr(P) motif found in many tyrosine-phosphorylated proteins. This domain is found in IRS/Dok/SNT proteins that are the major adapters for RTK and cytokine signaling. This domain binds both peptides and headgroups of phosphatidylinositides, utilizing two distinct binding motifs to mediate spatial organization and localization within cells. The IRS-type PTB domain is found alone or in ...
Complete information for PID1 gene (Protein Coding), Phosphotyrosine Interaction Domain Containing 1, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Metabolic syndrome describes a complex set of obesity-related disorders that enhance diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein-tyrosine phosphatase lb (PTPlb) deletion mice (L-PTPlb-/-) suggests that hepatic PTPlb inhibition would mitigate metabolic syndrome progression through amelioration of hepatic insulin resistance, endoplasmic reticulum stress, and whole-body lipid metabolism. However, the network alterations underlying these phenotypes are poorly understood. Mass spectrometry was used to quantitatively discover protein phosphotyrosine network changes in L-PTP lb-/- mice relative to control mice under both normal and high-fat diet conditions. A phosphosite set enrichment analysis was developed to identify numerous pathways exhibiting PTPlb- and diet-dependent phosphotyrosine regulation. Detection of PTP lb-dependent phosphotyrosine sites on lipid metabolic proteins initiated global lipidomics characterization of corresponding liver samples and revealed ...
1K2M: Solution structure of the yeast Rad53 FHA2 complexed with a phosphothreonine peptide pTXXL: comparison with the structures of FHA2-pYXL and FHA1-pTXXD complexes.
Actin Colocalizes with Tir and Phosphotyrosine (PY) Staining in RBC Infected with EPEC and Exposed to Extract(A) Images of RBC infected with EPEC and exposed to
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Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J.. Tyrosine kinases play a prominent role in human cancer, yet the oncogenic signaling pathways driving cell proliferation and survival have been difficult to identify, in part because of the complexity of the pathways and in part because of low cellular levels of tyrosine phosphorylation. In general, global phosphoproteomic approaches reveal small numbers of peptides containing phosphotyrosine. We have developed a strategy that emphasizes the phosphotyrosine component of the phosphoproteome and identifies large numbers of tyrosine phosphorylation sites. Peptides containing phosphotyrosine are isolated directly from protease-digested cellular protein extracts with a phosphotyrosine-specific antibody and are identified by tandem mass spectrometry. Applying this approach to several cell systems, including cancer cell lines, shows it can be used to identify activated protein kinases and their ...
The B cell-restricted transmembrane glycoprotein CD22 is rapidly phosphorylated on tyrosine in response to cross-linking of the B cell antigen receptor, thereby generating phosphotyrosine motifs in the cytoplasmic domain which recruit intracellular effector proteins that contain Src homology 2 domains. By virtue of its interaction with these effector proteins CD22 modulates signal transduction through the B cell antigen receptor. To define further the molecular mechanism by which CD22 mediates its co-receptor function, phosphopeptide mapping experiments were conducted to determine which of the six tyrosine residues in the cytoplasmic domain are involved in recruitment of the stimulatory effector proteins phospholipase Cχ (PLCχ), phosphoinositide 3-kinase (PI3K), Grb2, and Syk. The results obtained indicate that the protein tyrosine kinase Syk interacts with multiple CD22- derived phosphopeptides in both immunoprecipitation and reverse Far Western assays. In contrast, the Grb2·Sos complex was ...
The development of monoclonal antibodies (mAbs) that recognize nearly all of the phosphorylated tyrosine residues, irrespective of the surrounding sequences, enables researchers to detect the phosphorylation state of proteins through the use of anti-phosphotyrosine western blotting. The availability of this simple, reliable, nonradioactive and yet sensitive method created a boom in signal transduction research. While the methodology of how to perform an anti-phosphotyrosine western blot remains unchanged since the procedure became widely used in the early part of 1990s, steady improvements in reagents and detection technologies have allowed researchers to detect tyrosine phosphorylation quantitatively, at unprecedented sensitivity. In addition to the improvements in the western blot-based systems, powerful new phosphotyrosine detection platforms, based on proteomic technologies, are emerging rapidly. This unit will describe in detail the steps needed to perform the standard anti-phosphotyrosine ...
