scholarly journals Normal TCR Signal Transduction in Mice That Lack Catalytically Active PTPN3 Protein Tyrosine Phosphatase

2007 ◽  
Vol 178 (6) ◽  
pp. 3680-3687 ◽  
Author(s):  
Timothy J. Bauler ◽  
Elizabeth D. Hughes ◽  
Yutaka Arimura ◽  
Tomas Mustelin ◽  
Thomas L. Saunders ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Tcr Signal Transduction ◽  
Catalytically Active

scholarly journals Disruption of Lymphocyte Function and Signaling in CD45–associated Protein–null Mice

1998 ◽  
Vol 187 (11) ◽  
pp. 1863-1870 ◽  
Author(s):  
Akio Matsuda ◽  
Satoshi Motoya ◽  
Shioko Kimura ◽  
Renee McInnis ◽  
Abby L. Maizel ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Antigen Receptor ◽  
Lymphocyte Function ◽  
Receptor Signaling ◽  
Protein Tyrosine ◽  
Antigen Receptor Signaling

CD45-AP specifically associates with CD45, a protein tyrosine phosphatase essential for lymphocyte differentiation and antigen receptor–mediated signal transduction. CD45 is thought to mediate antigen receptor signaling by dephosphorylating regulatory tyrosine residues on Src family protein tyrosine kinases such as Lck. However, the mechanism for regulating CD45 protein tyrosine phosphatase activity remains unclear. CD45-AP–null mice were created to examine the role of CD45-AP in CD45-mediated signal transduction. T and B lymphocytes showed reduced proliferation in response to antigen receptor stimulation. Both mixed leukocyte reaction and cytotoxic T lymphocyte functions of T cells were also markedly decreased in CD45-AP–null mice. Interestingly, the interaction between CD45 and Lck was significantly reduced in CD45-AP–null T cells, indicating that CD45-AP directly or indirectly mediates the interaction of CD45 with Lck. Our data indicate that CD45-AP is required for normal antigen receptor signaling and function in lymphocytes.

scholarly journals Protein-tyrosine Phosphatase Shp-1 Is a Negative Regulator of IL-4- and IL-13-dependent Signal Transduction

1998 ◽  
Vol 273 (51) ◽  
pp. 33893-33896 ◽  
Author(s):  
S. Jaharul Haque ◽  
Phyllis Harbor ◽  
Mina Tabrizi ◽  
Taolin Yi ◽  
Bryan R. G. Williams
Keyword(s):  
Signal Transduction ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
Protein Tyrosine ◽  
Dependent Signal

Protein Tyrosine Phosphatase Receptor Type O (PTPRO) Exhibits Tumor Suppressor Properties in K562 Cells by Dephosphorylating Bcr-Abl.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2914-2914
Author(s):  
Sarmila Majumder ◽  
Tasneem Motiwala ◽  
Kalpana Ghoshal ◽  
Huban Kutay ◽  
Jharna Datta ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Protein Tyrosine Phosphatase ◽  
Cpg Island ◽  
Tyrosine Phosphatase ◽  
Ectopic Expression ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
Receptor Type ◽  
Protein Tyrosine ◽  
Catalytically Active

