A protein-tyrosine phosphatase with sequence similarity to the SH2 domain of the protein-tyrosine kinases

Nature ◽  
1991 ◽  
Vol 352 (6337) ◽  
pp. 736-739 ◽  
Author(s):  
Shi-Hsiang Shen ◽  
Lison Bastien ◽  
Barry I. Posner ◽  
Pierre Chrétien
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Sequence Similarity ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Protein Tyrosine Kinases ◽  
Protein Tyrosine

scholarly journals Correction: A protein-tyrosine phosphatase with sequence similarity to the SH2 domain of the protein-tyrosine kinases

Nature ◽  
1991 ◽  
Vol 353 (6347) ◽  
pp. 868-868 ◽  
Author(s):  
Shi-Hsiang Shen ◽  
Lison Bastien ◽  
Barry I. Posner ◽  
Pierre Chrétien
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Sequence Similarity ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Protein Tyrosine Kinases ◽  
Protein Tyrosine

PTP-1B Is the Protein Tyrosine Phosphatase That Initiates Integrin αIIbβ3 Outside-In Signaling in Platelets.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 330-330
Author(s):  
Elena G. Arias-Salgado ◽  
Fawaz Haj ◽  
Christophe Dubois ◽  
Barbara C. Furie ◽  
Bruce Furie ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Intramolecular Interaction ◽  
Thrombus Formation ◽  
Tyrosine Phosphatase ◽  
Surface Expression ◽  
Sh2 Domain ◽  
Wild Type ◽  
Protein Tyrosine ◽  
Ptp 1B

Abstract Outside-in signaling is triggered by αIIbβ3 interaction with fibrinogen or von Willebrand factor and is required for effective platelet thrombus formation on damaged vascular surfaces. It requires ligand-induced αIIbβ3 clustering, which results in the activation of several Src family tyrosine kinases that are directly associated with αIIbβ3. However, the mechanism of Src activation by αIIbβ3 is incompletely understood. Here we demonstrate that the protein tyrosine phosphatase, PTP-1B, is required for integrin activation of c-Src and for outside-in signaling in platelets. In human or mouse platelets, c-Src was constitutively-associated with αIIbβ3 through an interaction that involved the β3 cytoplasmic domain and the c-Src SH3 domain. In resting platelets, the catalytic activity of this pool of c-Src was relatively low due to auto-inhibitory constraints imposed, in part, by an intramolecular interaction between the SH2 domain and the C-terminus of c-Src. This was promoted by phosphorylation of the C-terminal tyrosine of c-Src, tyrosine 529, by the Csk kinase. When platelets became adherent to fibrinogen or bound soluble fibrinogen in response to MnCl2, PTP-1B became associated with αIIbβ3 and c-Src, as determined by co-immunoprecipitation. At the same time, Csk dissociated from the integrin complex, c-Src tyrosine 529 became dephosphorylated, and c-Src became activated, as measured by phosphorylation of activation loop tyrosine 418. In marked contrast, gene-targeted mouse platelets deficient in PTP-1B (PTP-1B−/−) exhibited no dephosphorylation of c-Src tyrosine 529 and no activation of c-Src in response to fibrinogen binding. Furthermore, unlike wild-type platelets, PTP-1B−/− platelets exhibited little or no fibrinogen-dependent tyrosine phosphorylation of c-Src substrates, and they failed to undergo cytoskeletal reorganization or to spread on fibrinogen. These abnormalities of PTP-1B−/− platelets were due to defective outside-in signaling because surface expression of αIIbβ3 was normal, and fibrinogen bound normally in response to platelet stimulation with ADP or PAR-4 receptor agonists. When Fura-2-loaded platelets were infused and visualized by real time intravital microscopy during arterial thrombus development following laser injury to the cremaster microcirculation of a living mouse, PTP-1B−/− platelets exhibited significantly reduced intracellular free Ca2+ responses and formed smaller, less stable thrombi compared to wild-type platelets. Altogether, these studies establish that PTP-1B is a necessary, positive regulator of αIIbβ3-associated c-Src during the initiation phase of outside-in signaling in platelets. Consequently, disruption of specific interactions between αIIbβ3, c-Src and PTP-1B, or abnormalities in the activation of integrin-associated c-Src or PTP-1B, may cause defects in primary hemostasis. Moreover, these interactions provide potential targets for pharmacological blockade of outside-in signaling during arterial thrombosis.

scholarly journals Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1.

