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PubMed1995

Roles for a cytoplasmic tyrosine and tyrosine kinase activity in the interactions of Neu receptors with coated pits.

The neu proto-oncogene product, p185neu (HER2, c-ErbB-2), encodes a cell-surface tyrosine kinase receptor with high oncogenic potential, which correlates with increased tyrosine kinase activity and a rapid receptor internalization rate. To investigate the interactions and signal(s) leading to the endocytosis of Neu receptors, we employed lateral mobility and internalization studies. Fluorescence photobleaching recovery measurements revealed that activation of Neu receptors (induced by mutation or by agonistic antibodies) markedly reduced their mobile fractions. To elucidate the signals involved, other mutants, all carrying a constitutively dimerizing oncogenic mutation, were analyzed. A kinase-negative mutant and a mutant lacking all cytoplasmic tyrosine phosphorylation consensus sequences exhibited high mobile fractions, similar to nonactivated Neu. Retention of a single tyrosine autophosphorylation site (Tyr-1253) out of the five known such sites was sufficient to immobilize a large fraction of the receptor. For all mutants, internalization correlated with receptor immobilization and was blocked by treatments that interfere with coated pit structure, indicating that the immobilization is due to interactions with coated pits. This was supported by the coimmunoprecipitation of alpha-adaptin only with the constitutively activated Neu mutants. We conclude that activated Neu receptors become stably associated with coated pits via plasma membrane adaptor complexes (AP-2). Efficient Neu receptor endocytosis requires activation, a functional kinase domain, and at least one tyrosine autophosphorylation site.

3T3 Cells↗
PubMed1994

Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking.

Tyrosine phosphorylation of several cellular proteins is one of the earliest signaling events induced by cross-linking of the high-affinity receptor for immunoglobulin E (Fc epsilon RI) on mast cells or basophils. Tyrosine kinases activated during this process include the Src family kinases, Lyn, c-Yes, and c-Src, and members of another subfamily, Syk and PTK72 (identical or highly related to Syk). Recently, some of us described two novel tyrosine kinases, Emb and Emt, whose expression was limited to subsets of hematopoietic cells, including mast cells. Emb turned out to be identical to Btk, a gene product defective in human X-linked agammaglobulinemia and in X-linked immunodeficient (xid) mice. Here we report that Fc epsilon RI cross-linking induced rapid phosphorylation on tyrosine, serine, and threonine residues and activation of Btk in mouse bone marrow-derived mast cells. A small fraction of Btk translocated from the cytosol to the membrane compartment following receptor cross-linking. Tyrosine phosphorylation of Btk was not induced by either a Ca2+ ionophore (A23187), phorbol 12-myristate 13-acetate, or a combination of the two reagents. Co-immunoprecipitation between Btk and receptor subunit beta or gamma was not detected. The data collectively suggest that Btk is not associated with Fc epsilon but that its activation takes place prior to protein kinase C activation and plays a novel role in the Fc epsilon RI signaling pathway.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2004

Site-selective regulation of platelet-derived growth factor beta receptor tyrosine phosphorylation by T-cell protein tyrosine phosphatase.

The platelet-derived growth factor (PDGF) beta receptor mediates mitogenic and chemotactic signals. Like other tyrosine kinase receptors, the PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs). To explore whether T-cell PTP (TC-PTP) negatively regulates the PDGF beta receptor, we compared PDGF beta receptor tyrosine phosphorylation in wild-type and TC-PTP knockout (ko) mouse embryos. PDGF beta receptors were hyperphosphorylated in TC-PTP ko embryos. Fivefold-higher ligand-induced receptor phosphorylation was observed in TC-PTP ko mouse embryo fibroblasts (MEFs) as well. Reexpression of TC-PTP partly abolished this difference. As determined with site-specific phosphotyrosine antibodies, the extent of hyperphosphorylation varied among different autophosphorylation sites. The phospholipase Cgamma1 binding site Y1021, previously implicated in chemotaxis, displayed the largest increase in phosphorylation. The increase in Y1021 phosphorylation was accompanied by increased phospholipase Cgamma1 activity and migratory hyperresponsiveness to PDGF. PDGF beta receptor tyrosine phosphorylation in PTP-1B ko MEFs but not in PTPepsilon ko MEFs was also higher than that in control cells. This increase occurred with a site distribution different from that seen after TC-PTP depletion. PDGF-induced migration was not increased in PTP-1B ko cells. In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.