The crystal structures of a cysteine-215--,serine mutant of protein tyrosine phosphatase 1B complexed with high-affinity peptide substrates corresponding to an autophosphorylation site of the epidermal growth factor receptor were determined. Peptide binding to the protein phosphatase was accompanied by a conformational change of a surface loop that created a phosphotyrosine recognition pocket and induced a catalytically competent form of the enzyme. The phosphotyrosine side chain is buried within the period and anchors the peptide substrate to its binding site. Hydrogen bonds between peptide main-chain atoms and the protein contribute to binding affinity, and specific interactions of acidic residues of the peptide with basic residues on the surface of the enzyme confer sequence specificity. Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B.,Jia Z, Barford D, Flint AJ, Tonks NK Science. 1995 Jun 23;268(5218):1754-8. PMID:7540771[3] From ...
A hybridoma cell line is disclosed that secretes monoclonal antibodies which serve as a high titer, reproducible, biological reagent useful in biological/medical research for isolating and identifying phosphotyrosine-containing proteins. In addition, the antibodies have potential uses in diagnosis of a variety of diseases, including certain cancers. The antibodies, which have demonstrated affinity for a variety of molecules containing o-phosphotyrosine residues, were prepared using a synthetic analog, p-azobenzyl phosphonate (ABP) covalently linked to a carrier protein, as the antigen.
5636 Over-expression and/or enhanced activation of the epidermal growth factor receptor (EGFr) are frequently observed in human cancers, correlating with poor prognosis. Anti-phosphotyrosine affinity chromatography and uLC-MSMS mass spectrometry methods were used to define signaling networks associated with EGFr constitutive activation and pharmacological inhibition. The squamous carcinoma cell line HN5, which over-expresses EGFr and displays sustained EGFr kinase activation, was employed as a model system. Inhibition of the EGFr kinase activity by OSI-774 (Tarceva; 1uM, 1 hour) largely abrogated anti-phosphotyrosine protein detection, indicating EGFr is the major source of phosphotyrosine-mediated signaling within HN5 cells and is activated in the absence of exogenous ligand. Analysis of uLC-MSMS spectra identified one hundred and forty three proteins from multiple biological and chromatography experiments, comprising proteins containing phosphotyrosine or which form stable complexes therewith. ...
1IJR: A novel phosphotyrosine mimetic 4-carboxymethyloxy-3-phosphonophenylalanine (Cpp): exploitation in the design of nonpeptide inhibitors of pp60(Src) SH2 domain.
Site-directed mutagenesis of a synthetic gene coding for low-M(r) phosphotyrosine protein phosphatase from bovine liver has been carried out. The two histidine residues in the enzyme have been mutated to glutamine; both single and double mutants were produced. The mutated and non-mutated sequences have been expressed in Escherichia coli as fusion proteins, in which the low-M(r) phosphotyrosine protein phosphatase was linked to the C-terminal end of the maltose-binding protein. The fusion enzymes were easily purified by single-step affinity chromatography. The mutants were studied for their kinetic properties. Both single mutants showed decreased kcat. values (30 and 7% residual activities for His66 and His72 respectively), and alterations of the Ki values relative to four-competitive inhibitors were observed. The kinetic mechanism of p-nitrophenyl phosphate hydrolysis in the presence of both single mutants was determined and compared with that of the non-mutated enzyme. The rate-determining step ...
TY - JOUR. T1 - Exploitation of host cell signaling machinery. T2 - Activation of macrophage phosphotyrosine phosphatases as a novel mechanism of molecular microbial pathogenesis. AU - Nandan, D.. AU - Knutson, Keith L. AU - Lo, R.. AU - Reiner, N. E.. PY - 2000. Y1 - 2000. N2 - Intracellular pathogens, particularly those that target host mononuclear phagocytes, have evolved strategies to either evade or inhibit cellular mechanisms of host defense. Mycobacterium tuberculosis and Leishmania donovani exemplify a diverse group of microorganisms that have developed the ability to invade and replicate within host macrophages, leading to disease expression. Recent studies have suggested that the pathogenesis of intracellular infection may involve interference with host cell signaling. Drawing upon examples from in vitro models that focused on M. tuberculosis and L. donovani, we review evidence that activation of host cell phosphotyrosine phosphatases may contribute to pathogenesis. A leading candidate ...
