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: 10.43). 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, Aug 18, 2015
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    • "Indirect immunofluorescence microscopy demonstrated partial nuclear Shp2 localization in TPA-induced L8057 cells and primary fetal liver-derived murine Mks (Supplemental Fig. S7). This is consistent with earlier reports of partial Shp2 nuclear localization (Yuan et al. 2003; Xu et al. 2005). We next validated the interaction between RUNX1 and Shp2 by independent SA pull-down experiments from TPAinduced L8057 cells containing Flag-Bio RUNX1, reverse coimmunoprecipitation (co-IP) assays of endogenous Shp2 and Flag-Bio RUNX1, and GST pull-down assays of recombinant RUNX1 and Shp2 (Fig. 6A–C). "
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    ABSTRACT: Hematopoietic development occurs in complex microenvironments and is influenced by key signaling events. Yet how these pathways communicate with master hematopoietic transcription factors to coordinate differentiation remains incompletely understood. The transcription factor RUNX1 plays essential roles in definitive hematopoietic stem cell (HSC) ontogeny, HSC maintenance, megakaryocyte (Mk) maturation, and lymphocyte differentiation. It is also the most frequent target of genetic alterations in human leukemia. Here, we report that RUNX1 is phosphorylated by Src family kinases (SFKs) and that this occurs on multiple tyrosine residues located within its negative regulatory DNA-binding and autoinhibitory domains. Retroviral transduction, chemical inhibitor, and genetic studies demonstrate a negative regulatory role of tyrosine phosphorylation on RUNX1 activity in Mk and CD8 T-cell differentiation. We also demonstrate that the nonreceptor tyrosine phosphatase Shp2 binds directly to RUNX1 and contributes to its dephosphorylation. Last, we show that RUNX1 tyrosine phosphorylation correlates with reduced GATA1 and enhanced SWI/SNF interactions. These findings link SFK and Shp2 signaling pathways to the regulation of RUNX1 activity in hematopoiesis via control of RUNX1 multiprotein complex assembly.
    Genes & development 07/2012; 26(14):1587-601. DOI:10.1101/gad.192054.112 · 12.64 Impact Factor
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    • "In addition, somatic gain-of-function mutations in PTPN11 occur in JMML and some other cases of leukemias, indicating that SHP2 is a bona fide oncoprotein (Mohi and Neel, 2007; Chan and Feng, 2007). Consistent with this notion, the level of SHP2 is elevated in adult leukemias without PTPN11 mutations (Xu et al., 2005) and the SHP2-binding scaffolding/adaptor protein Gab2, which is overexpressed in a significant percentage of human breast cancers, promotes mammary cell hyperproliferation via enhanced SHP2 activity (Bentires-Alj et al., 2006). Also notably, SHP2 is a major target of the Helicobacter pylori (H. "
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    Molecular cell 07/2011; 43(1):45-56. DOI:10.1016/j.molcel.2011.05.014 · 14.46 Impact Factor
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    • "Shp2-regulated Ras-Erk1/2 MAP kinase pathway, SFKs, and FAK are involved in tumor growth and metastasis. Overexpression of Shp2 has been observed in infiltrating breast carcinoma [66] and in primary leukemia cells [67]. It was reported that inhibition of Shp2 with a catalytic-inactive Shp2 mutant (Shp2C459S) abolished anchorage-independent growth of breast cancer cell lines and knockdown of Shp2 in BT20 and BT474 breast cancer cells resulted in a normal breast epithelial morphology [68]. "
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