Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development

Qu, Cheng‐Kui; Nguyen, Suzanne; Chen, Jianzhu; Feng, Gen‐Sheng

doi:10.1182/blood.v97.4.911

Cited by 108 publications

(83 citation statements)

References 21 publications

(36 reference statements)

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“…SHP-2 is profoundly required for early hematopoietic development, and its deletion is embryonically lethal. 51 Our studies indicate that Gab2 alone as a molecular target would have hematopoietic consequences, but these would still be tolerable compared with complete ablation of PI-3K or MAPK function. However, Gab2 deficiency combined with LY294002 treatment dramatically blocked pS6 activation in c-Kit ϩ Lin Ϫ cells.…”

Section: Discussionmentioning

confidence: 78%

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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Section: Discussionmentioning

confidence: 78%

Abnormal hematopoiesis in Gab2 mutant mice

Zhang

Díaz-Flores

et al. 2007

Blood

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“…These results stand in contrast to the negative role of the closely related SHP-1 phosphatase in hematopoietic cell signaling. Indeed, our subsequent genetic analyses of hematopoietic development in the SHP-2/SHP-1 double mutant embryos confirmed opposing roles for SHP-2 and SHP-1 in regulating hematopoietic-lineage determination (Qu et al, 2001).…”

Section: Introductionmentioning

confidence: 64%

“…methylcellulose IMDM medium containing 30% FBS, glutamine (10 À4 M), b-mecaptoethanol (3.3 Â 10 À5 M), and a combination of hematopoietic growth factors (5% pokeweed mitogen-stimulated spleen cell conditioned medium, 20 ng/ml IL-3, 50 ng/ml SCF, 2 U/ml EPO, and 0.1 mM hemin) (Qu et al, , 2001Yu et al, 2002). After 7 days of culture at 371C in a 5% CO 2 incubator, hematopoietic cell colonies were counted under an inverted microscope.…”

Section: Immunoprecipitation and Immunoblottingmentioning

confidence: 99%

A negative role of SHP-2 tyrosine phosphatase in growth factor-dependent hematopoietic cell survival

Chen

Bunting

et al. 2004

Oncogene

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SHP-2 tyrosine phosphatase is highly expressed in hematopoietic cells; however, the function of SHP-2 in hematopoietic cell processes is not fully understood. Recent identification of SHP-2 mutations in childhood leukemia further emphasizes the importance of SHP-2 regulation in hematopoietic cells. We previously reported that SHP-2 played a positive role in IL-3-induced activation of Jak2 kinase in a catalytic-dependent manner. Interestingly, enforced expression of wild-type (WT) SHP-2 in Ba/F3 cells enhanced growth factor deprivation-induced apoptosis. Biochemical analyses revealed that although IL-3 activation of Jak2 kinase was increased, tyrosyl phosphorylation of its downstream substrate STAT5 was disproportionately decreased by the overexpression of SHP-2. Following IL-3 deprivation, the tyrosyl phosphorylation of STAT5 that is required for its antiapoptotic activity was rapidly diminished in SHP-2 overexpressing cells. As a result, reduction of the putative downstream targets of STAT5-Bcl-X L and pim-1 was accelerated by overexpression of SHP-2. Further investigation showed that SHP-2 associated with STAT5, and that it was indeed able to dephosphorylate STAT5. Finally, overexpression of SHP-2 in primary bone marrow hematopoietic progenitor cells compromised their differentiative and proliferative potential, and enhanced growth factor withdrawal-induced cell death. And, the effect of SHP-2 overexpression on growth factor-dependent survival was diminished in STAT5-deficient hematopoietic cells. Taken together, these results suggest that SHP-2 tyrosine phosphatase negatively regulates hematopoietic cell survival by dephosphorylation of STAT5.

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“…These results stand in sharp contrast to the negative role of the closely related SHP-1 phosphatase in hematopoietic cell signaling. Indeed, our subsequent genetic analyses of hematopoietic development in the SHP-2/SHP-1 double mutant mice confirmed opposing roles for SHP-2 and SHP-1 in regulating hematopoietic-lineage determination (Qu et al, 2001).…”

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confidence: 68%

Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development

Cited by 108 publications

References 21 publications

Abnormal hematopoiesis in Gab2 mutant mice

Abnormal hematopoiesis in Gab2 mutant mice

A negative role of SHP-2 tyrosine phosphatase in growth factor-dependent hematopoietic cell survival

Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling

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