Abstract Regulation of protein phosphorylation by concerted action of protein kinases and phosphatases is important for normal physiological processes. Altered function or expression of one or more components of these regulatory molecules leads to many pathological conditions including cancer. We have previously shown that the truncated form of the receptor-type protein tyrosine phosphatase PTPROt predominantly expressed in haematopoietic cells is suppressed in Chronic Lymphocytic Leukemia (B-CLL). A direct correlation of CpG island methylation and reduced expression of the gene was observed in primary CLL samples and in several leukemia cell lines. To assess the functional significance of loss of PTPROt function in leukemia, we selected K562 cells as a model system, as PTPROt expression is silenced in these cells and is reactivated upon treatment with DNA hypomethylating agents. Ectopic expression of the catalytically active PTPROt inhibited growth of K562 cells and their clonogenic survival in soft agar (a characteristic of cancer cells). Further, cells expressing PTPROt exhibited delayed entry into S-phase from G0/G1 phase. Induction of apoptosis increased significantly in K562 cells expressing functional phosphatase upon serum withdrawal or exposure to the apoptogenic agent camptothecin. Tumorigenic potential of K562 cells in athymic nude mice was also significantly reduced upon ectopic expression of PTPROt. Finally, we demonstrate that the Bcr-Abl fusion protein, product of abnormal chromosomal translocation [t(9;22)] in chronic myelogenous leukemia, is a substrate of PTPROt. Tyrosine phosphorylation of this potent kinase was markedly reduced in K562 cells expressing the catalytically active PTPROt. Enhanced dephosphorylation of Bcr-Abl by PTPROt both in vivo and in vitro explains the observed phenotypes of the PTPROt expressing K562 cells. These data taken together delineate the molecular mechanism of tumor suppressor function of PTPROt in leukemic cells characterized by Philadelphia chromosome. (This work was supported by a grant CA101956 from the National Institutes of Health).

scholarly journals CD148 Is a Membrane Protein Tyrosine Phosphatase Present in All Hematopoietic Lineages and Is Involved in Signal Transduction on Lymphocytes

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2800-2809 ◽  
Author(s):  
Miguel Angel de la Fuente-Garcı́a ◽  
Josep Maria Nicolás ◽  
John H. Freed ◽  
Eduard Palou ◽  
Andrew P. Thomas ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Protein Tyrosine Phosphatase ◽  
International Workshop ◽  
Tyrosine Phosphatase ◽  
Peripheral Blood Lymphocytes ◽  
Protein Tyrosine ◽  
N Terminus ◽  
The One ◽  
Lymphoid Cell Lines ◽  
Monocytes And Lymphocytes

Evidence is presented showing that a protein tyrosine phosphatase different from CD45 is present on the membrane of human hematopoietic cells. The molecule recognized by the monoclonal antibody 143-41, which has been classified as CD148 in the VI International Workshop on Leukocyte Differentiation Antigens, was immunopurified and sequenced. The sequence obtained from N-terminus as well as from two different CNBr-digested peptides showed a close identity with a previously described tyrosine phosphatase named HPTP-η/DEP-1. CD148 is present on all hematopoietic lineages, being expressed with higher intensity on granulocytes than on monocytes and lymphocytes. Interestingly, whereas it is clearly present on peripheral blood lymphocytes, it is poorly expressed on different lymphoid cell lines of T and B origin. When this protein tyrosine phosphatase was cocrosslinked with CD3, an inhibition of the normally observed calcium mobilization was observed. This inhibition correlates with a decrease in phospholipase C-γ (PLC-γ) phosphorylation and is similar to the one observed with CD45. In addition, it is shown that the crosslinking of the CD148 alone is also able to induce an increase in [Ca2+]i. This increase is abolished in the presence of genistein and by cocrosslinking with CD45. These data, together with the induction of tyrosine phosphorylation on several substrates, including PLC-γ, after CD148 crosslinking, suggest the involvement of a tyrosine kinase-based signaling pathway in this process. In conclusion, the data presented show that CD148 corresponds to a previously described protein tyrosine phosphatase HPTP-η/DEP-1 and that this molecule is involved in signal transduction in lymphocytes.

