An osteoclastic protein-tyrosine phosphatase regulates the β3-integrin, syk, and shp1 signaling through respective src-dependent phosphorylation in osteoclasts

2012 ◽  
Vol 302 (11) ◽  
pp. C1676-C1686 ◽  
Author(s):  
K.-H. William Lau ◽  
Virginia Stiffel ◽  
Mehran Amoui
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Protein Tyrosine Kinase ◽  
Glutathione Transferase ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
Raw264.7 Cells ◽  
Major Protein ◽  
Protein Tyrosine ◽  
Sirna Treatment ◽  
Β3 Integrin

This study utilized the glutathione transferase (GST) pull-down assay to identify novel substrates of an osteoclastic protein-tyrosine phosphatase, PTP-oc. Consistent with the previous findings that the phosphorylated tyr-527 (pY527) of Src is a substrate of PTP-oc, the major protein pulled down with the phosphatase-deficient (PD)-PTP-oc-GST trapping mutant in RAW264.7 cells was Src. The GST-PD-PTP-oc also pulled down pY-Syk and pY-β3-integrin, but not after PP2 pretreatment. However, PTP-oc transgenic osteoclasts or PTP-oc-overexpressing RAW264.7 cells had elevated, and not reduced, levels of pY525/526-Syk and pY759-β3 integrin, and the PTP-oc siRNA treatment drastically reduced levels of pY525/526 Syk and pY759-β3-integrin in RAW264.7 cells. These findings are incompatible with the premise that they are substrates of PTP-oc. The PTP-oc-dependent increases in pY525/526-Syk and pY759-β3-integrin levels were completely blocked by PP2, indicating that these effects are secondary to PTP-oc-mediated activation of the Src protein-tyrosine kinase (PTK). Overexpression of PTP-oc increased, and siRNA-mediated suppression of PTP-oc reduced, pY160-Vav1, pY173-Vav3, and pY783-PLCγ levels, and Rac1 activation, which are downstream mediators of the ITAM/Syk signaling. Overexpression of PTP-oc also increased, and PTP-oc siRNA treatment decreased, the pY-Shp1 levels, which were blocked by PP2. Since Shp1 is a negative regulator of osteoclast activity and is a key mediator of the ITIM signaling, these findings suggest that PTP-oc is an upstream suppressor of the ITIM/Shp1 signaling through PTP-oc-induced Src-dependent Shp1 phosphorylation. In summary, PTP-oc plays a central regulatory role in the concerted regulation of the β3-integrin, the ITAM/Syk, and the ITIM/Shp1 signaling indirectly through activation of Src PTK.

scholarly journals Protein tyrosine phosphatase receptor type C (PTPRC or CD45)

2021 ◽  
pp. jclinpath-2020-206927
Author(s):  
Maryam Ahmed Al Barashdi ◽  
Ahlam Ali ◽  
Mary Frances McMullin ◽  
Ken Mills
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Protein Tyrosine Kinase ◽  
Biological Activities ◽  
Tyrosine Phosphatase ◽  
Cell Types ◽  
Receptor Type ◽  
Future Research ◽  
Protein Tyrosine ◽  
Type C ◽  
Almost All

The leucocyte common antigen, protein tyrosine phosphatase receptor type C (PTPRC), also known as CD45, is a transmembrane glycoprotein, expressed on almost all haematopoietic cells except for mature erythrocytes, and is an essential regulator of T and B cell antigen receptor-mediated activation. Disruption of the equilibrium between protein tyrosine kinase and phosphatase activity (from CD45 and others) can result in immunodeficiency, autoimmunity, or malignancy. CD45 is normally present on the cell surface, therefore it works upstream of a large signalling network which differs between cell types, and thus the effects of CD45 on these cells are also different. However, it is becoming clear that CD45 plays an essential role in the innate immune system and this is likely to be a key area for future research. In this review of PTPRC (CD45), its structure and biological activities as well as abnormal expression of CD45 in leukaemia and lymphoma will be discussed.

scholarly journals Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR−/− mouse model of atherosclerosis

2017 ◽  
Vol 131 (20) ◽  
pp. 2489-2501 ◽  
Author(s):  
Dawn Thompson ◽  
Nicola Morrice ◽  
Louise Grant ◽  
 Samantha Le Sommer ◽  
Emma K. Lees ◽  
...  
Keyword(s):  
Mouse Model ◽  
Atherosclerotic Plaque ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Plaque Formation ◽  
Negative Regulator ◽  
Protein Tyrosine Phosphatase 1B ◽  
Cvd Risk ◽  
Protein Tyrosine ◽  
Atherosclerotic Plaque Formation

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with type 1 or type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here, we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in an LDLR−/− mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR−/− mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied by a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction in CVD risk.

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.

