Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe a new member of the receptor protein tyrosine phosphatase family, R-PTP-kappa, cDNA cloning predicts that R-PTP-kappa is synthesized from a precursor protein of 1,457 amino acids. Its intracellular domain displays the classical tandemly repeated protein tyrosine phosphatase homology, separated from the transmembrane segment by an uncharacteristically large juxta-membrane region. The extracellular domain of the R-PTP-kappa precursor protein contains an immunoglobulin-like domain and four fibronectin type III-like repeats, preceded by a signal peptide and a region of about 150 amino acids with similarity to the Xenopus A5 antigen, a putative neuronal recognition molecule (S. Takagi, T. Hsrata, K. Agata, M. Mochii, G. Eguchi, and H. Fujisawa, Neuron 7:295-307, 1991). Antibodies directed against the intra- and extracellular domains reveal that the R-PTP-kappa precursor protein undergoes proteolytic processing, following which both cleavage products remain associated. By site-directed mutagenesis, the likely cleavage site was shown to be a consensus sequence for cleavage by the processing endopeptidase furin, located in the fourth fibronectin type III-like repeat. In situ hybridization analysis indicates that expression of R-PTP-kappa in the central nervous system is developmentally regulated, with highest expression seen in actively developing areas and, in the adult, in areas capable of developmental plasticity such as the hippocampal formation and cerebral cortex. The mouse R-PTP-kappa gene maps to chromosome 10, at approximately 21 centimorgans from the centromere.
Mol Cell Biol 1993 May
PMID:Cloning and characterization of R-PTP-kappa, a new member of the receptor protein tyrosine phosphatase family with a proteolytically cleaved cellular adhesion molecule-like extracellular region. 847 52

Transforming growth factor beta 1 (TGF-beta 1) exerts a positive effect on the transcription of genes coding for several extracellular matrix-related products, including collagen I. We have previously identified a strong TGF-beta 1-responsive element (TbRE) in the upstream promoter sequence of the alpha 2(I) collagen (COL1A2) gene. Our experiments have shown that TGF-beta 1 stimulates COL1A2 transcription by increasing binding of an Sp1-containing complex (TbRC) to the TbRE. They have also suggested that the change occurs via posttranslational modification of a protein(s) directly or indirectly interacting with Sp1. Here, we provide evidence showing that tyrosine dephosphorylation of nuclear proteins mimics the stimulation of COL1A2 transcription by the TGF-beta 1-activated signaling pathway. Preincubation of nuclear extracts with protein tyrosine phosphatase (PTPase) but not with protein phosphatase type 2A (PP2A), a serine/threonine phosphatase, enhanced binding of the TbRC to the same degree as culturing cells in TGF-beta 1. Consistent with these in vitro findings, genistein, a tyrosine kinase inhibitor, led to markedly increased COL1A2 gene expression, whereas sodium orthovanadate, a tyrosine phosphatase inhibitor, decreased it substantially. These results were supported by transfection experiments showing that genistein and sodium orthovanadate have opposite effects on TbRE-mediated transcription. Moreover, nuclear proteins isolated from genistein-treated cells were found to interact with the TbRE significantly more than those from untreated cells. Furthermore, pretreatment of cells with sodium orthovanadate virtually abrogated nuclear protein binding to the TbRE, but not to a neighboring cis-acting element unresponsive to TGF-beta 1. The results of this study, therefore, provide the first correlation between tyrosine dephosphorylation, increased binding of a transcriptional complex, and TGF-beta 1 stimulation of gene expression.
Mol Cell Biol 1995 Dec
PMID:Tyrosine dephosphorylation of nuclear proteins mimics transforming growth factor beta 1 stimulation of alpha 2(I) collagen gene expression. 852 47

