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PubMed1990

A quantitative assay for tyrosine sulfation and tyrosine phosphorylation in peptides.

A method was developed to measure sulfation and phosphorylation of tyrosine in proteins after alkaline hydrolysis, ion-exchange chromatography, reaction with [3H]dinitrofluorobenzene and subsequent thin-layer chromatography. The method allows the detection of 10-20 pmol of modified tyrosine and was applied to determine the content of tyrosine-phosphate and -sulfate in fibrinogens, thyroglobulin, alpha-casein, cytochrome c and glyceraldehyde dehydrogenase.

Chemical Phenomena↗

PubMedDate not supplied

[Spectroscopy of intermolecular interactions of a tyrosine chromophore. III. Classification of the state of tyrosine residues in proteins based on their electron spectra].

Absorption and fluorescence spectra of some tyrosine-containing proteins were analysed. Comparison of the peculiarities of fluorescence and absorption of the tyrosine chromophore in the model compounds and proteins suggested a new classification of the states of tyrosine residues in proteins: I -- tyrosyls with hydrated OH-group (lambda mf approximately equal to 304 nm); II -- tyrosyls, whose hydroxyl group forms the hydrogen bond inside the protein in a hydrophobic surrounding or in the globular fold in structured water layer (lambda mf = 306-307 nm); III -- tyrosyls whose OH-group is deprotonated in the excited state (lambda mf approximately equal to 330-350 nm).

Proteins↗

PubMed1983

Regulation of tyrosine hydroxylase mRNA by glucocorticoid and cyclic AMP in a rat pheochromocytoma cell line. Isolation of a cDNA clone for tyrosine hydroxylase mRNA.

Treatment of a subclone of the PC12 pheochromocytoma cell line, PC8b, with either dexamethasone or 8-bromo cyclic AMP resulted in increased translational activity of tyrosine hydroxylase mRNA (mRNATH). Poly(A+)-containing RNA from cells treated with both inducers was used to construct a cDNA library. Double-stranded cDNA was inserted into the PstI site of pBR322 using GC tailing, and plasmids were used to transform Escherichia coli HB101. Colonies containing plasmids with inserted sequences were initially screened by DNA dot hybridization, and those positive colonies were then screened by hybrid selected translation. One plasmid, pTH.4, was identified as containing a 400-base pair sequence complementary to mRNATH. Nick-translated pTH.4 DNA was used to identify mRNATH as containing approximately 1800 nucleotides by Northern blot analysis. PC8b cells treated with either dexamethasone or 8-bromo cyclic AMP yielded greater mRNATH hybridization on Northern blot analysis and accumulated higher molecular weight tyrosine hydroxylase RNA species. Following treatment of cells with inducers, the temporal increase in tyrosine hydroxylase enzyme activity was associated in all cases with an increase in the translational activity and relative amount of mRNATH, and the fold increase in the latter two parameters was equal to or greater than the increase in enzyme activity.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1995

CD50 (ICAM-3) is phosphorylated on tyrosine and is associated with tyrosine kinase activity in human neutrophils.

CD50 (ICAM-3) is expressed at a high level on resting blood granulocytes, monocytes, and lymphocytes. The constitutive high expression of CD50 on resting leukocytes suggests that it is an important LFA-1 ligand in the initiation of the immune/inflammatory response. Using a radiolabeling technique initially designed to detect ecto-protein kinase activity, we found that CD50 mAbs immunoprecipitated a approximately 125- to 170-kDa phosphoprotein from human neutrophils. Phosphorylation was increased after stimulation with the chemotactic agent FMLP, platelet-activating factor, 12-O-tetradecanoyl-phorbol-13-acetate, and the calcium ionophore A23187. This increase in phosphorylation was transient with the maximal phosphorylation, being observed by 1 min. Phosphoamino acid analysis revealed that CD50 contained predominantly phosphotyrosine. Although this assay system was designed initially to detect ecto-protein kinase activity, subsequent studies have shown that membrane proteins can be phosphorylated on the cytoplasmic domain under these conditions. When CD50 was immunoprecipitated from solubilized neutrophils, protein tyrosine kinase activity associated with CD50 was detected in the immunoprecipitate. The data suggest that phosphorylation of CD50 on tyrosine by an associated tyrosine kinase plays a role in the function of CD50.