A mammalian adaptor protein with conserved Src homology 2 and phosphotyrosine-binding domains is related to Shc and is specifically expressed in the brain Academic Article ...
Protein tyrosine phosphatases (PTP) catalyze the dephosphorylation of phosphotyrosine peptides; they regulate phosphotyrosine levels in signal transduction pathways. The depth of the active site cleft renders the enzyme specific for phosphorylated Tyr (pTyr) residues, instead of pSer or pThr. This family has a distinctive active site signature motif, HCSAGxGRxG. Characterized as either transmembrane, receptor-like or non-transmembrane (soluble) PTPs. Receptor-like PTP domains tend to occur in two copies in the cytoplasmic region of the transmembrane proteins, only one copy may be active. ...
Studies on the Role of the SH2 Domain-Containing Phosphotyrosine Phosphatase, PTP2C, in Insulin Signaling. A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the Degree of Doctor of Philosophy in Biochemistry by Michelle Kuhne DARTMOUTH COLLEGE Hanover, New Hampshire 22 May 1995 ...
RTK BRET-2 Assays Are Dependent on Autophosphorylation of Specific Tyrosine Residues. Phosphorylated tyrosine residues localized in the intracellular carboxyl terminus of EGFR (Heldin, 1995) and specific phosphotyrosine binding or SH2 domains in the effector proteins (Schlessinger and Lemmon, 2003) mediate all the EGFR effector interactions we studied in Fig. 2. EGFR tyrosines 1068, 1086, 1101, 1114, 1148, and 1173 are involved in direct or indirect binding of the effector Grb2 (Schulze et al., 2005). We mutated these tyrosine residues to phenylalanine to verify that the EGFR/Grb2 BRET-2 signal is dependent on their phosphorylation. Introducing all six Tyr-to-Phe alterations into EGFR-Luc abolished the EGF-induced BRET-2/Grb2 response by 90 ± 0.9% compared with wild-type EGFR-Luc (Fig. 2f). We observed 66 ± 0.9% and 42 ± 1.0% impairment of the BRET-2/Grb2 responses for EGFR-Luc isoforms carrying five (Y1068F, Y1086F, Y1101F, Y1114F, Y1173F) or four (Y1086F, Y1101F, Y1114F, Y1173F) of the six ...
Cloning, purification, and properties of a phosphotyrosine protein phosphatase from Streptomyces coelicolor A3(2).: We describe the isolation and characterizati
Detection of phosphorylation by western blotting is an important procedure to elucidate molecular mechanisms in signal transduction pathways involving kinases and phosphatases. Anti-phospho-tyrosine monoclonal antibodies have been widely used because they react with plethora of proteins containing phosphorylated tyrosine residues. In contrast, the monoclonal antibodies against phospho-serine or threonine residues are unpopular, since their affinity and specificity are less than optimal. To achieve precise characterization of signaling events, it is desirable to raise a good anti-phospho-site-specific antibody to clearly detect phosphorylated species. However, raising this type of antibody is costly and time-consuming, and sometimes results in failure.. Use of Phos-tag may provide an alternative method to detect phosphorylated proteins. Phos-tag is a dinuclear metal complex that acts as a novel phosphate-binding tag. Phos-tag molecules preferentially capture phosphomonoester dianions bound to ...
Tyrosine phosphorylation of Syk after stimulation of NK cells with targets. For each sample, 107 NK cells were mixed with 5 × 106 cells of either (A) C1R, (B)
After the intraportal injection of EGF, the EGF receptor (EGFR) is rapidly internalized into hepatic endosomes where it remains largely receptor bound (Lai et al., 1989. J. Cell Biol. 109:2751-2760). In the present study, we evaluated the phosphotyrosine content of EGFRs at the cell surface and in endosomes in order to assess the consequences of internalization. Quantitative estimates of specific radioactivity of the EGFR in these two compartments revealed that tyrosine phosphorylation of the EGFR was observed at the cell surface within 30 s of ligand administration. However, the EGFR was also highly phosphorylated in endosomes reaching levels of tyrosine phosphorylation significantly higher than those of the cell surface receptor at 5 and 15 min after EGF injection. A 55-kD tyrosine phosphorylated polypeptide (pyp55) was observed in association with the EGFR at the cell surface within 30 s of EGF injection. The protein was also found in association with the EGFR in endosomes as evidenced by ...