The B cell antigen receptor complex (BCR) is composed of a membrane-spanning immunoglobulin molecule (mIg) non-covalently associated with heterodimers of the transmembrane proteins Ig-alpha and Ig-beta. The cytoplasmic domains of Ig-alpha and Ig-beta do not contain kinase domains but are phosphorylated on tyrosine residues immediately upon receptor ligation. The mechanism and kinase responsible for initial Ig-alpha and Ig-beta phosphorylation following receptor ligation is unknown, In an attempt to better understand this process, Ig-alpha and Ig-beta phosphorylation was examined in response to treatment of permeabilized B cells with the pharmacologic agents, aluminum fluoride (AlFx) and sodium orthovanadate (Na3VO4). AlFx is known to stimulate GTP-binding proteins while Na3VO4 inhibits protein tyrosine phosphatases (PTPs), both of which are involved in the BCR signalling cascade. In these studies, AlFx and Na3VO4 stimulated rapid tyrosine phosphorylation of Ig-alpha, Ig-beta, and additional cellular proteins, including the protein tyrosine kinase (PTK) Lyn. The tyrosine phosphorylation does not appear to be mediated through GTP-binding proteins, since GTP gamma S did not stimulate tyrosine phosphorylation. As expected, however, PTPs modulate the phosphorylation state of these proteins since another PTP inhibitor, phenylarsine oxide (PAO), increased phosphorylation of Ig-alpha, Ig-beta and other proteins in this system. Interestingly, the extent and kinetics of the mIg-associated Lyn and Ig-alpha/Ig-beta phosphorylation was correlated, suggesting that Lyn may mediate receptor phosphorylation. Alternatively, Lyn, may be a downstream effector of phosphorylated Ig-alpha and Ig-beta as suggested by the reported ability of biphosphorylated Ig-alpha to activate Fyn PTK in vitro. Finally, all components necessary for Na3VO4, but not AlFx, stimulation of phosphorylation are membrane associated. The data are consistent with modulation of phosphorylation of Ig-alpha and Ig-beta through both PTP inhibition and AlFx treatment, and a common intermediary in or effector of these phosphorylation pathways appears to be the Lyn kinase.
Mol Immunol 1995 Nov
PMID:Manipulation of B cell antigen receptor tyrosine phosphorylation using aluminum fluoride and sodium orthovanadate. 855 52

Treatment of rat parotid acinar cells with sodium orthovanadate (an inhibitor of protein tyrosine phosphatase) caused a dose-dependent inhibition of phosphatase activity as measured by the hydrolysis of para nitrophenylphosphate (pNPP). Inclusion of 50 microM sodium orthovanadate in in vitro gland cultures prevented the amylase secretion from both untreated control and isoproterenol-stimulated parotid acinar cells. Four different tyrosine-phosphorylated proteins with M(r) 40, 70 and 95 kDa, respectively, were identified in secretory granule preparations from rat parotid glands by immunoblot using a monospecific antibody for phosphotyrosine. An increase in the phosphorylation levels of these phosphoproteins was noted in the presence of 50 microM sodium orthovanadate, suggesting that a protein tyrosine phosphatase (PTPase) is involved in parotid gland protein dephosphorylation reactions. Using antibody to Syp (a PTPase belonging to class 1D), a major fraction of subcellular activity was found to be associated with secretory granule membranes. These results suggest the possible involvement of a PTPase (Syp) in parotid gland secretory mechanisms.
Mol Cell Biochem 1995 Nov 08
PMID:Effect of vanadate on amylase secretion and protein tyrosine phosphatase activity in the rat parotid gland. 860 16

