Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML)

Scherr, Michaela; Chaturvedi, Anuhar; Battmer, Karin; Dallmann, Iris; Schultheis, Beate; Ganser, Arnold; Eder, Matthias

doi:10.1182/blood-2005-08-3087

Cited by 117 publications

(97 citation statements)

References 39 publications

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“…Stat5ab À/À mice die perinatally and liver hematopoietic progenitors from these mice transfected with Bcr-Abl fail to generate leukemia in recipient mice (Hoelbl et al, 2006). RNAi-mediated reduction in Stat5 inhibits Bcr-Abl-dependent proliferation, but not cytokine-dependent proliferation and reduces myeloid colony formation in CML patient samples (Scherr et al, 2006). The inability of Stat5 RNAi to inhibit cytokinedependent proliferation suggests that Stat5 is more important in mediating Bcr-Abl-specific signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Bcr-Abl induces autocrine IGF-1 signaling

et al. 2008

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Section: Discussionmentioning

confidence: 99%

Bcr-Abl induces autocrine IGF-1 signaling

et al. 2008

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“…21 Gab2 is already well defined as a potential leukemic target that is of particular relevance for activation of PI-3K signaling by BCR-ABL. 17 The role of PI-3K pathway activation in leukemogenesis has been extensively studied.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, enhanced sensitivity of chronic myeloid leukemia (CML) to antiproliferative drugs can be achieved by combined inhibition of STAT5 and Gab2 expression. 21 Given the important roles for Gab2 in normal and oncogenic cytokine signaling, we thus set out to define its role in hematopoiesis. Here, we report that Gab2 Ϫ/Ϫ mouse BM has significant defects that are consistent with a major cell-intrinsic role in potentiating responses to early-acting cytokines.…”

Section: Introductionmentioning

confidence: 99%

Abnormal hematopoiesis in Gab2 mutant mice

Zhang

Díaz-Flores

et al. 2007

Blood

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Gab2 is an important adapter molecule for cytokine signaling. Despite its major role in signaling by receptors associated with hematopoiesis, the role of Gab2 in hematopoiesis has not been addressed. We report that despite normal numbers of peripheral blood cells, bone marrow cells, and c-Kit ؉ Lin ؊ Sca-1 ؉ (KLS) cells, Gab2-deficient hematopoietic cells are deficient in cytokine responsiveness. Significant reductions in the number of colonyforming units in culture (CFU-C) in the presence of limiting cytokine concentrations were observed, and these defects could be completely corrected by retroviral complementation. In earlier hematopoiesis, Gab2-deficient KLS cells isolated in vitro responded poorly to hematopoietic growth factors, resulting in an up to 11-fold reduction in response to a cocktail of stem cell factor, flt3 ligand, and thrombopoietin. Gab2-deficient c-Kit ؉ Lin ؊ cells also demonstrate impaired activation of extracellular signal-regulated kinase (ERK) and S6 in response to IL-3, which supports defects in activating the phosphatidylinositol-3 kinase (PI-3K) and mitogen-associated protein kinase (MAPK) IntroductionOne of the most prominent motifs in signaling molecules is the Src homology-2 (SH2) domain found in JAKs, signal transducers and activators of transcription (STATs), Grb2, p85, Shc, and others. These SH2 domains are able to bind and "dock" with the phosphorylated tyrosine residues that are common in signal transduction pathways. Multiple protein-binding motifs are present in many of the adapter molecules, leading to multimeric complexes that may also include CrkL, PLC, SHIP, and SHP-2. The Grb2-associated binding protein (Gab) family of adapter proteins (Gab1, Gab2, Gab3) include a family of scaffolding/docking/adapter molecules involved in multiple signaling pathways, including the phosphatidylinositol-3 kinase (PI-3K) and mitogen-associated protein kinase (MAPK) pathways, and include multiple proteinbinding sites. [1][2][3] These proteins are tyrosine phosphorylated following cytokine stimulation and are able to interact with a large number of partners. The mechanisms that confer specificity in directing which interactions occur in any particular cell type upon cytokine stimulation remain to be determined. Gab1 deficiency results in embryonic lethality, and conditional deletion of Gab1 shows a role for Gab1 in promoting extracellular signal-regulated kinase (ERK) activation in hepatic function. 4,5 Gab1 acts as an adapter protein to link gp130 signaling to the ERK pathway. 6 In contrast, Gab3 knockout mice do not show major phenotypes. 2 Gab2 is tyrosine phosphorylated by several early-acting cytokine receptors such as flt3, c-Kit, IL-3R, and c-Mpl, and contains proline-rich and pleckstrin homology (PH) domains that promote binding to signaling molecules. 1,7,8 This cytokine activation profile is very similar to STAT5. Gab2 activates the PI-3K and MAPK pathways and can regulate hematopoietic cell migration functions. 9 Gab proteins also contain a large number of consensus serine/...

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“…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).…”

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confidence: 99%

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

Hellmuth

Grosskopf

Lum

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

206

182

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The protein tyrosine phosphatase Shp2 is a positive regulator of growth factor signaling. Gain-of-function mutations in several types of leukemia define Shp2 as a bona fide oncogene. We performed a high-throughput in silico screen for small-molecular-weight compounds that bind the catalytic site of Shp2. We have identified the phenylhydrazonopyrazolone sulfonate PHPS1 as a potent and cellpermeable inhibitor, which is specific for Shp2 over the closely related tyrosine phosphatases Shp1 and PTP1B. PHPS1 inhibits Shp2-dependent cellular events such as hepatocyte growth factor/scatter factor (HGF/SF)-induced epithelial cell scattering and branching morphogenesis. PHPS1 also blocks Shp2-dependent downstream signaling, namely HGF/SF-induced sustained phosphorylation of the Erk1/2 MAP kinases and dephosphorylation of paxillin. Furthermore, PHPS1 efficiently inhibits activation of Erk1/2 by the leukemia-associated Shp2 mutant, Shp2-E76K, and blocks the anchorage-independent growth of a variety of human tumor cell lines. The PHPS compound class is therefore suitable for further development of therapeutics for the treatment of Shp2-dependent diseases.chemical biology ͉ growth factor signaling ͉ phosphatase inhibition ͉ virtual drug screening

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Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML)

Cited by 117 publications

References 39 publications

Bcr-Abl induces autocrine IGF-1 signaling

Bcr-Abl induces autocrine IGF-1 signaling

Abnormal hematopoiesis in Gab2 mutant mice

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

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