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

Oncogene volume 23, pages 3659–3669 (2004)Cite this article

Abstract

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-XL 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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Acknowledgements

We thank Ms. Teresa Hawley for cell sorting and Drs James Ihle, Robert Hawley, Achsah Keegan, and Christine Couldrey for the reagents, helpful discussions, and critical reading of the manuscript. This work was supported by The US National Institutes of Health Grant R01 HL68212 (to CKQ).

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Authors and Affiliations

  1. Department of Hematopoiesis, Jerome H Holland Laboratory for the Biomedical Sciences, American Red Cross, 15601 Crabbs Branch Way, Rockville, 20855, MD, USA

    Jing Chen, Wen-Mei Yu, Kevin D Bunting & Cheng-Kui Qu

  2. Department of Anatomy and Cell Biology, George Washington University Medical Center, 2300 I Street, NW, Washington, 20037, DC, USA

    Kevin D Bunting & Cheng-Kui Qu

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  1. Jing Chen
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  2. Wen-Mei Yu
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Correspondence to Cheng-Kui Qu.

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Chen, J., Yu, WM., Bunting, K. et al. A negative role of SHP-2 tyrosine phosphatase in growth factor-dependent hematopoietic cell survival. Oncogene 23, 3659–3669 (2004). https://doi.org/10.1038/sj.onc.1207471

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