Although Rafs play a central role in signal transduction, the mechanism(s) by which they become activated is poorly understood. Raf-1 activation is dependent on the protein's ability to bind Ras, but Ras binding is insufficient to activate Raf-1 tyrosine phosphorylation to this Ras-induced activation, in the absence of an over-expressed tyrosine kinase. We demonstrate that Raf-1 purified form Sf9 cells coinfected with baculovirus Ras but not Src could be inactivated by protein tyrosine phosphatase PTP-1B. 14-3-3 and Hsp90 proteins blocked both the tyrosine dephosphorylation and inactivation of Raf-1, suggesting that Raf-1 activity is phosphotyrosine dependent. In Ras-transformed NIH 3T3 cells, a minority of Raf-1 protein was membrane associated, but essentially all Raf-1 activity and Raf-1 phosphotyrosine fractionated with plasma membranes. Thus, the tyrosine-phosphorylated and active pool of Raf-1 constitute a membrane-localized subfraction which could also be inactivated with PTP-1B. By contrast, B-Raf has aspartic acid residues at positions homologous to those of the phosphorylated tyrosines (at 340 and 341) of Raf-1 and displays a high basal level of activity. B-Raf was not detectably tyrosine phosphorylated, membrane localized, or further activated upon Ras transformation, even though B-Raf has been shown to bind to Ras in vitro. We conclude that tyrosine phosphorylation is an essential component of the mechanism by which Ras activates Raf-1 kinase activity and that steady-state activated Ras is insufficient to activate B-Raf in vivo.
Mol Cell Biol 1996 Mar
PMID:Ras-induced activation of Raf-1 is dependent on tyrosine phosphorylation. 862 47

PTP3, the third nonreceptor protein tyrosine phosphatase identified in Dictyostelium discoideum, has a single catalytic protein tyrosine phosphatase domain. Recombinant PTP3 exhibited phosphatase activity that was inhibited by vanadate. PTP3 is expressed at a moderate level during growth. The level of transcripts increased between growth and 8 h of development and declined thereafter. Expression of lacZ under the control of the PTP3 promoter indicated a spatial localization of PTP3 in the anterior-like and prestalk cell types. There are two copies of the PTP3 gene in this haploid organism. Disruption of one copy led to a slow-growth phenotype. We were unable to obtain a strain with disruptions in both PTP3 genes. Overexpression of wild-type PTP3 led to slower growth rates and the formation of large aggregation streams. These streams split into smaller aggregates, many of which then arrested in development. Overexpression of a catalytically inactive mutation (Cys to Ser) had no effect on growth rate; however, this strain also formed large aggregation streams that later split up into large and small mound structures and became fruiting bodies of various sizes. Antiphosphotyrosine Western blot (immunoblot) analysis of total cell proteins showed that the pattern of protein tyrosine phosphorylation was specifically altered in PTP3 mutants. Addition of growth medium to starving cells and a subsequent replacement with nonnutrient buffer led to reciprocal changes in the pattern of several phosphotyrosine proteins, including a protein of approximately 130 kDa. Analysis of strains overexpressing active or inactive PTP3 suggested that p130 is a potential substrate of PTP3. A transient posttranslational phosphorylation of PTP3 further supported the role of PTP3 in these processes. The data obtained strongly suggest new regulatory functions for PTP3 that are distinct from those described earlier for D. discoideum PTP1 and PTP2.
Mol Cell Biol 1996 May
PMID:Multiple roles of the novel protein tyrosine phosphatase PTP3 during Dictyostelium growth and development. 862 11

Within seconds after the flagella of mt+ and mt- Chlamydomonas gametes adhere during fertilization, their flagellar adenylyl cyclase is activated several fold and preparation for cell fusion is initiated. Our previous studies indicated that early events in this pathway, including control of adenylyl cyclase, are regulated by phosphorylation and dephosphorylation. Here, we describe a soluble, flagellar protein kinase activity that is regulated by flagellar adhesion. A 48-kDa, soluble flagellar protein was consistently phosphorylated in an in vitro assay in flagella isolated from nonadhering mt+ and mt- gametes, but not in flagella isolated from mt+ and mt- gametes that had been adhering for 1 min. Although the 48-kDa protein was present in the flagella isolated from adhering gametes, we demonstrate that its protein kinase was inactivated by flagellar adhesion. Immunoblot analysis and inhibitor studies indicate that the 48-kDa protein in nonadhering gametes is phosphorylated by a protein tyrosine kinase. In vivo experiments showing that the protein tyrosine phosphatase inhibitor sodium orthovanadate inhibits fertilization suggest that protein dephosphorylation may be required for signal transduction. The 48-kDa protein and its protein kinase may be among the first elements of a novel signalling pathway that couples interaction of flagellar adhesion molecules to gamete activation.
Mol Biol Cell 1996 Apr
PMID:Cell adhesion-dependent inactivation of a soluble protein kinase during fertilization in Chlamydomonas. 873 96