Prostaglandin E1 inhibits IL-6-induced MCP-1 expression by interfering specifically in IL-6-dependent ERK1/2, but not STAT3, activation

2008 ◽  
Vol 412 (1) ◽  
pp. 65-72 ◽  
Author(s):  
Radoslaw M. Sobota ◽  
Pia J. Müller ◽  
Peter C. Heinrich ◽  
Fred Schaper
Keyword(s):  
Signal Transduction ◽  
Cross Talk ◽  
Protein Tyrosine Phosphatase ◽  
Prostaglandin E1 ◽  
Acute Phase Proteins ◽  
Tyrosine Phosphatase ◽  
Mitogen Activated Protein Kinase ◽  
Cell Protein ◽  
Potent Inducer ◽  
Protein Tyrosine

IL (interleukin)-6 exerts pro- as well as anti-inflammatory activities. Beside many other activities, IL-6 is the major inducer of acute phase proteins in the liver, acts as a differentiation factor for blood cells, as migration factor for T-cells and is a potent inducer of the chemokine MCP-1 (monocyte chemoattractant protein-1). Recent studies have focused on the negative regulation of IL-6 signal transduction through the IL-6-induced feedback inhibitors SOCS (suppressor of cytokine signalling) 1 and SOCS3 or the protein tyrosine phosphatases SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) and TcPTP (T-cell protein tyrosine phosphatase). Studies on the cross-talk between pro-inflammatory mediators (IL-1, tumour necrosis factor, lipopolysaccharide) and IL-6 elucidated further regulatory mechanisms. Less is known about the regulation of IL-6 signal transduction by hormone/cytokine signalling through G-protein-coupled receptors. This is particularly surprising since many of these hormones (such as prostaglandins and chemokines) play an important role in inflammatory processes. In the present study, we have investigated the inhibitory activity of PGE1 (prostaglandin E1) on IL-6-induced MCP-1 expression and have elucidated the underlying molecular mechanism. Surprisingly, PGE1 does not affect IL-6-induced STAT (signal transducer and activator of transcription) 3 activation, but does affect ERK (extracellular-signal-regulated kinase) 1/2 activation which is crucial for IL-6-dependent expression of MCP-1. In summary, we have discovered a specific cross-talk between the adenylate cyclase cascade and the IL-6-induced MAPK (mitogen-activated protein kinase) cascade and have investigated its impact on IL-6-dependent gene expression.

scholarly journals Functions of the Ectodomain and Cytoplasmic Tyrosine Phosphatase Domains of Receptor Protein Tyrosine Phosphatase Dlar In Vivo

2003 ◽  
Vol 23 (19) ◽  
pp. 6909-6921 ◽  
Author(s):  
Neil X. Krueger ◽  
R. Sreekantha Reddy ◽  
Karl Johnson ◽  
Jack Bateman ◽  
Nancy Kaufmann ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
P Element ◽  
Receptor Protein ◽  
Loss Of Function ◽  
Protein Tyrosine ◽  
Receptor Protein Tyrosine Phosphatase ◽  
Catalytically Active

ABSTRACT The receptor protein tyrosine phosphatase (PTPase) Dlar has an ectodomain consisting of three immunoglobulin (Ig)-like domains and nine fibronectin type III (FnIII) repeats and a cytoplasmic domain consisting of two PTPase domains, membrane-proximal PTP-D1 and C-terminal PTP-D2. A series of mutant Dlar transgenes were introduced into the Drosophila genome via P-element transformation and were then assayed for their capacity to rescue phenotypes caused by homozygous loss-of-function genotypes. The Ig-like domains, but not the FnIII domains, are essential for survival. Conversely, the FnIII domains, but not the Ig-like domains, are required during oogenesis, suggesting that different domains of the Dlar ectodomain are involved in distinct functions during Drosophila development. All detectable PTPase activity maps to PTP-D1 in vitro. The catalytically inactive mutants of Dlar were able to rescue Dlar −/− lethality nearly as efficiently as wild-type Dlar transgenes, while this ability was impaired in the PTP-D2 deletion mutants DlarΔPTP-D2 and Dlarbypass . Dlar-C1929S, in which PTP-D2 has been inactivated, increases the frequency of bypass phenotype observed in Dlar −/− genotypes, but only if PTP-D1 is catalytically active in the transgene. These results indicate multiple roles for PTP-D2, perhaps by acting as a docking domain for downstream elements and as a regulator of PTP-D1.

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