Tumour necrosis factor (TNF) is a potent mitogen for some fibroblast cell lines. Here we have examined the TNF-mediated changes in protein phosphorylation in Swiss 3T3 and human FS-4 fibroblasts, and compared them with changes observed after the treatment of cells with other mitogens, such as platelet-derived growth factor (PDGF) and bombesin. TNF stimulated the rapid phosphorylation of two 41,000-Mr and two 43,000-Mr cytosol proteins on tyrosine, threonine and/or serine, as did PDGF, epidermal growth factor and fibroblast growth factor; the increased levels of this mitogen-induced protein-tyrosine phosphorylation correlated well with the extent of mitogen-induced DNA synthesis as determined by the percentage of labelled nuclei. In contrast, bombesin, which is an even better mitogen for Swiss 3T3 cells than TNF, stimulated the tyrosine phosphorylation of 41,000-Mr and 43,000-Mr proteins only to a limited extent. On the other hand, bombesin and PDGF stimulated the rapid serine phosphorylation of ...
Class I phosphoinositide 3-kinases (PI3Ks) are bifunctional enzymes possessing lipid kinase activity and the capacity to phosphorylate their catalytic and/or regulatory subunits. In this study, in vitro autophosphorylation of the G protein-sensitive p85-coupled class I(A) PI3K beta and p101-coupled class I(B) PI3K gamma was examined. Autophosphorylation sites of both PI3K isoforms were mapped to C-terminal serine residues of the catalytic p110 subunit (i.e. serine 1070 of p110 beta and serine 1101 of p110 gamma). Like other class I(A) PI3K isoforms, autophosphorylation of p110 beta resulted in down-regulated PI3K beta lipid kinase activity. However, no inhibitory effect of p110 gamma autophosphorylation on PI3K gamma lipid kinase activity was observed. Moreover, PI3K beta and PI3K gamma differed in the regulation of their autophosphorylation. Whereas p110 beta autophosphorylation was stimulated neither by G beta gamma complexes nor by a phosphotyrosyl peptide derived from the platelet-derived ...
Aberrant activity of tyrosine-phosphorylated proteins is commonly associated with HCC metastasis. Cell signaling events driven by these proteins are implicated in numerous processes that alter cancer cell behavior. Exploring the activities and signaling pathways of these proteins in HCC metastasis may help in identifying new candidate molecules for HCC-targeted therapy. Hep3B (a nonmetastatic HCC cell line) and MHCC97H (a highly metastatic HCC cell line) were used in this study, and the tyrosine-phosphorylated proteins expressed in these cell lines were profiled by a phosphoproteomics technique based on LC-MS/MS. Protein-protein interaction and functional clustering analyses were performed to determine the activities of the identified proteins and the signaling pathways closely related to HCC metastasis. In both cell lines, a total of 247 phosphotyrosine (pTyr) proteins containing 281 pTyr sites were identified without any stimulation. The involvement of almost 30% of these in liver or liver cancer has
Aberrant activity of tyrosine-phosphorylated proteins is commonly associated with HCC metastasis. Cell signaling events driven by these proteins are implicated in numerous processes that alter cancer cell behavior. Exploring the activities and signaling pathways of these proteins in HCC metastasis may help in identifying new candidate molecules for HCC-targeted therapy. Hep3B (a nonmetastatic HCC cell line) and MHCC97H (a highly metastatic HCC cell line) were used in this study, and the tyrosine-phosphorylated proteins expressed in these cell lines were profiled by a phosphoproteomics technique based on LC-MS/MS. Protein-protein interaction and functional clustering analyses were performed to determine the activities of the identified proteins and the signaling pathways closely related to HCC metastasis. In both cell lines, a total of 247 phosphotyrosine (pTyr) proteins containing 281 pTyr sites were identified without any stimulation. The involvement of almost 30% of these in liver or liver cancer has
We recently identified a novel adaptor protein, termed dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1), that possesses a Src homology (SH2) domain and a pleckstrin homology (PH) domain. DAPP1 exhibits a high-affinity interaction with PtdIns(3,4,5)P3 and PtdIns(3,4)P2, which bind to the PH domain. In the present study we show that when DAPP1 is expressed in HEK-293 cells, the agonists insulin, insulin-like growth factor-1 and epidermal growth factor induce the phosphorylation of DAPP1 at Tyr139. Treatment of cells with phosphoinositide 3-kinase (PI 3-kinase) inhibitors or expression of a dominant-negative PI 3-kinase prevent phosphorylation of DAPP1 at Tyr139, and a PH-domain mutant of DAPP1, which does not interact with PtdIns(3,4,5)P3 or PtdIns(3,4)P2, is not phosphorylated at Tyr139 following agonist stimulation of cells. Overexpression of a constitutively active form of PI 3-kinase induced the phosphorylation of DAPP1 in unstimulated cells. We demonstrated that Tyr139 of ...
