scholarly journals SH2 Domain-Containing Phosphatase-2 Protein-Tyrosine Phosphatase Promotes FcεRI-Induced Activation of Fyn and Erk Pathways Leading to TNFα Release from Bone Marrow-Derived Mast Cells

2009 ◽  
Vol 183 (8) ◽  
pp. 4940-4947 ◽  
Author(s):  
Victor A. McPherson ◽  
Namit Sharma ◽  
Stephanie Everingham ◽  
Julie Smith ◽  
Helen H. Zhu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cells ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Protein Tyrosine

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.

Constitutive Activation of SHP2 Protein Tyrosine Phosphatase Cooperates with HoxA10 Overexpression for Progression to Acute Myeloid Leukemia in a Murine Model

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 752-752
Author(s):  
Hao Wang ◽  
Stephan Lindsey ◽  
Iwona Konieczna ◽  
Elizabeth Horvath ◽  
Ling Bei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Protein Tyrosine Phosphatase ◽  
Myeloid Leukemia ◽  
Tyrosine Phosphatase ◽  
Post Translational Modification ◽  
Protein Tyrosine ◽  
Acute Myeloid ◽  
Myeloid Progenitors

Abstract HOX genes encode highly conserved homeodomain (HD) transcription factors and are arranged in four groups (A–D). During definitive hematopoiesis, HOX gene expression is activated 3′ to 5′ through each group. Therefore, HOX1-4 are actively transcribed in hematopoietic stem cells and HOX7-11 in committed progenitors. Under normal conditions, HoxA7-11 expression decreases during CD34+ to CD34− maturation. Abnormal Hox expression is characteristic of several poor prognosis subtypes of Acute Myeloid Leukemia (AML) including AML with translocations or duplications of the MLL gene. In such leukemias, expression of HoxB3, B4 and A7-11 is sustained in CD34−CD38+ cells. In murine bone marrow transplantation experiments, expression of MLL fusion proteins, HoxA9 or HoxA10 induces a myeloproliferative disorder (MPD) characterized by increased neutrophils (PMN). Over time, the mice progress to AML with circulating myeloid blasts. These results suggest overexpression of HoxA9 or HoxA10 is adequate for MPD, but differentiation block (AML) requires additional lesions. We found that HoxA9 and HoxA10 proteins not only decrease in expression during the CD34+ to CD34− transition, but also are tyrosine phosphorylated. In additional studies, we found that HoxA10 tyrosine phosphorylation state is relevant for differentiation stage-specific target gene expression during myelopoiesis. HoxA10 represses genes encoding phagocyte effector proteins in undifferentiated myeloid cells. During myelopoiesis, phosphorylation of conserved HD-HoxA10 tyrosines decreases binding to these genes, permitting phenotypic and functional differentiation. HoxA10 activates transcription of the gene encoding Mkp2 (Dusp4) in myeloid progenitors. Decrease in HoxA10-binding to this gene as differentiation proceeds decreases transcription and renders the cells susceptible to Jnk induced apoptosis. Therefore, we hypothesized that genetic lesions which influence post translational modification might cooperate with HoxA10 overexpression to lead from MPD to AML. In myeloid progenitors, HoxA10 is maintained in a non-phosphorylated state by SHP2 protein tyrosine phosphatase. SHP2 activity decreases as differentiation proceeds. Activating mutations in SHP2 have been described in AML. We found that such activated SHP2 mutants dephosphorylate HoxA10 through out ex vivo myelopoiesis. Therefore, we investigated cooperation between these two leukemia associated abnormalities in vivo. Mice were transplanted with bone marrow overexpressing HoxA10 (or empty vector control) with or without activated SHP2 (E76K). To control for SHP2 overexpression, other mice were transplanted with bone marrow overexpressing HoxA10 and wild type SHP2. Mice transplanted with bone marrow overexpressing HoxA10 (±SHP2) developed MPD which evolved to AML over 4 mos, consistent with previous observations. However, mice transplanted with bone marrow overexpressing HoxA10 and E76K SHP2 developed AML within 4 wks. This rapid development of AML correlated with abnormalities in expression of myeloid specific HoxA10 target genes. These studies indicate the importance of HoxA10 post translational modification for physiologically relevant function and identify cooperating lesions which may be significant for disease progression in human AML.