Animals↗
PubMed2003

Junctional protein MAGI-3 interacts with receptor tyrosine phosphatase beta (RPTP beta) and tyrosine-phosphorylated proteins.

Receptor protein tyrosine phosphatase beta (RPTP beta) mediates cell-cell and cell-matrix interactions. By searching for intracellular proteins that interact with the cytoplasmic region of this phosphatase using the two-hybrid method, we identified several proteins containing PDZ domains. One of these proteins, MAGI-3, contains a guanylate-kinase-like region, six PDZ and two WW domains. The interaction between RPTP beta and MAGI-3 was confirmed by co-immunoprecipitation and pulldown experiments in transfected cells. Immunofluorescence and immunoelectron microscopy revealed that MAGI-3 is concentrated in specific sites at the plasma membrane and in the nucleus. In epithelial cells, MAGI-3 was localized with ZO-1 and cingulin at tight junctions, whereas in primary cultured astrocytes it was found in E-cadherin-based cell-cell contacts and in focal adhesion sites. Although MAGI-3 itself was not phosphorylated on tyrosine residues, it became associated with tyrosine-phosphorylated proteins following a short treatment of the cells with vanadate. In glioblastoma SF763T cells MAGI-3 was associated with a tyrosine-phosphorylated protein with the apparent molecular weight of 130 kDa, whereas in Caco2 cells it was associated with a 90 kDa protein. Finally, we show that p130 served as a substrate for RPTP beta and that its dephosphorylation required the C-terminal sequence of the phosphatase, which mediated the interaction with MAGI-3. These findings suggest a possible role for MAGI-3 as a scaffolding molecule that links receptor tyrosine phosphatase with its substrates at the plasma membrane.

Adherens Junctions↗
PubMed2002

Regulation of Lck and Fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule.

Leukocyte common antigen-related molecule (LAR) is a receptor-like protein tyrosine phosphatase (PTPase) with two PTPase domains. In the present study, we detected the expression of LAR in the brain, kidney, and thymus of mice using anti-LAR PTPase domain subunit monoclonal antibody (mAb) YU1. In the thymus, LAR was expressed on CD4(-)CD8(-) and CD4(-)CD8(low) thymocytes. The development of thymocytes in CD45 knockout mice is blocked partially in the maturation of CD4(-)CD8(-) to CD4(+)CD8(+). We postulated that LAR regulates Lck and Fyn in the immature thymocytes. Transfection of wild-type LAR activated extracellular signal-regulated kinase signal transduction pathway in CD45-deficient Jurkat cells stimulated with anti-CD3 mAb. LAR mutants, with Cys to Ser mutation in the catalytic center of PTPase D1, bound to tyrosine-phosphorylated Lck and Fyn, and LAR PTPase domain 2 was tyrosine phosphorylated by Fyn tyrosine kinase. The phosphorylated LAR was associated with Fyn Src homology 2 domain. Moreover, LAR dephosphorylated phosphorylated tyrosine residues in both the COOH terminus and kinase domain of Fyn in vitro. Our results indicate that Lck and Fyn would be substrates of LAR in immature thymocytes and that each LAR PTPase domain plays distinct functional roles in phosphorylation and dephosphorylation.

Amino Acid Motifs↗
PubMed1994

Tyrosine kinase and CD45 tyrosine phosphatase activity mediate p21ras activation in B cells stimulated through the antigen receptor.

Cross-linking of the Ag receptor (AgR) induces intracellular signaling events in B cells, such as p21ras activation, that lead to their proliferation and differentiation. This event is accompanied by the tyrosine phosphorylation of the p21ras-associated GTPase-activating protein p120 ras.GAP, raising the possibility that AgR-stimulated p21ras activity is regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPases) in B cells. To test this possibility, we examined the effects of PTK and PTPase inhibitors on protein tyrosine phosphorylation and p21ras activation induced by AgR cross-linking in TNP-specific TA3 7.9 murine B lymphoma cells. Although AgR-induced protein tyrosine phosphorylation was inhibited by the PTK inhibitors genistein and herbimycin A, it was enhanced by exposure to the PTPase inhibitor phenylarsine oxide (PAO). Cross-linking of the AgR by Ag or F(ab')2 anti-IgM induced a rapid (within 5 min) two- to threefold increase in p21ras activation in 7.9 B cells. Interestingly, a second peak of p21ras activation was evident at approximately 40 min after stimulation. Genistein and herbimycin A and PAO each blocked AgR-stimulated p21ras activation. Similarly, Ag-induced p21ras activation was inhibited by pretreatment of 7.9 B cells with an anti-CD45 mAb (detects the 220-kDa B cell isoform of CD45). Moreover, p21ras activation was induced by Ag and F(ab')2 anti-IgM in CD45+ but not CD45- J558L microns 3 B cells. These data indicate that p21ras activation induced by AgR cross-linking in B cells is regulated by both PTK and CD45 PTPase activities.