Epidermal growth factor (EGF) rapidly stimulates receptor autophosphorylation in A-431 cells. After 1 min the phosphorylated receptor can be identified at the plasma membrane using an anti-phosphotyrosine antibody. With further incubation at 37 degrees C, approximately 50% of the phosphorylated EGF receptor was internalized (t1/2 = 5 min) and associated with the tubulovesicular system and later with multivesicular bodies, but not the nucleus. During this period, there was no change in the extent or sites of phosphorylation. At all times the phosphotyrosine remained on the cytoplasmic side of the membrane, opposite to the EGF ligand identified by anti-EGF antibody. These data indicate that (a) the tyrosine-phosphorylated EGF receptor is internalized in its activated form providing a mechanism for translocation of the receptor kinase to substrates in the cell interior; (b) the internalized receptor remains intact for at least 60 min, does not associate with the nucleus, and does not generate any ...
The role of fibroblast growth factor-2 (FGF-2) in maintaining undifferentiated human embryonic stem cells (hESC) was investigated using a targeted phosphoproteomics approach to specifically profile tyrosine phosphorylation events following FGF-2 stimulation. A cumulative total number of 735 unique tyrosine phosphorylation sites on 430 proteins were identified, by far the largest inventory to date for hESC. Early signaling events in FGF-2 stimulated hESC were quantitatively monitored using stable isotope dimethyl labeling, resulting in temporal tyrosine phosphorylation profiles of 316 unique phosphotyrosine peptides originating from 188 proteins. Apart from the rapid activation of all four FGF receptors, trans-activation of several other receptor tyrosine kinases (RTKs) was observed as well as induced tyrosine phosphorylation of downstream proteins such as PI3-K, MAPK and several Src family members. Both PI3-K and MAPK have been linked to hESC maintenance through FGF-2 mediated signaling. The ...
TY - JOUR. T1 - Systemic analysis of tyrosine phosphorylated proteins in angiopoietin-1 induced signaling pathway of endothelial cells. AU - Kim, Young-Mee. AU - Seo, Jawon. AU - Yung, Hee Kim. AU - Jeong, Jaeho. AU - Hye, Joon Joo. AU - Lee, Dong Hee. AU - Gou, Young Koh. AU - Lee, Kong Joo. PY - 2007/8/1. Y1 - 2007/8/1. N2 - Angiogenesis is an essential process in physiological and pathological processes and is well-regulated to maintain the cellular homeostasis by balancing the endothelial cells in proliferation and apoptosis. Angiopoietin-1 (Ang1) regulates angiogenesis as a ligand of Tie 2 receptor tyrosine kinase. However, the regulation pathways are not well-understood. To date, only a few of the signaling molecules involved in the Tie 2 receptor tyrosine kinase-mediated angiogenesis have been identified. In this study, we systematically identified tyrosine-phosphorylated proteins in Ang1-induced signaling cascade in human umbilical vein endothelial cells (HUVECs), employing proteomic ...