Antigens, CD↗

PubMed1995

Modulation of biological tyrosine reactions by tyrosine phosphorylation.

This review focuses on the influence of tyrosine phosphorylation on the biological reactions of tyrosine. Reactions that are modulated by this amino acid modification include dityrosine formation, thyroid hormone synthesis, and DOPA formation. In addition, we show that the reactivity of tyrosine in the common Lowry method of determination of protein concentrations is lost upon phosphorylation of the amino acid.

Animals↗

PubMed1996

The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase.

After interferon-gamma (IFN-gamma) treatment of cells the appearance of tyrosine phosphorylated Stat1 in the nucleus was maximal within 20-30 min, remained for 2-2.5 h and activated molecules disappeared by 4 h. In the absence of continued signaling from the receptor (imposed by staurosporine treatment) previously activated Stat1 disappeared completely within 60 min, implying continuous generation and removal of active molecules during extended IFN-gamma treatment. Proteasome inhibitors prolonged the time of activation of Stat1 by prolonging signaling from the receptor but not by blocking removal of already activated Stat1 molecules. By analyzing with 35S labeling the distribution of total Stat1 and activated Stat1, we concluded that the Stat1 molecules promptly cycle into the nucleus as tyrosine phosphorylated molecules and later return quantitatively to the cytoplasm as non-phosphorylated molecules. Therefore, the removal of the activated Stat1 molecules from the nucleus appears not to be proteolytic but must depend on a protein tyrosine phosphatase(s).

Acetylcysteine↗

PubMed1998

Regulation of apoptosis by tyrosine-containing domains of IL-4R alpha: Y497 and Y713, but not the STAT6-docking tyrosines, signal protection from apoptosis.

IL-4 is a cytokine with important antiapoptotic activity. We have analyzed the role that tyrosine-containing domains within the cytoplasmic tail of IL-4R alpha play in IL-4-mediated protection from apoptosis. 32D cells expressing a wt huIL-4R alpha or one truncated at aa 557 were protected by huIL-4 from apoptosis while cells expressing a receptor truncated at aa 657 were not, suggesting that the carboxyl-terminal domain signals protection from apoptosis. However, changing Y713 within this region to phenylalanine had no effect. To analyze the contribution of tyrosine-containing domains independently, we transplanted regions of the huIL-4R alpha to a truncated form of the huIL-2R beta that could not signal protection from apoptosis. Transplantation of the huIL-4R alpha domains containing Y497 or Y713 partially prevented cell death and together signaled protection from apoptosis in response to IL-2 as well as the wt IL-2R beta. Mutation of Y497 and Y713 to phenylalanine inhibited protection. In contrast, transplantation of the domain containing the potential STAT6-docking tyrosines alone had no effect, yet it inhibited the protection mediated by the other domains. Although IL-4R alpha signals Shc and SH2-containing inositol phosphatase (SHIP) phosphorylation, we could not establish an association between their activation and protection from apoptosis. Taken together, this study suggests that the domains of the huIL-4R alpha containing Y497 and Y713 positively regulate protection from apoptosis while the domain containing the STAT6 docking sites suppresses this protection, and that additional signaling molecules other than insulin receptor substrate-1 (IRS1), Shc, or SHIP may be involved in antiapoptotic signaling.

Animals↗

PubMed2001

Effect of angiotensin II type 2 receptor on tyrosine kinase Pyk2 and c-Jun NH2-terminal kinase via SHP-1 tyrosine phosphatase activity: evidence from vascular-targeted transgenic mice of AT2 receptor.

Angiotensin II (Ang II) has two major receptor isoforms, AT1 and AT2. AT1 transphosphorylates Ca(2+)-sensitive tyrosine kinase Pyk2 to activate c-Jun NH2-terminal kinase (JNK). Although AT2 inactivates extracellular signal-regulated kinase (ERK) via tyrosine phosphatases (PTP), the action of AT2 on Pyk2 and JNK remains undefined. Using AT2-overexpressing vascular smooth muscle cells (AT2-VSMC) from AT2-transgenic mice, we studied these undefined actions of AT2. AT1-mediated JNK activity was increased 2.2-fold by AT2 inhibition, which was abolished by orthovanadate. AT2 did not affect AT1-mediated Pyk2 phosphorylation, but attenuated c-Jun mRNA accumulation by 32%. The activity of src-homology 2 domain-containing PTP (SHP-1) was significantly upregulated 1 min after AT2 stimulation. Stable overexpression of SHP-1 dominant negative mutant in AT2-VSMC completely abolished AT2-mediated inhibition of JNK activation and c-Jun expression. These findings suggest that AT2 inhibits JNK activity by affecting the downstream signal of Pyk2 in a SHP-1-dependent manner, leading to a decrease in c-Jun expression.