Effects of protein tyrosine kinase and protein tyrosine phosphatase on apical K+ channels in the TAL

2001 ◽  
Vol 281 (4) ◽  
pp. C1188-C1195 ◽  
Author(s):  
Rui-Min Gu ◽  
Yuan Wei ◽  
John R. Falck ◽  
U. Murali Krishna ◽  
Wen-Hui Wang
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Phosphatase ◽  
Protein Tyrosine Kinase ◽  
Tyrosine Phosphatase ◽  
K Channel ◽  
Thick Ascending Limb ◽  
Patch Clamp Technique ◽  
K Channels ◽  
Protein Tyrosine ◽  
Herbimycin A

We have previously demonstrated that the protein level of c-Src, a nonreceptor type of protein tyrosine kinase (PTK), was higher in the renal medulla from rats on a K-deficient (KD) diet than that in rats on a high-K (HK) diet (Wang WH, Lerea KM, Chan M, and Giebisch G. Am J Physiol Renal Physiol 278: F165–F171, 2000). We have now used the patch-clamp technique to investigate the role of PTK in regulating the apical K channels in the medullary thick ascending limb (mTAL) of the rat kidney. Inhibition of PTK with herbimycin A increased NP o, a product of channel number ( N) and open probability ( P o), of the 70-pS K channel from 0.12 to 0.42 in the mTAL only from rats on a KD diet but had no significant effect in tubules from animals on a HK diet. In contrast, herbimycin A did not affect the activity of the 30-pS K channel in the mTAL from rats on a KD diet. Moreover, addition of N-methylsulfonyl-12,12-dibromododec-11-enamide, an agent that inhibits the cytochrome P-450-dependent production of 20-hydroxyeicosatetraenoic acid, further increased NP o of the 70-pS K channel in the presence of herbimycin A. Furthermore, Western blot detected the presence of PTP-1D, a membrane-associated protein tyrosine phosphatase (PTP), in the renal outer medulla. Inhibition of PTP with phenylarsine oxide (PAO) decreased NP o of the 70-pS K channel in the mTAL from rats on a HK diet. However, PAO did not inhibit the activity of the 30-pS K channel in the mTAL. The effect of PAO on the 70-pS K channel was due to indirectly stimulating PTK because pretreatment of the mTAL with herbimycin A abolished the inhibitory effect of PAO. Finally, addition of exogenous c-Src reversibly blocked the activity of the 70-pS K channel in inside-out patches. We conclude that PTK and PTP have no effect on the low-conductance K channels in the mTAL and that PTK-induced tyrosine phosphorylation inhibits, whereas PTP-induced tyrosine dephosphorylation stimulates, the apical 70-pS K channel in the mTAL.

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

Deletion of the Protein Tyrosine Phosphatase Gene PTPN2 in T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 141-141
Author(s):  
Maria Kleppe ◽  
Idoya Lahortiga ◽  
Tiama El Chaar ◽  
Kim De Keersmaecker ◽  
Nicole Mentens ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Protein Tyrosine Phosphatase ◽  
Lymphoblastic Leukemia ◽  
Tyrosine Phosphatase ◽  
Janus Kinase ◽  
Negative Regulator ◽  
Aberrant Expression ◽  
Protein Tyrosine ◽  
Knock Down

Abstract Abstract 141 Introduction: T-cell lymphoblastic leukemia (T-ALL) arises from clonal expansion of a lymphoid progenitor that has undergone stepwise alteration at distinct stages of differentiation. It is suggested that a set of cooperative mutations that affect different pathways are required before thymocytes become fully malignant. Despite major improvements in our understanding of the molecular genetics of T-ALL, the underlying mechanisms that lead to the abnormal proliferation and enhanced survival of the leukemic cells remain largely unknown. Results: Array CGH analysis revealed an acquired homozygous microdeletion at chromosome 18p11 in 6 % of T-ALL cases. The deleted region was only 125 kb in size and restricted to the PTPN2 (protein tyrosine phosphatase, non-receptor type 2) locus. PTPN2 encodes an intracellular non-transmembrane tyrosine-specific phosphatase that functions as a negative regulator of a variety of signaling proteins including several members of the janus kinase (JAK) and of signal transducer and activator of transcription (STAT) families, growth factor receptors and SRC family kinases. Homozygous deletion of PTPN2 was specifically found in cases with aberrant expression of the TLX1 transcription factor, with two cases also harboring the NUP214-ABL1 fusion. Analysis of additional TLX1 positive cases by quantitative PCR identified loss of one copy of PTPN2 in 5 out of 20 cases. No mutations were detected in the coding region of PTPN2. To determine the effect of loss of PTPN2 in T-cells, we downregulated the expression of PTPN2 using RNAi technology. siRNA mediated knock-down of PTPN2 affected activation of JAK1 associated cytokine receptors implicated in T-cell development. Ligand stimulation of IL7 and interferon gamma receptor resulted in an augmented and prolonged phosphorylation of JAK1 as well as downstream targets STAT1 and STAT5 in T-ALL cell lines with knock-down of PTPN2. In addition, knock- down of Ptpn2 sensitized the pro B-cell line Ba/F3 to transformation by wild type JAK1 confirming a clear relationship between loss of PTPN2 and JAK1 activation. Knock-down of PTPN2 expression also provided a proliferative advantage and reduced sensitivity to kinase inhibitors in lymphoblastic leukemia cell lines HSB-2 and ALL-SIL. Conclusion: In conclusion, our data provide genetic and functional evidence for a tumor suppressor role of PTPN2 in T-ALL and warrant testing of JAK inhibitors for the treatment of this specific subset of T-ALLs as well as further analysis of a potential negative impact of loss of PTPN2 on responsiveness to anti-cancer treatments. Disclosures: Ferrando: Merck, Pfizer: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document