We have used unbiased phosphoproteomic approaches, based on quantitative mass spectrometry using stable isotope labeling with amino acids in cell culture (SILAC), to identify tyrosine phosphorylated proteins in isogenic human bronchial epithelial cells (HBECs) and human lung adenocarcinoma cell lines, expressing either of the two mutant alleles of EGFR (L858R and Del E746-A750), or a mutant KRAS allele, which are common in human lung adenocarcinomas. Tyrosine phosphorylation of signaling molecules was greater in HBECs expressing the mutant EGFRs than in cells expressing WT EGFR or mutant KRAS. Receptor tyrosine kinases (such as EGFR, ERBB2, MET, and IGF1R), and Mig-6, an inhibitor of EGFR signaling, were more phosphorylated in HBECs expressing mutant EGFR than in cells expressing WT EGFR or mutant RAS. Phosphorylation of some proteins differed in the two EGFR mutant-expressing cells; for example, some cell junction proteins (β-catenin, plakoglobin, and E-cadherin) were more phosphorylated in ...
TY - JOUR. T1 - Phosphoproteomics identified Endofin, DCBLD2, and KIAA0582 as novel tyrosine phosphorylation targets of EGF signaling and Iressa in human cancer cells. AU - Chen, Yunhao. AU - Low, Teck Yew. AU - Choong, Lee Yee. AU - Ray, Rajarshi Sankar. AU - Tan, Yee Ling. AU - Toy, Weiyi. AU - Lin, Qingsong. AU - Boon, Keong Ang. AU - Chee, Hong Wong. AU - Lim, Simin. AU - Li, Bin. AU - Hew, Choy Leong. AU - Sze, Newman Siu Kwan. AU - Druker, Brian. AU - Lim, Yoon Pin. PY - 2007/7. Y1 - 2007/7. N2 - With the completion of the human genome project, analysis of enriched phosphotyrosyl proteins from epidermal growth factor (EGF)-induced phosphotyrosine proteome permits the identification of novel downstream substrates of the EGF receptor (EGFR). Using cICAT-based LC-MS/MS method, we identified and relatively quantified the tyrosine phosphorylation levels of 21 proteins between control and EGF-treated A431 human cervical cancer cells. Of these, Endofin, DCBLD2, and KIAA0582 were validated to be ...
The activation of the phosphotyrosine phosphatase eta (r-PTP eta) is responsible for the somatostatin inhibition of PC Cl3 thyroid cell proliferation
Filopodia of growth cones are key elements in the transduction of extracellular cues that guide axon growth during development. How they are specialized to carry out this role is poorly understood. We previously had found tyrosine phosphorylated protein to be heavily concentrated at the tips of many filopodia of Aplysia growth cones in certain culturing conditions, suggesting that tyrosine phosphorylation might be involved in filopodial specialization. Immunocytochemistry was used to analyze the protein composition of the tip aggregates to determine whether there was an association of the tip phosphorylation with any important extracellular cue. beta 1 integrin, a subunit of the receptor for laminin-type neurite growth promoters, coconcentrated with phosphotyrosine at filopodial tips of both Aplysia and mouse growth cones. Several observations indicated that the association of beta 1 integrin with phosphotyrosine is close. beta 1 integrin and phosphotyrosine are known to colocalize at focal ...
Protein tyrosine phosphorylation controls many aspects of signaling in multicellular organisms. One of the major consequences of tyrosine phosphorylation is the creation of binding sites for proteins containing Src homology 2 (SH2) domains. To profile the global tyrosine phosphorylation state of the cell, we have developed proteomic binding assays encompassing nearly the full complement ofhuman SH2 domains. Here we provide a global view of SH2 domain binding to cellular proteins based on large-scale far-western analyses. We also use reverse-phase protein arrays to generate comprehensive, quantitative SH2 binding profiles for phosphopeptides, recombinant proteins, and entire proteomes. As an example, we profiled the adhesion-dependent SH2 binding interactions in fibroblasts and identified specific focal adhesion complex proteins whose tyrosine phosphorylation and binding to SH2 domains are modulated by adhesion. These results demonstrate that high-throughput comprehensive SH2 profiling provides valuable
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Thrombospondin-1 (TSP) induces endothelial cell (EC) actin reorganization and focal adhesion disassembly and influences multiple EC functions. To determine whether TSP might regulate EC-EC interactions, we studied the effect of exogenous TSP on the movement of albumin across postconfluent EC monolayers. TSP increased transendothelial albumin flux in a dose-dependent manner at concentrations ≥1 μg/ml (2.2 nM). Increases in albumin flux were observed as early as 1 h after exposure to 30 μg/ml (71 nM) TSP. Inhibition of tyrosine kinases with herbimycin A or genistein protected against the TSP-induced barrier dysfunction by >80% and >50%, respectively. TSP-exposed monolayers exhibited actin reorganization and intercellular gap formation, whereas pretreatment with herbimycin A protected against this effect. Increased staining of phosphotyrosine-containing proteins was observed in plaque-like structures and at the intercellular boundaries of TSP-treated cells. In the presence of protein tyrosine ...