Gamma interferon (IFN-gamma) signals to the nucleus through the activation, by tyrosine phosphorylation, of the latent cytoplasmic transcription factor Stat1 (signal transducer and activator of transcription). It has been demonstrated that the activity of Stat1 is dependent on tyrosine phosphorylation which is regulated by Jak tyrosine kinases as well as by the as-yet-unidentified protein tyrosine phosphatase. We report that the N-terminal domain of Stat1, which is highly conserved among all STAT family members, is required for its tyrosine dephosphorylation. A single amino acid substitution (Arg-31 to Ala) in the Stat1 N-terminal domain inhibited Stat1 tyrosine dephosphorylation. The deletion of the Stat1 N-terminal domain resulted in a mutant Stat1 protein which was constitutively phosphorylated on Tyr-701. Upon IFN-gamma stimulation, the tyrosine phosphorylation of this mutant protein was further enhanced but was not down-regulated by protein tyrosine phosphatase in vivo. When expressed in NIH 3T3 cells, this mutant protein greatly enhanced the antiproliferative activity of IFN-gamma. We suggest that the N-terminal domains of STATs are crucial for modulating STAT activities through regulating the tyrosine dephosphorylation of STATs.
Mol Cell Biol 1996 Sep
PMID:Enhancement of antiproliferative activity of gamma interferon by the specific inhibition of tyrosine dephosphorylation of Stat1. 875 52

Incubation of Hela cells in the presence of insulin results in suppression of p53 expression. Treatment of cells with vanadate, an inhibitor of protein tyrosine phosphatase, likewise led to a dramatic reduction in the level of p53 transcript. On the other hand, significant induction of p53 message was demonstrated when Hela cells were exposed to genistein, a protein tyrosine kinase inhibitor. When cells were cultured in the presence of phosphotyrosine, there was a marked decrease in p53 expression. Neither phosphoserine nor phosphothreonine had an effect on p53 expression. Furthermore, simultaneous presence of both insulin and phosphotyrosine did not result in a greater suppression of the p53 message than when either of the agents was acting singly.
Biochem Mol Biol Int 1996 Mar
PMID:Regulation of p53 expression in HeLa cells. 882 21

Protein tyrosine phosphorylation is thought to play an important role in the regulation of neural function. We reported previously that CL100, a cytoplasmic type protein tyrosine phosphatase (PTP), was induced after transient forebrain ischemia. In the present study, changes in the mRNA levels after ischemia of PRL-1, a cytoplasmic type PTP and immediate-early gene similar to CL100, was examined. In situ hybridization histochemistry showed that PRL-1 mRNA was expressed in normal adult rats in neurons and oligodendrocytes in widespread regions including the cerebral cortex, hippocampus and cerebellum. PRL-1 mRNA was expressed in the developing brains on embryonic days 15 and 19 and postnatal day 1. Northern blot analysis showed that PRL-1 mRNA was induced from 6 h to 9 h after reperfusion in the cerebral cortex of postischemic rats. These findings suggest that PRL-1 plays a role in neurons and oliogodendrocytes, and that expression of PRL-1 mRNA is regulated by a mechanism different from those of other immediate-early genes such as c-fos and c-jun.
Brain Res Mol Brain Res 1996 Aug
PMID:PRL-1, a protein tyrosine phosphatase, is expressed in neurons and oligodendrocytes in the brain and induced in the cerebral cortex following transient forebrain ischemia. 884 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>