1996 ◽  
Vol 16 (12) ◽  
pp. 6985-6992 ◽  
Author(s):  
H Jiao ◽  
K Berrada ◽  
W Yang ◽  
M Tabrizi ◽  
L C Platanias ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Binding Activity ◽  
Sh2 Domain ◽  
Erythropoietin Receptor ◽  
Protein Tyrosine ◽  
Sh2 Domains

SHP-1 is an SH2-containing cytoplasmic tyrosine phosphatase that is widely distributed in cells of the hematopoietic system. SHP-1 plays an important role in the signal transduction of many cytokine receptors, including the receptor for erythropoietin, by associating via its SH2 domains to the receptors and dephosphorylating key substrates. Recent studies have suggested that SHP-1 regulates the function of Jak family tyrosine kinases, as shown by its constitutive association with the Tyk2 kinase and the hyperphosphorylation of Jak kinases in the motheaten cells that lack functional SHP-1. We have examined the interactions of SHP-1 with two tyrosine kinases activated during engagement of the erythropoietin receptor, the Janus family kinase Jak-2 and the c-fps/fes kinase. Immunoblotting studies with extracts from mouse hematopoietic cells demonstrated that Jak2, but not c-fes, was present in anti-SHP-1 immunoprecipitates, suggesting that SHP-1 selectively associates with Jak2 in vivo. Consistent with this, when SHP-1 was coexpressed with these kinases in Cos-7 cells, it associated with and dephosphorylated Jak2 but not c-fes. Transient cotransfection of truncated forms of SHP-1 with Jak2 demonstrated that the SHP-1-Jak2 interaction is direct and is mediated by a novel binding activity present in the N terminus of SHP-1, independently of SH2 domain-phosphotyrosine interaction. Such SHP-1-Jak2 interaction resulted in induction of the enzymatic activity of the phosphatase in in vitro protein tyrosine phosphatase assays. Interestingly, association of the SH2n domain of SHP-1 with the tyrosine phosphorylated erythropoietin receptor modestly potentiated but was not essential for SHP-1-mediated dephosphorylation of Jak2 and had no effect on c-fes phosphorylation. These data indicate that the main mechanism for regulation of Jak2 phosphorylation by SHP-1 involves a direct, SH2-independent interaction with Jak2 and suggest the existence of similar mechanisms for other members of the Jak family of kinases. They also suggest that such interactions may provide one of the mechanisms that control SHP-1 substrate specificity.

Protein tyrosine phosphatase-α complexes with the IGF-I receptor and undergoes IGF-I-stimulated tyrosine phosphorylation that mediates cell migration

2009 ◽  
Vol 297 (1) ◽  
pp. C133-C139 ◽  
Author(s):  
Shirley C. Chen ◽  
Ranvikram S. Khanna ◽  
Darrell C. Bessette ◽  
Lionel A. Samayawardhena ◽  
Catherine J. Pallen
Keyword(s):  
Cell Migration ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Phosphorylation Site ◽  
Protein Tyrosine ◽  
Fibroblast Migration ◽  
Igf I ◽  
In Cells

Protein tyrosine phosphatase-α (PTPα) is a widely expressed receptor-type phosphatase that functions in multiple signaling systems. The actions of PTPα can be regulated by its phosphorylation on serine and tyrosine residues, although little is known about the conditions that promote PTPα phosphorylation. In this study, we tested the ability of several extracellular factors to stimulate PTPα tyrosine phosphorylation. The growth factors IGF-I and acidic FGF induced the highest increase in PTPα phosphorylation at tyrosine 789, followed by PMA and lysophosphatidic acid, while EGF had little effect. Further investigation of IGF-I-induced PTPα tyrosine phosphorylation demonstrated that this occurs through a novel Src family kinase-independent mechanism that does not require focal adhesion kinase, phosphatidylinositol 3-kinase, or MEK. We also show that PTPα physically interacts with the IGF-I receptor. In contrast to IGF-I-induced PTPα phosphorylation, this association does not require IGF-I. The interaction of PTPα and the IGF-I receptor is independent of PTPα catalytic activity, and expression of exogenous PTPα does not promote IGF-I receptor tyrosine dephosphorylation, indicating that PTPα does not act as an IGF-I receptor phosphatase. However, PTPα mediates IGF-I signaling, because IGF-I-stimulated fibroblast migration was reduced by ∼50% in cells lacking PTPα or in cells with mutant PTPα lacking the tyrosine 789 phosphorylation site. Our results suggest that PTPα tyrosine phosphorylation can occur in response to diverse stimuli and can be mediated by various tyrosine kinases. In the case of IGF-I, we propose that IGF-I-induced tyrosine 789 phosphorylation of PTPα, possibly catalyzed by the PTPα-associated IGF-I receptor tyrosine kinase, is required for efficient cell migration in response to this growth factor.