Animals↗
PubMed1994

Receptor tyrosine phosphatase R-PTP-alpha is tyrosine-phosphorylated and associated with the adaptor protein Grb2.

Receptor tyrosine phosphatases (R-PTPases) have generated interest because of their suspected involvement in cellular signal transduction. The adaptor protein Grb2 has been implicated in coupling receptor tyrosine kinases to Ras. We report that a ubiquitous R-PTPase, R-PTP-alpha, is tyrosine-phosphorylated and associated in vivo with the Grb2 protein. This association can be reproduced in stably and transiently transfected cells, as well as in vitro using recombinant Grb2 protein. Association requires the presence of an intact SH2 domain in Grb2, as well as tyrosine phosphorylation of R-PTP-alpha. This observation links a receptor tyrosine phosphatase with a key component of a central cellular signalling pathway and provides a basis for addressing R-PTP-alpha function.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Regulation of protein tyrosine phosphorylation in human sperm by a calcium/calmodulin-dependent mechanism: identification of A kinase anchor proteins as major substrates for tyrosine phosphorylation.

Signal transduction pathways regulate various aspects of mammalian sperm function. When human sperm were incubated in a medium supporting capacitation, proteins became tyrosine-phosphorylated in a time-dependent manner. This phosphorylation was inhibited by genistein, a protein tyrosine kinase inhibitor. Phosphorylation was also reduced when sperm were incubated either in the presence of increasing concentrations of extracellular Ca2+ or in a medium containing the Ca2+ ionophore A23187. This Ca2+-induced dephosphorylation was calmodulin-dependent, suggesting that calcineurin was involved. In this regard, the calcineurin inhibitor deltamethrin inhibited the Ca2+ ionophore-induced dephosphorylation. A limited number of Mr 80,000-105,000 polypeptides were the most prominent phosphotyrosine-containing proteins present in human sperm. Unlike mouse sperm, which contains a tyrosine-phosphorylated isoform of hexokinase, a phosphotyrosine-containing hexokinase in human sperm was not detected. Most of the tyrosine-phosphorylated proteins were Triton X-100-insoluble and were localized to the principal piece of the flagellum, the region where the cytoskeletal fibrous sheath is found. Prominent phosphotyrosine-containing proteins of Mr 82,000 and 97,000 were identified as the human homologues of mouse sperm AKAP82, the major fibrous sheath protein, and pro-AKAP82, its precursor polypeptide, respectively. These proteins are A Kinase Anchor Proteins, polypeptides that sequester protein kinase A to subcellular locations. Taken together, these results suggest that protein tyrosine phosphorylation may be part of a signal transduction cascade(s) regulating events pertaining to capacitation and/or motility in mammalian sperm and that an interrelationship between tyrosine kinase and cAMP signaling pathways exists in these cells.

Alkaloids↗
PubMed2000

Association of Lyn tyrosine kinase to the GM-CSF and IL-3 receptor common betac subunit and role of Src tyrosine kinases in DNA synthesis and anti-apoptosis.

BACKGROUND: After GM-CSF or IL-3 stimulation, the activation of JAK2 tyrosine kinase and members of the Src family of tyrosine kinases takes place, followed by phosphorylation of betac tyrosine residues and the recruitment of SH2 containing molecules to the receptor complex. The exact role of Src kinases such as Lyn in this and other downstream signal transduction events remains unclear. RESULTS: We investigated the association of Lyn kinase with betac using synthetic peptides derived from the eight betac tyrosine residues and the Box 1 motif. We found that Lyn kinase GST fusion proteins bind to peptides corresponding to the membrane proximal region of betac and to peptides containing specific betac derived phosphorylated tyrosine residues. We also determined that betac tyrosine residues Y1,2 as well as Y7 and Y8 can act as substrates of Lyn. We further analysed the role of the Src kinases in DNA synthesis and anti-apoptosis downstream of GM-CSF by using the Src kinase inhibitor PP1 in murine BA/F3 cells stably expressing a series of mutant betac receptors. CONCLUSIONS: Lyn binds to betac derived peptides through multiple interactions, and may play an important role in betac phosphorylation. Src family kinases also play an essential role in GM-CSF mediated DNA synthesis, as well as an important role in anti-apoptosis in response to GM-CSF.

