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

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. IntroductionThe Src homology 2 (SH2) domain containing phosphotyrosine phosphatase 2 (Shp2), a ubiquitously expressed enzyme, plays a crucial role in normal hematopoietic cell development. [1][2][3] In vitro hematopoietic differentiation assay showed a severe suppression of erythroid/myeloid progenitor cell development from homozygous mutant (Shp2 ⌬46-110 ) embryonic stem (ES) cells. 1 Consistently, neither erythroid nor myeloid progenitor cells of Shp2 ⌬46-110 origin were detectable in the fetal liver or bone marrow of chimeric animals that were derived from aggregation of mutant ES cells and wild-type embryos, although a significant contribution of mutant cells was observed in a few other organs or tissue of the chimeras. 2 Subsequent experiments using the Rag-2 (recombination activating protein-2)-deficient blastocyst complementation assay demonstrated a function of Shp2 for lymphopoiesis in a cell-autonomous manner, and differentiation of lymphoid cell lineages in Shp2 Ϫ/Ϫ / Rag-2 Ϫ/Ϫ chimeric mice was blocked before pro-T-and pro-B-cell stages. 4 Together, these observations suggest a stringent requirement for a functional Shp2 in normal hematopoietic cell development in mammals.Upon stimulation of factor-dependent cell lines with interleukin-6 (IL-6), leukemia inhibitory factor (LIF), IL-3/granulocyte macrophage-colony-stimulating factor (GM-CSF), or erythropoietin (Epo), Shp2 rapidly becomes tyrosine-phosphorylated. 5,6 Cells expressing a mutant gp130 that results in elimination of tyrosine phosphorylation fail to proliferate upon ligand stimulation. 7 Shp2 appears to play a positive role in activation of Akt and Erk signaling pathways, which promote cell proliferation/ survival and block cell apoptosis, critical events in tumorigenesis. [8][9][10] Functional analysis suggested that Shp2 may act in both catalytic-dependent and -independent manners in mediating IL-3-stimulated proliferation and survival of hematopoietic cells. 11 Several studies have...

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

“…Shp2 is mutationally activated in human tumors, in particular in pediatric leukemias (2), and is up-regulated in adult leukemias (5). Moreover, Shp2 is essential for signaling by the receptor tyrosine kinase Met, which is itself found mutated or overexpressed in many different human cancers (20) and linked to metastasis (56).…”

“…Distinct somatic gain-of-function mutations in PTPN11/SHP2 have been identified in Ͼ30% of the most common pediatric leukemia, juvenile myelomonocytic leukemia (JMML), and in myelodysplastic syndrome, acute myeloid leukemia, and some solid tumors (2,4). The presence of activated or up-regulated Shp2 protein (5) in human cancers and other disease makes Shp2 an excellent target for generating interfering substances (6).…”

Low expression of SHP-2 is associated with less favorable prostate cancer outcomes

“…The function of nuclear SHP-2 in prostate cancer could be involved in migration and invasion since nuclear expression correlated with extracapsular extension of the cancer. Prior studies have also reported SHP-2 in the nucleus [16][17][18][19]. Since SHP-2 lacks a typical nuclear localization signal sequence, it could be transported to the nucleus in association with proteins such as Gab1 [19].…”

Shp2, a novel oncogenic tyrosine phosphatase and potential therapeutic target for human leukemia

“…Most recently, PTPN11 gene has been firmly established as the first proto-oncogene that encodes a protein tyrosine phosphatase [1][2][3]. In the hematopoietic system, most if not all function of Shp2 is to act as a positive component that is essential for proliferation and/or survival of hematopoietic cells through regulation of signaling pathways involving Erk, Akt and STAT5 [1][2][3][4]. Over the past few years, a number of disease-associated Shp2 mutants have been identified in human leukemia and other malignancies [1,3,4].…”

“…In the hematopoietic system, most if not all function of Shp2 is to act as a positive component that is essential for proliferation and/or survival of hematopoietic cells through regulation of signaling pathways involving Erk, Akt and STAT5 [1][2][3][4]. Over the past few years, a number of disease-associated Shp2 mutants have been identified in human leukemia and other malignancies [1,3,4]. Recently, studies from our laboratories and others strongly suggest that dysregulation of wild-type Shp2 enzyme may be involved in the pathogenesis of adult leukemia [4][5][6][7].…”