Angiotensin Receptor Antagonists↗

PubMed1999

Fyn and Lck tyrosine kinases regulate tyrosine phosphorylation of p105CasL, a member of the p130Cas docking protein family, in T-cell receptor-mediated signalling.

We have previously shown that engagement of the T-cell receptor (TCR)/CD3 complex with anti-CD3 antibody induces tyrosine phosphorylation of p105CasL (CasL), a member of the p130Cas docking protein family. In the present work, we attempted to determine which protein tyrosine kinases (PTKs) regulate TCR-mediated phosphorylation of CasL. We show here that an association between CasL and two types of Src family PTKs, Fyn and Lck, is induced by anti-CD3 cross-linking of human H9 T cells. In contrast, ZAP-70, another PTK that also plays a critical role in the TCR signalling, failed to bind CasL, even after anti-CD3 stimulation. In vitro kinase assays revealed that Fyn and Lck, but not ZAP-70, were capable of phosphorylating CasL. Moreover, we found that CasL was constitutively hyperphosphorylated in vivo in splenocytes of MRL-MP-lpr/lpr mice, in which overproduction and excessive activation of Fyn and Lck have previously been shown to occur. Constitutive in vivo binding of CasL to both kinases was also demonstrated in lpr splenocytes. These results strongly suggest that CasL is a substrate for Fyn and Lck PTKs in TCR signal transduction.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Sequence requirements for association of protein-tyrosine phosphatase PEP with the Src homology 3 domain of inhibitory tyrosine protein kinase p50(csk).

Previously, we reported that the inhibitory tyrosine protein kinase p50(csk) is physically associated with the protein-tyrosine phosphatase PEP in hematopoietic cells. This interaction was shown to involve the Src homology 3 (SH3) region of Csk and a proline-rich sequence of PEP termed P1 (SRRTDDEIPPPLPERTPESFIVVEE). In this report, we have attempted to understand the structural basis for the highly specific association of these two molecules in vivo. Our studies revealed that the proline-rich core of the P1 region of PEP (PPPLPERT) was necessary but not sufficient for binding to p50(csk). Additional sequences located carboxyl to this motif were also needed for binding to the Csk SH3 domain in vitro and in vivo. Further analyses revealed that two aliphatic residues (isoleucine 625 and valine 626; PESFIVVEE) were especially important for this effect. In addition to clarifying the molecular basis for the selective ability of PEP to associate with Csk, these results constitute further evidence that sequences outside proline-rich cores dictate the specificity of SH3 domain-mediated interactions in vivo.

Amino Acid Sequence↗

PubMed2000

Multiple interactions between receptor protein-tyrosine phosphatase (RPTP) alpha and membrane-distal protein-tyrosine phosphatase domains of various RPTPs.

Receptor protein-tyrosine phosphatase (RPTP) alpha belongs to the large family of receptor protein-tyrosine phosphatases containing two tandem phosphatase domains. Most of the catalytic activity is retained in the first, membrane-proximal domain (RPTPalpha-D1), and little is known about the function of the second, membrane-distal domain (RPTPalpha-D2). We investigated whether proteins bound to RPTPalpha using the two-hybrid system and found that the second domain of RPTPsigma interacted with the juxtamembrane domain of RPTPalpha. We confirmed this interaction by co-immunoprecipitation experiments. Furthermore, RPTPalpha not only interacted with RPTPsigma-D2 but also with RPTPalpha-D2, LAR-D2, RPTPdelta-D2, and RPTPmu-D2, members of various RPTP subfamilies, although with different affinities. In the yeast two-hybrid system and in glutathione S-transferase pull-down assays, we show that the RPTP-D2s interacted directly with the wedge structure of RPTPalpha-D1 that has been demonstrated to be involved in inactivation of the RPTPalpha-D1/RPTPalpha-D1 homodimer. The interaction was specific because the equivalent wedge structure in LAR was unable to interact with RPTPalpha-D2 or LAR-D2. In vivo, we show that other interaction sites exist as well, including the C terminus of RPTPalpha-D2. The observation that RPTPalpha, but not LAR, bound to multiple RPTP-D2s with varying affinities suggests a specific mechanism of cross-talk between RPTPs that may regulate their biological function.

