Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia

Department of Hematology, Second Affiliated Hospital, School of Medicine, Cancer Institute, Zhejiang University, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310009, China.
Blood (Impact Factor: 10.45). 12/2005; 106(9):3142-9. DOI: 10.1182/blood-2004-10-4057
Source: PubMed

ABSTRACT Shp2 tyrosine phosphatase plays a critical role in hematopoiesis, and dominant active mutations have been detected in the human gene PTPN11, encoding Shp2, in child leukemia patients. We report here that although no such mutations were detected in 44 adult leukemia patients screened, Shp2 expression levels were significantly elevated in primary leukemia cells and leukemia cell lines, as compared with normal hematopoietic progenitor cells. The Shp2 protein amounts correlated well with the hyperproliferative capacity but were inversely associated with the differentiation degree of leukemia cells. Suppression of Shp2 expression induced apoptosis and inhibition of leukemic cell clonogenic growth. Notably, the majority of Shp2 was preferentially localized to the plasma membrane and was constitutively phosphorylated on tyrosine in leukemia cells, and also in normal hematopoietic cells following mitogenic stimulation. Based on these results, we propose that aberrantly increased expression of Shp2 may contribute, collaboratively with other factors, to leukemogenesis.

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Available from: Xiaoxian Gan, Sep 27, 2015
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    • "PTPN11 encodes src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2), a tyrosine phosphatase with critical cell properties, including the regulation of proliferation, apoptosis, and differentiation (7). SHP2 expression levels are elevated in AML and are related to the hyperproliferative capacity and the degree of differentiation of primary leukemia cells (8). Animal models lacking SHP2 expression in hematopoietic tissues presented peripheral blood and bone marrow cytopenia (9,10), in addition to increased apoptosis and a reduced quiescence and repopulation capacity of hematopoietic stem cells (10). "
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    ABSTRACT: The aim of this study was to evaluate the expression of protein tyrosine kinase 2 and protein tyrosine phosphatase non-receptor type 11, which respectively encode focal adhesion kinase protein and src homology 2 domain-containing protein-tyrosine phosphatase 2, in hematopoietic cells from patients with myelodysplastic syndromes. Protein tyrosine kinase 2 and tyrosine phosphatase non-receptor type 11 expressions were analyzed by quantitative polymerase chain reaction in bone marrow cells from patients with myelodysplastic syndromes and healthy donors. Protein tyrosine kinase 2 and tyrosine phosphatase non-receptor type 11 expressions did not significantly differ between normal cells and myelodysplastic cells. Our data suggest that despite the relevance of focal adhesion kinase and src homology 2 domain-containing protein-tyrosine phosphatase 2 in hematopoietic disorders, their mRNA expression do not significantly differ between total bone marrow cells from patients with myelodysplastic syndromes and healthy donors.
    Clinics (São Paulo, Brazil) 10/2013; 68(10):1371-5. DOI:10.6061/clinics/2013(10)13 · 1.19 Impact Factor
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    • "In another study, by Xu et al., Shp2 [Src homology 2 (SH2) domain-containing phosphotyrosine phosphatase 2] expression was investigated in 20 patients with AML, 12 patients with acute lymphocytic leukemia (ALL), 18 with chronic myeloid leukemia (CML), one with chronic lymphocytic leukemia (CLL), and one patient diagnosed with biphenotypic leukemia [14]. Comparison of primary leukemia cells with normal hematopoietic progenitor cells demonstrates that Shp2 expression significantly increased in primary leukemia cells. "
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    ABSTRACT: Protein tyrosine phosphatases regulate physiological processes including growth, differentiation, metabolism and the cell cycle. Together with tyrosine kinases, they control the phosphorylation state of tyrosine residues of signaling proteins. An increased level of protein phosphorylation results in abnormal proliferation and many cancer types show a mutation or deletion of a protein tyrosine phosphatase gene. In this study we evaluated the protein tyrosine phosphatase activity in acute leukemia patients. Tyrosine phosphatase activity in bone marrow mononuclear cells of acute leukemia patients was measured using a tyrosine phosphatase assay system kit and compared with a control group. We found that tyrosine phosphatase activity in acute leukemia patients was high compared to the controls. According to subgroups of acute leukemia, tyrosine phosphatase activity in the AML-M2 subgroup was high compared to the controls. The effect of increased level of protein tyrosine phosphatase activity on leukemogenesis needs further evaluation. Studies in a large group of patients are needed to emphasize the importance of tyrosine phosphatase activity in acute leukemia patients.
    Contemporary Oncology / Wspólczesna Onkologia 03/2013; 17(1):83-87. DOI:10.5114/wo.2013.33780 · 0.22 Impact Factor
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    • "In this work, we studied the role of Shp2 in FcεRΙ signaling utilizing Shp2-specific shRNAs expressed by retroviruses to inhibit Shp2 expression in RBL cells. Although previous reports have demonstrated a crucial contribution of Shp2 in development [35], proliferation [29], [36]–[38], and tumor suppression [39]–[41], little is known about the role of Shp2 in mast cell-dependent allergic reactions. Our results demonstrate an essential role of Shp2 in FcεRI-mediated RBL cell activation. "
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    ABSTRACT: The protein-tyrosine phosphatase (PTP) Shp2 has been implicated in many immunoreceptor signaling pathways, but its role in immunoreceptor FcεRI signaling, which leads to the activation of mast cells and blood basophils, is still largely undefined. Using Shp2 knockdown RBL-2H3 (RBL) mast cells, we here reported that Shp2 is required for the activation of RBL cells induced by FcεRI. FcεRΙ-evoked degranulation, calcium mobilization, and synthesis of cytokine transcripts (IL-1β, IL-10, and monocyte chemoattractant protein 1 (MCP-1)) were reduced in Shp2 knockdown RBL cells. Signaling regulatory mechanism investigation using immunoblotting, immunoprecipitation, and GST pull-down assay reveals that the down-regulation of Shp2 expression in RBL cells leads to decreased activities of Fyn, PLCγ, JNK, p38MAPK, and Ras/Erk1/2 after FcεRΙ aggregation. Further studies suggest that Paxillin phosphoryaltion was also impaired, but PAG phosphorylation was normal after FcεRΙ stimulation as a consequence of the inhibition of Shp2 expression in RBL cells. Collectively, our data strongly indicate that Shp2 is essential for the activation of RBL cells in response to FcεRΙ aggregation. Shp2 regulates this process through Fyn and Ras with no involvement of PAG. In addition, we identify Paxillin as an indirect substrate of Shp2 in FcεRΙ-initiated signaling of RBL cells.
    PLoS ONE 07/2012; 7(7):e40566. DOI:10.1371/journal.pone.0040566 · 3.23 Impact Factor
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