Amino Acid Sequence↗
PubMed1996

Regulation of Src family tyrosine kinase activities in adherent human neutrophils. Evidence that reactive oxygen intermediates produced by adherent neutrophils increase the activity of the p58c-fgr and p53/56lyn tyrosine kinases.

Src family tyrosine kinases have been implicated in the adhesion-dependent activation of neutrophil functions (Yan, S. R., Fumagalli, L., and Berton, G. (1995) J. Inflamm. 45, 297-312; Lowell, C. A., Fumagalli, L., and Berton, G. (1996) J. Cell Biol. 133, 895-910). Because the activity of tyrosine kinases can be affected by oxidants, we investigated whether reactive oxygen intermediates (ROI) produced by adherent neutrophils regulate Src family kinase activities. Inhibition of ROI production by diphenylene iodonium, an inhibitor of NADPH oxidase, or degradation of H2O2 by exogenously added catalase inhibited the adhesion-stimulated activities of p58(c-fgr) and p53/56(lyn). In addition, adhesion-stimulated p58(c-fgr) and p53/56(lyn) activities were greatly reduced in neutrophils from patients with chronic granulomatous disease (CGD) that are deficient in the production of ROI. Exogenously added H2O2 increased p58(c-fgr) and p53/56(lyn) activities in nonadherent neutrophils. Although ROI regulated the activities of p58(c-fgr) and p53/56(lyn), they did not affect the redistribution of the two kinases to a Triton X-100-insoluble, cytoskeletal fraction that occurs in adherent neutrophils. Tyrosine phosphorylation of proteins in adherent, CGD neutrophils was only partially inhibited, suggesting that the full activation of p58(c-fgr) and p53/56(lyn), which depends on endogenously produced ROI, does not represent an absolute requirement for protein tyrosine phosphorylation. The adhesion-stimulated activity of the tyrosine kinase p72(syk) was not affected by catalase in normal neutrophils, and it was comparable in normal and CGD neutrophils. These findings suggest that ROI endogenously produced by adherent neutrophils regulate Src family kinases activity selectively and establish the existence of a cross-talk between reorganization of the cytoskeleton, production of ROI, and Src family tyrosine kinase activities in signaling by adhesion.

Catalase↗
PubMed2005

Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase.

Tau is a major microtubule-associated protein of axons and is also the principal component of the paired helical filaments (PHFs) that comprise the neurofibrillary tangles found in Alzheimer's disease and other tauopathies. Besides phosphorylation of tau on serine and threonine residues in both normal tau and tau from neurofibrillary tangles, Tyr-18 was reported to be a site of phosphorylation by the Src-family kinase Fyn. We examined whether tyrosine residues other than Tyr-18 are phosphorylated in tau and whether other tyrosine kinases might phosphorylate tau. Using mass spectrometry, we positively identified phosphorylated Tyr-394 in PHF-tau from an Alzheimer brain and in human fetal brain tau. When wild-type human tau was transfected into fibroblasts or neuroblastoma cells, treatment with pervanadate caused tau to become phosphorylated on tyrosine by endogenous kinases. By replacing each of the five tyrosines in tau with phenylalanine, we identified Tyr-394 as the major site of tyrosine phosphorylation in tau. Tyrosine phosphorylation of tau was inhibited by PP2 (4-amino-5-(4-chlorophenyl-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), which is known to inhibit Src-family kinases and c-Abl. Cotransfection of tau and kinases showed that Tyr-18 was the major site for Fyn phosphorylation, but Tyr-394 was the main residue for Abl. In vitro, Abl phosphorylated tau directly. Abl could be coprecipitated with tau and was present in pretangle neurons in brain sections from Alzheimer cases. These results show that phosphorylation of tau on Tyr-394 is a physiological event that is potentially part of a signal relay and suggest that Abl could have a pathogenic role in Alzheimer's disease.

Aged, 80 and over↗
PubMed2001

Expression of the small tyrosine phosphatase (Stp1) in Saccharomyces cerevisiae: a study on protein tyrosine phosphorylation.