Animals↗

PubMed2004

Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor Sprouty.

Src homology 2-containing phosphotyrosine phosphatase (Shp2) functions as a positive effector in receptor tyrosine kinase (RTK) signaling immediately proximal to activated receptors. However, neither its physiological substrate(s) nor its mechanism of action in RTK signaling has been defined. In this study, we demonstrate that Sprouty (Spry) is a possible target of Shp2. Spry acts as a conserved inhibitor of RTK signaling, and tyrosine phosphorylation of Spry is indispensable for its inhibitory activity. Shp2 was able to dephosphorylate fibroblast growth factor receptor-induced phosphotyrosines on Spry both in vivo and in vitro. Shp2-mediated dephosphorylation of Spry resulted in dissociation of Spry from Grb2. Furthermore, Shp2 could reverse the inhibitory effect of Spry on FGF-induced neurite outgrowth and MAP kinase activation. These findings suggest that Shp2 acts as a positive regulator in RTK signaling by dephosphorylating and inactivating Spry.

Animals↗

PubMed1996

The nonreceptor protein tyrosine phosphatase corkscrew functions in multiple receptor tyrosine kinase pathways in Drosophila.

Corkscrew (csw) encodes a nonreceptor protein tyrosine phosphatase (PTPase) that has been implicated in signaling from the Torso receptor tyrosine kinase (RTK). csw mutations, unlike tor mutations, are associated with zygotic lethality, indicating that Csw plays additional roles during development. We have conducted a detailed phenotypic analysis of csw mutations to identify these additional functions of Csw. Our results indicate that Csw operates positively downstream of other Drosophila RTKs such as the Drosophila epidermal growth factor receptor (DER), the fibroblast growth factor receptor (Breathless), and likely other RTKs. This model is substantiated by specific dosage interactions between csw and DER. It is proposed that Csw is part of the evolutionarily conserved "signaling cassette" that operates downstream of all RTKs. In support of this hypothesis, we demonstrate that SHP-2, a vertebrate PTPase similar to Csw and previously implicated in RTK signaling, encodes the functional vertebrate homologue of Csw.

Alleles↗

PubMed2003

Purification and characterization of T cell protein tyrosine phosphatase reveals significant functional homology to protein tyrosine phosphatase-1B.

We have developed a protocol for rapid purification of T cell protein tyrosine phosphatase (TCPTP) and the structurally related protein tyrosine phosphatase-1B (PTP-1B) from bacterial cells. The pH profile for TCPTP was bell-shaped with an optimum of 5.5. The catalytic domain and full-length versions of TCPTP bound a potent inhibitor with affinities similar to those of PTP-1B. The K(m) values for the catalytic domains of TCPTP and PTP-1B increased with increasing ionic strength, whereas the k(cat) values remained unchanged. Arrhenius plots revealed that TCPTP and PTP-1B possess similar activation energies of 25.3+/-1.2 and 18.4+/-3.0 kJ/mol, respectively. Increasing solvent microviscosity (up to 40% (w/v) sucrose) did not affect k(cat)/K(m) of either enzyme. However, high sucrose concentrations protected both enzymes from thermal inactivation. These studies show that, although they share a 72% amino acid sequence identity within their catalytic domains, TCPTP and PTP-1B are functionally very similar in vitro.

Amino Acid Sequence↗

PubMed1998

Cell-contact-dependent signalling in axon growth and guidance: Eph receptor tyrosine kinases and receptor protein tyrosine phosphatase beta.