Molecular cloning of a novel protein-tyrosine phosphatase SH-PTP3 with sequence similarity to the src -homology region 2

FEBS Letters ◽  
1992 ◽  
Vol 314 (3) ◽  
pp. 335-339 ◽  
Author(s):  
Masaaki Adachi ◽  
Masuo Sekiya ◽  
Toshiki Miyachi ◽  
Keiki Matsuno ◽  
Yuji Hinoda ◽  
...  
Keyword(s):  
Molecular Cloning ◽  
Protein Tyrosine Phosphatase ◽  
Sequence Similarity ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Homology Region ◽  
Src Homology ◽  
Novel Protein

scholarly journals Regulation of Microtubule Nucleation in Mouse Bone Marrow-Derived Mast Cells by Protein Tyrosine Phosphatase SHP-1

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 345 ◽  
Author(s):  
Klebanovych ◽  
Sládková ◽  
Sulimenko ◽  
Vosecká ◽  
Čapek ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cells ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Negative Regulator ◽  
Mast Cell Activation ◽  
Mouse Bone Marrow ◽  
Microtubule Nucleation ◽  
Protein Tyrosine

The antigen-mediated activation of mast cells initiates signaling events leading to their degranulation, to the release of inflammatory mediators, and to the synthesis of cytokines and chemokines. Although rapid and transient microtubule reorganization during activation has been described, the molecular mechanisms that control their rearrangement are largely unknown. Microtubule nucleation is mediated by γ-tubulin complexes. In this study, we report on the regulation of microtubule nucleation in bone marrow-derived mast cells (BMMCs) by Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1; Ptpn6). Reciprocal immunoprecipitation experiments and pull-down assays revealed that SHP-1 is present in complexes containing γ-tubulin complex proteins and protein tyrosine kinase Syk. Microtubule regrowth experiments in cells with deleted SHP-1 showed a stimulation of microtubule nucleation, and phenotypic rescue experiments confirmed that SHP-1 represents a negative regulator of microtubule nucleation in BMMCs. Moreover, the inhibition of the SHP-1 activity by inhibitors TPI-1 and NSC87877 also augmented microtubule nucleation. The regulation was due to changes in γ-tubulin accumulation. Further experiments with antigen-activated cells showed that the deletion of SHP-1 stimulated the generation of microtubule protrusions, the activity of Syk kinase, and degranulation. Our data suggest a novel mechanism for the suppression of microtubule formation in the later stages of mast cell activation.

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.

mSiglec-E, a novel mouse CD33-related siglec (sialic acid-binding immunoglobulin-like lectin) that recruits Src homology 2 (SH2)-domain-containing protein tyrosine phosphatases SHP-1 and SHP-2

2001 ◽  
Vol 353 (3) ◽  
pp. 483-492 ◽  
Author(s):  
Zhenbao YU ◽  
Meryem MAOUI ◽  
Liangtang WU ◽  
Denis BANVILLE ◽  
Shi-Hsiang SHEN
Keyword(s):  
Sialic Acid ◽  
Sequence Similarity ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Sh2 Domain ◽  
Immunoglobulin Superfamily ◽  
Protein Tyrosine ◽  
Src Homology 2 ◽  
Sialic Acid Binding ◽  
Src Homology

The sialic acid-binding immunoglobulin-like lectins (siglecs) represent a recently defined distinct subset of the immunoglobulin superfamily. By using the Src homology 2 (SH2)-domain-containing protein tyrosine phosphatase SHP-1 as bait in a yeast two-hybrid screen, we have identified a new member of the mouse siglec family, mSiglec-E. The mSiglec-E cDNA encodes a protein of 467 amino acids that contains three extracellular immunoglobulin-like domains, a transmembrane region and a cytoplasmic tail bearing two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). mSiglec-E is highly expressed in mouse spleen, a tissue rich in leucocytes. The ITIMs of mSiglec-E can recruit SHP-1 and SHP-2, two inhibitory regulators of immunoreceptor signal transduction. This suggests that the function of mSiglec-E is probably an involvement in haematopoietic cells and the immune system as an inhibitory receptor. When expressed in COS-7 cells, mSiglec-E was able to mediate sialic acid-dependent binding to human red blood cells, suggesting that mSiglec-E may function through cell–cell interactions. In comparison with the known members of the siglec family, mSiglec-E exhibits a high degree of sequence similarity to both human siglec-7 and siglec-9. The gene encoding mSiglec-E is localized in the same chromosome as that encoding mouse CD33. Phylogenetic analysis reveals that neither mouse mSiglec-E nor CD33 shows a clear relationship with any human siglecs so far identified.

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