Small tyrosine phoshatase 1 (Stp1) is a Schizosaccharomyces pombe low-molecular-mass phosphotyrosine-phosphatase 50% identical to Saccharomyces cerevisiae Ltp1. In order to investigate the role of Stp1 in yeast, a mutant was generated having the characteristic of a dominant negative molecule. Changes in protein tyrosine phosphorylation in S. cerevisiae proteome in response to Stp1 or its dominant negative mutant expression were analyzed by high-resolution two-dimensional (2-D) electrophoresis. The most remarkable result is the modification by phosphorylation on tyrosine of several proteins involved in carbohydrate metabolism. Twelve proteins were identified on the basis of their positions in the anti-phosphotyrosine immunoblot of the 2-D electrophoresis. Ten of these present tyrosyl residues that are within the consensus sequence for protein kinase CK2 (casein kinase-2). These data open the possibility for the identification of Stp1 substrates in yeast and provide hints about the nature of tyrosine phosphorylating agents in yeast and in other organisms where bona fide tyrosine kinases are lacking.

Acrylic Resins↗
PubMed1995

Protein tyrosine phosphorylation during sea urchin fertilization: microtubule dynamics require tyrosine kinase activity.

Protein tyrosine phosphorylation plays an important role in cell growth, mitosis, and tumorigenesis. It has also been implicated in meiotic maturation and fertilization. We have used anti-phosphotyrosine immunofluorescence and immunoblotting to identify sperm and egg proteins which are phosphorylated on tyrosine residues prior to and during sea urchin fertilization. On immunoblots of sperm proteins, the monoclonal anti-phosphotyrosine antibody detected three major proteins with molecular weights of 44, 82, and 100 kD, and six minor bands at 46, 48, 70, 76, 95, and 150 kD. These phosphotyrosyl proteins were localized to the sperm acrosomal and centriolar fossae. In contrast, staining was found globally in unfertilized eggs, and the antibody recognized two major egg phosphotyrosyl proteins of molecular weights 42 and 50 kD, and five minor bands at 40, 90, 116, 130, and 150 kD. While immunofluorescent staining remained throughout the fertilized egg cytoplasm, there were dynamic changes in the staining intensity of single bands. The 90 kD immunoreactive band increased in intensity, and the 40 and 42 kD bands disappeared by 15 min after fertilization. Loss of the 40 and 42 kD bands was due to dephosphorylation by okadaic acid-sensitive phosphatase(s). The 50 kD immunoreactive protein was unchanged up to the 8-cell stage and was still present in blastulae, indicating its importance throughout fertilization and early development. Alterations in the pattern of phosphotyrosine-containing proteins during fertilization did not depend on nascent proteins and could not be completely mimicked by increasing intracellular calcium, pH, and protein kinase C activity alone. Since changes in the fertilization pattern of phosphotyrosyl proteins occurred during formation of the sperm aster and mitotic spindle, we analyzed the role of protein tyrosine kinase activity in these processes using the tyrosine kinase specific inhibitor, erbstatin. Both the sperm aster and mitotic spindle were disrupted, indicating an involvement of tyrosine phosphorylation in these processes during interphase and mitosis. We conclude that the changes in phosphotyrosyl proteins play an important role in fertilization and early development of sea urchin eggs. Control of microtubule assembly into the sperm aster and mitotic spindle of the first cell cycle are examples of such roles.

Animals↗
PubMed1995

Human T lymphocyte activation induces tyrosine phosphorylation of alpha-tubulin and its association with the SH2 domain of the p59fyn protein tyrosine kinase.

A glutathione-S-transferase-src-homology domain 2 (GST-SH2) fusion protein was employed to identify molecules interacting with the protein tyrosine kinase p59fyn. Among several proteins which bound to the fyn SH2 domain in lysates of human Jurkat T lymphocytes, alpha- and beta-tubulin were identified by N-terminal sequencing. Further analysis established that alpha-tubulin exists as a tyrosine-phosphorylated protein in Jurkat cells, where it interacts with p59fyn, but not with p56lck. By contrast, in untransformed resting human T lymphocytes alpha-tubulin is not detectable as a tyrosine phosphorylated protein. However, following T cell activation, it becomes rapidly phosphorylated on tyrosine residues and subsequently associates with the SH2 domain of fyn. Interestingly, constitutively tyrosine-phosphorylated alpha-tubulin that is able to interact with the fyn-SH2 domain is expressed in peripheral blood T lymphoblasts isolated from leukemic patients in the absence of external stimulation.

Amino Acid Sequence↗
PubMed1997

Bacterial LPS and IFN-gamma trigger the tyrosine phosphorylation of vav in macrophages: evidence for involvement of the hck tyrosine kinase.