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a transducer of growth factor, cytokine, integrin, and hormone signaling pathways that regulate processes such as cell proliferation, differentiation, adhesion, migration, and apoptosis and plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with several types of leukemias, and solid tumors. This makes SHP2 an attractive target for developing new anticancer therapy. Several small molecules have been developed for inhibition of this important phosphatase, which serve as chemical tools to probe the role of SHP2 in disease and lead compounds for optimization. Nevertheless improvements are required to improve these lead compounds with better potency, selectivity and cell permeability. To gain structural insights for development of potent and selective Shp2 inhibitors, we synthesized a non-hydrolysable phosphotyrosine peptide mimetic, based on reported Shp2 substrate ...
Ligand stimulation of growth factor receptors with intrinsic protein-tyrosine kinase activity initiates the assembly of multienzyme signalling complexes. This is mediated by binding of proteins with src homology 2 (SH2) domains to receptor autophosphorylation sites. Among the proteins involved in complex formation is phosphatidylinositol (PI) 3-kinase, a heterodimeric enzyme composed of 85 kDa and 110 kDa subunits, which binds to receptor (and non-receptor) phosphotyrosine residues through the two SH2 domains in the p85 subunit. p85 acts as an adaptor protein and possibly a regulator of the p110 catalytic subunit that phosphorylates phosphoinositides at the D-3 position of the inositol ring. p85 subunit is composed of several distinct functional domains: one SH3 and two SH2 domains, a p110 binding site and a region with homology to BCR. Expression of these domains in E. coli as GST-fusion proteins has allowed definition by nuclear magnetic resonance (NMR) of three-dimensional structures for the ...
T-lymphocytes play a crucial role in the immune response, both as direct effector cells and as regulatory cells that modulate the functions of other cell types. One of the earliest recognizable events after TCR stimulation is activation of LCK (p56lck) and FYN (p59fyn), which results in phosphorylation of tyrosine residues. Subsequently, ZAP70 tyrosine kinase is recruited to the TCR where it is activated by LCK through tyrosine phosphorylation. ZAP70 is a key signaling molecule in T cells, where it couples the antigen-activated TCR to downstream signaling pathways.28 Once ZAP70 has been activated, LCK and ZAP70 presumably act synergistically to phosphorylate specific downstream substrates, which in turn orchestrate the cytoplasmic signaling cascades leading to T-cell activation. These central roles of LCK and ZAP70 in TCR signaling have been amply documented. ZAP70 causes phosphorylation of LAT (linker for activation of T-cells), which in turn activates important downstream signaling pathways, ...
The full story is described in this publication: Voinov VG, Bennett SE, Beckman JS, Barofsky DF. ECD of tyrosine phosphorylation in a triple quadrupole mass spectrometer with a radio-frequency-free electromagnetostatic cell. J Am Soc Mass Spectrom. 2014 Oct;25(10):1730-8. PMC4163116.. Analysis of post-translational modifications such as phosphorylation using CID is challenging because the phosphate is easily and unpredictably dislodged by collisions. Thus, phosphorylation is difficult to quantify by CID. ...
J:32205 OBryan JP, et al., A mammalian adaptor protein with conserved Src homology 2 and phosphotyrosine-binding domains is related to Shc and is specifically expressed in the brain. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2729-34 ...
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