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

Aberrant Epigenetic Suppression of the Ptprot Gene Encoding a Protein Tyrosine Phosphatase Targeting KIT in Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1322-1322
Author(s):  
Tasneem Motiwala ◽  
Satavisha Roy ◽  
Shujun Liu ◽  
Sebastian Schwind ◽  
Rainer Claus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Catalytic Site ◽  
Protein Tyrosine ◽  
Hypomethylating Agent ◽  
Epigenetic Suppression ◽  
Oncogenic Function

Abstract Abstract 1322 Recent studies have suggested that deregulated expression of tyrosine phosphatases and the resulting alteration in the phosphorylation status of their substrates play a significant role in the oncogenic function of tyrosine-phosphorylated proteins. Over the past decade we have been studying the tumor suppressive function of protein tyrosine phosphatase receptor-type O (PTPRO). The gene for PTPRO encodes two functional isoforms, full-length form (PTPRO-FL) and a truncated form (PTPROt) that are expressed in a tissue-specific manner. PTPROt is primarily expressed in hematopoietic cells. It is, however, transcriptionally and epigenetically suppressed in CLL-like cell lines and primary CLL [Clin Cancer Res. 2007 Jun 1;13(11):3174–81, Blood. 2011 Dec 1;118(23):6132–40]. We have now shown that PTPROt is also hypermethylated in a discovery set of primary AML samples (n=77) provided by the University hospital Ulm biobank relative to bone marrow from normal controls. Analysis of the AML cell lines Kasumi-1 and ME-1 cells also showed dramatically reduced PTPROt expression relative to THP-1 and MV4-11 cells. Treatment of Kasumi-1 cells with the hypomethylating agent decitabine led to re-activation of PTPROt at both RNA and protein levels. PTPRO CpG island (CGI), methylated in Kasumi-1 cells, became hypomethylated following treatment with decitabine. Similarly, bone marrow samples from elderly AML patients who received decitabine 20 mg/m2/day – 10 days on the OSU 07017 study exhibited hypomethylation and upregulation of PTPROt. To further evaluate the functional significance of hypermethylation and silencing of PTPROt in AML, we then searched for potential kinase substrates of the protein. Kasumi-1 and ME-1 cells (where PTPROt is suppressed) are both CBF cell lines characterized by RUNX1/RUNX1T1 [(8;21) translocation] and CBFB/MYH11 [inv(16)], respectively. While CBF AML patients are generally classified within a more favorable cytogenetic group, those cases harboring mutation in the KIT gene that results in constitutively active receptor tyrosine kinase have a poor outcome. In addition, increased expression of the encoded kinase protein occurs in ∼80% of CBF AML, regardless of KIT mutational status. Kasumi-1 and ME-1 cells are also characterized by mutated (constitutively active) and over-expressed KIT, respectively. Since tyrosine phosphorylation regulates the enzymatic activity and oncogenic function of KIT protein we hypothesized that this kinase could be a substrate of PTPROt and that expression of PTPROt would be critical to maintain control of its activity. Indeed, using in vitro substrate-trapping assay we demonstrated that KIT is a direct substrate of PTPROt. Further, in vivo studies conducted by co-transfecting KITD816V and PTPROt (wild type or catalytic site mutant) in H293T cells showed that phosphorylation of KIT at Y719, a read-out for KIT activity, was reduced when KIT was co-expressed with PTPROt-WT but not with vector control or catalytic site mutant of PTPROt. These observations suggest that suppression of PTPROt in CBF AML with over-expressed or mutated KIT could contribute to the leukemogeneic function of KIT. Given that the epigenetic suppression of PTPROt can be reversed by hypomethylating agent decitabine, it is possible that combination of decitabine and tyrosine kinase inhibitors with or without chemotherapy may represent a novel therapeutic approach in CBF AML. [Supported by grant CA101956] Disclosures: No relevant conflicts of interest to declare.

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