We and others have previously reported that tyrosine kinases play key roles in the activation of macrophages by both bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). However, little is known regarding the substrates of tyrosine phosphorylation that mediate macrophage activation and the resultant production of inflammatory mediators. In lymphocytes and other hematopoietic lineages, tyrosine phosphorylation of the proto-oncogene vav appears to be an essential component of cell activation. In this study, we demonstrate that both LPS and rIFN-gamma trigger the prompt, dose-dependent tyrosine phosphorylation of vav in murine RAW 264.7 macrophages. In addition, vav is physically associated with the src-related kinase hck in murine macrophages, and antisense oligonucleotides specific for murine hck block both LPS and rIFN-gamma-mediated vav phosphorylation. These findings suggest that hck probably mediates vav tyrosine phosphorylation during macrophage activation and that LPS and rIFN-gamma-mediated signaling pathways partially overlap.

Animals↗
PubMed2005

Oxidation and tyrosine phosphorylation: synergistic or antagonistic cues in protein tyrosine phosphatase.

Protein tyrosine phosphatases (PTPs) have been generally recognised as key modulators of cell proliferation, differentiation, adhesion and motility. During signalling, several PTPs undergo two posttranslational modifications that greatly affect their enzymatic activity: tyrosine phosphorylation and cysteine oxidation. Although these modifications share their reversibility depending on the intracellular environment, their effects on enzymatic activity are opposite, tyrosine phosphorylation being correlated to enzyme activation and thiol oxidation to complete inactivation. Several papers have suggested that both these modifications occur in response to the same stimuli i.e. cell proliferation induced by numerous growth factors and cytokines. Conversely, the possibility that these two regulation mechanisms act simultaneously on PTPs has not been established and very few reports investigated this dual regulation of PTPs. To underline the relevance of the question, we discuss several possibilities: (i) that tyrosine phosphorylation and cysteine oxidation of PTPs may share the same target molecules but with different kinetics; (ii) that PTP phosphorylation and oxidation may take place on different subcellular pools of the same protein and (iii) that these two modifications, although having divergent effects on enzyme activity, cooperate in the integrated and coordinated function of PTPs during receptor tyrosine kinase signalling. We believe that our perspective will open new perspectives on an ancient problem--the apparent contradiction of opposing enzymatic regulation of many PTPs--thus clarifying their role as positive or negative transducers (or both) of many extracellular stimuli.

Cysteine↗
PubMed2000

Role of receptor protein tyrosine phosphatase alpha (RPTPalpha) and tyrosine phosphorylation in the serotonergic inhibition of voltage-dependent potassium channels.

The activity of voltage-gated potassium (Kv) channels can be dynamically modulated by several events, including neurotransmitter-stimulated biochemical cascades mediated by G-protein-coupled receptors. By using a heterologous expression system, we show that activating the 5-HT2C receptor inhibits both Kv1.1 and Kv1.2 channels through a tyrosine phosphorylation mechanism. The major molecular determinants of channel inhibition were identified as two tyrosine residues located in the N-terminal region of the Kv channel subunit. Furthermore, we demonstrate that receptor protein tyrosine phosphatase alpha (RPTPalpha), a receptor protein tyrosine phosphatase, co-ordinates the inhibition process mediated via 5-HT2C receptors. We therefore propose that the serotonergic regulation of human Kv1.1 and Kv1.2 channel activity by the 5-HT2C receptor involves the dual coordination of both RPTPalpha and specific tyrosine kinases coupled to this receptor.

Animals↗
PubMed1976

Studies on phenylalanine and tyrosine hydroxylation by rat brain tyrosine hydroxylase.

Tyrosine hydroxylase (EC1.14.16.2), presumably the rate-limiting enzyme in the biosynthesis of catecholamines, is known to catalyze the hydroxylation of both phenylalanine and tyrosine. Using both an isolated enzyme preparation and a synaptosomal preparation, where some architectural integrity of the tissue has been preserved, we have attempted to evaluate the manner in which these two substrates are hydroxylated by rat brain tyrosine hydroxylase. In the presence of tetrahydrobiopterin the isolated enzyme catalyzes the hydroxylation of phenylalanine to 3,4-dihydroxyphenylalanine with the release of free tyrosine as an obligatory intermediate. In contrast, the rat brain striatal synaptosomal preparation in the presence of endogenous cofactor converts phenylalanine to 3,4-dihydroxyphenylalanine without the release of free tyrosine.

Animals↗