The growth and guidance of axons involves the recognition of complex environmental cues by receptor proteins on the surface of the growth cone and their interpretation by cellular machinery, leading to changes in cellular behaviour. Recent advances have demonstrated that the ligands for Eph receptor tyrosine kinases, the ephrins, act as repulsive axon guidance cues, and that Eph receptors are required for correct axonal navigation in vivo. Members of the receptor protein tyrosine phosphatase (RPTP) family also play important roles in axon guidance and growth. RPTP beta and Eph receptors interact with cell-surface-bound ligands, and there is increasing evidence that both transmembrane ephrins and contactin, a ligand for RPTP beta, may possess an intrinsic signalling function. Thus, the cell-contact-dependent interactions between these receptors and ligands may lead to initiation of bidirectional signals that regulate axonal growth and migration.

Animals↗

PubMed1998

Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases.

3-Substituted indolin-2-ones have been designed and synthesized as a novel class of tyrosine kinase inhibitors which exhibit selectivity toward different receptor tyrosine kinases (RTKs). These compounds have been evaluated for their relative inhibitory properties against a panel of RTKs in intact cells. By modifying the 3-substituted indolin-2-ones, we have identified compounds which showed selective inhibition of the ligand-dependent autophosphorylation of various RTKs at submicromolar levels in cells. Structure-activity analysis for these compounds and their relative potency and selectivity to inhibit particular RTKs has determined that (1) 3-[(five-membered heteroaryl ring)methylidenyl]indolin-2-ones are highly specific against the VEGF (Flk-1) RTK activity, (2) 3-(substituted benzylidenyl)indolin-2-ones containing bulky group(s) in the phenyl ring at the C-3 position of indolin-2-ones showed high selectivity toward the EGF and Her-2 RTKs, and (3) the compound containing an extended side chain at the C-3 position of the indolin-2-one (16) exhibited high potency and selectivity when tested against the PDGF and VEGF (Flk-1) RTKs. Recent published crystallographic data for two of these 3-substituted indolin-2-ones provides a rationale to suggest that these compounds may bind in the ATP binding pocket of RTKs. The structure-activity analysis supports the use of subsets of these compounds as specific chemical leads for the development of RTK-specific drugs with broad application for the treatment of human diseases.

Cells, Cultured↗

PubMed1997

Transphosphorylation of Bruton's tyrosine kinase on tyrosine 551 is critical for B cell antigen receptor function.

Bruton's tyrosine kinase (Btk) is required for B cell development and B cell antigen receptor (BCR) function. Cross-linking of BCR induces phosphorylation of Btk at Tyr551 and Tyr223. However, the functional requirement of these phosphorylation for BCR signaling remains unclear. We demonstrate here that mutation of Tyr551, not Tyr223, abrogates the BCR-induced calcium mobilization. Not only Lyn, but also Syk was required for tyrosine phosphorylation of Btk in BCR signaling. These results suggest that transphosphorylation of Btk on Tyr551 is essential for BCR function and that this phosphorylation is mediated through the concerted actions of Lyn and Syk.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2000

The carboxyl-terminal tyrosine residue of protein-tyrosine phosphatase alpha mediates association with focal adhesion plaques.

The receptor protein-tyrosine phosphatase alpha (PTPalpha) is involved in the activation of c-Src kinase as well as in down-regulation of the insulin signal. To investigate the role of PTPalpha in activation of the Src kinase in more detail we tried to overexpress this phosphatase in NIH3T3 fibroblasts. Although PTPalpha has been overexpressed in rat embryonic fibroblasts and in embryonic carcinoma cells and should increase mitogenic responses we were not able to achieve a detectable overexpression. In contrast, expression of partially (C442S) or completely inactive (C442S,C732S) PTPalpha or of phosphatase active PTPalpha containing mutation Y781F or Y798F was possible. The level of expression, however, was reduced to background after several passages of lines expressing PTPalphaC442S,C732S and PTPalphaY781F. When employed in a focus formation assay, only infection with virus encoding PTPalphaY798F induced Src-dependent formation of foci. In immunofluorescence studies, PTPalphaC442S and PTPalphaY781F but not PTPalphaY798F colocalized with proteins found in focal adhesion plaques. Treatment of PTPalphaC442S-overexpressing cells with vanadate abolished this colocalization and led to proteolytic processing of the phosphatase. We conclude that tyrosine 798 in PTPalpha is important for localization at focal adhesion plaques. Inhibition of phosphatases by vanadate treatment releases PTPalpha from focal adhesions.

3T3 Cells↗