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

Oncogene volume 22, pages 5995–6004 (2003)Cite this article

Abstract

SHP-2 tyrosine phosphatase is highly expressed in hematopoietic cells, however, the function of SHP-2 in hematopoietic cell signaling is not well understood. Here we focus on the role of SHP-2 phosphatase in the signal transduction of interleukin (IL)-3, a cytokine involved in hematopoietic cell survival, proliferation, and differentiation. We established immortalized SHP-2−/− hematopoietic cell pools and showed that IL-3-induced proliferative response was diminished in SHP-2−/− cells. Moreover, inhibition of the catalytic activity of SHP-2 in wild-type (WT) bone marrow hematopoietic progenitor cells and Ba/F3 cells by overexpression of catalytically inactive SHP-2 mutant suppressed their differentiative and proliferative responses to IL-3, demonstrating an important positive role for SHP-2 in IL-3 signal transduction. Further biochemical analyses revealed that IL-3-induced Jak/Stat, Erk, and PI3 kinase pathways in SHP-2−/− cells were impaired and reintroduction of WT SHP-2 into mutant cells partially restored IL-3 signaling. Interestingly, in catalytically inactive SHP-2-overexpressing Ba/F3 cells, although IL-3-induced activation of Jak2 and Erk kinases was reduced and shortened, PI3 kinase activation remained unaltered. Taken together, these results suggest that SHP-2 tyrosine phosphatase plays multiple roles in IL-3 signal transduction, functioning in both catalytic-dependent and -independent manners in the Jak/Stat, Erk, and PI3 kinase pathways.

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References

  • Bennett AM, Hausdorff SF, O'Reilly AM, Freeman RM and Neel BG . (1996). Mol. Cell. Biol., 16, 1189–1202.

  • Bennett AM, Tang TL, Sugimoto S, Walsh CT and Neel BG . (1994). Proc. Natl. Acad. Sci. USA., 91, 7335–7339.

  • Bone H, Dechert U, Jirik F, Schrader JW and Welham MJ . (1997). J. Biol. Chem., 272, 14470–14476.

  • Bone H and Welham MJ . (2000). Cell Signal., 12, 183–194.

  • Frearson JA and Alexander DR . (1998). J. Exp. Med., 187, 1417–1426.

  • Gu H, Maeda H, Moon JJ, Lord JD, Yoakim M, Nelson BH and Neel BG . (2000). Mol. Cell. Biol., 20, 7109–7120.

  • Gu H, Pratt JC, Burakoff SJ and Neel BG . (1998). Mol. Cell, 2, 729–740.

  • Hadari YR, Kouhara H, Lax I and Schlessinger J . (1998). Mol. Cell. Biol., 18, 3966–3973.

  • Hawley RG, Fong AZ, Lu M and Hawley TS . (1994). Oncogene, 9, 1–12.

  • Ihle JN, Thierfelder W, Teglund S, Stravapodis D, Wang D, Feng J and Parganas E . (1998). Ann. N. Y. Acad. Sci., 865, 1–9.

  • Inagaki K, Noguchi T, Matozaki T, Horikawa T, Fukunaga K, Tsuda M, Ichihashi M and Kasuga M . (2000). Oncogene, 19, 75–84.

  • Itoh T, Liu R, Yokota T, Arai KI and Watanabe S . (1998). Mol. Cell. Biol., 18, 742–752.

  • Li W, Nishimura R, Kashishian A, Batzer AG, Kim WJ, Cooper JA and Schlessinger J . (1994). Mol. Cell. Biol., 14, 509–517.

  • Maegawa H, Hasegawa M, Sugai S, Obata T, Ugi S, Morino K, Egawa K, Fujita T, Sakamoto T, Nishio Y, Kojima H, Haneda M, Yasuda H, Kikkawa R and Kashiwagi A . (1999). J. Biol. Chem., 274, 30236–30243.

  • Manes S, Mira E, Gomez-Mouton C, Zhao ZJ, Lacalle RA and Martinez AC . (1999). Mol. Cell. Biol., 19, 3125–3135.

  • Miyakawa Y, Rojnuckarin P, Habib T and Kaushansky K . (2001). J. Biol. Chem., 276, 2494–2502.

  • Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U and Pfeffer K . (1998). Cell, 93, 397–409.

  • Nishida K, Yoshida Y, Itoh M, Fukada T, Ohtani T, Shirogane T, Atsumi T, Takahashi-Tezuka M, Ishihara K, Hibi M and Hirano T . (1999). Blood, 93, 1809–1816.

  • Okuda K, Foster R and Griffin JD . (1999). Ann. N. Y. Acad. Sci., 872, 305–312; discussion 312–313.

  • Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, Grosveld G and Ihle JN . (1998). Cell, 93, 385–395.

  • Persons DA, Allay JA, Allay ER, Ashmun RA, Orlic D, Jane SM, Cunningham JM and Nienhuis AW . (1999). Blood, 93, 488–499.

  • Pratt JC, Weiss M, Sieff CA, Shoelson SE, Burakoff SJ and Ravichandran KS . (1996). J. Biol. Chem., 271, 12137–12140.

  • Qu CK . (2002). Biochim. Biophys. Acta, 1592, 297–301.

  • Qu CK, Nguyen S, Chen J and Feng GS . (2001). Blood, 97, 911–914.

  • Qu CK, Shi ZQ, Shen R, Tsai FY, Orkin SH and Feng GS . (1997). Mol. Cell. Biol., 17, 5499–5507.

  • Qu CK, Yu WM, Azzarelli B, Cooper S, Broxmeyer HE and Feng GS . (1998). Mol. Cell. Biol., 18, 6075–6082.

  • Qu CK, Yu WM, Azzarelli B and Feng GS . (1999). Proc. Natl. Acad. Sci. USA, 96, 8528–8533.

  • Reddy EP, Korapati A, Chaturvedi P and Rane S . (2000). Oncogene, 19, 2532–2547.

  • Saxton TM, Henkemeyer M, Gasca S, Shen R, Rossi DJ, Shalaby F, Feng GS and Pawson T . (1997). EMBO J., 16, 2352–2364.

  • Shi ZQ, Lu W and Feng GS . (1998). J. Biol. Chem., 273, 4904–4908.

  • Tang TL, Freeman Jr RM, O'Reilly AM, Neel BG and Sokol SY . (1995). Cell, 80, 473–483.

  • Tonks NK and Neel BG . (2001). Curr. Opin. Cell Biol., 13, 182–195.

  • Vogel W, Lammers R, Huang J and Ullrich A . (1993). Science, 259, 1611–1614.

  • Watanabe S, Itoh T and Arai K . (1996). J. Biol. Chem., 271, 12681–12686.

  • Welham MJ, Dechert U, Leslie KB, Jirik F and Schrader JW . (1994). J. Biol. Chem., 269, 23764–23768.

  • Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S, Sawyer ST, Krystal G, Yi T, Nishada K, Hibi M, Hirano T and Platanias LC . (1999). J. Biol. Chem., 274, 24469–24474.

  • Yi T, Mui AL, Krystal G and Ihle JN . (1993). Mol. Cell. Biol., 13, 7577–7586.

  • Yu WM, Hawley TS, Hawley RG and Qu CK . (2002a). Blood, 100, 3828–3831.

  • Yu WM, Hawley TS, Hawley RG and Qu CK . (2002b). Blood, 99, 2351–2359.

  • Yuan L, Yu WM, Yuan Z, Haudenschild CC and Qu CK . (2003). J. Biol. Chem., 278, 15208–15216.

  • Zhang S and Broxmeyer HE . (1999). Biochem. Biophys. Res. Commun., 254, 440–445.

  • Zhang SQ, Tsiaras WG, Araki T, Wen G, Minichiello L, Klein R and Neel BG . (2002). Mol. Cell. Biol., 22, 4062–4072.

  • Zhao Z, Tan Z, Wright JH, Diltz CD, Shen SH, Krebs EG and Fischer EH . (1995). J. Biol. Chem., 270, 11765–11769.

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Acknowledgements

We thank Drs Gen-Sheng Feng, Kevin D Bunting, Joe Z Zhao, and Achsah D Keegan for the reagents, helpful discussions, and critical reading of the manuscript. This work was supported by The US National Institutes of Health grant R01HL68212 (to CKQ) and R01HL66305 (to RGH).

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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

    Wen-Mei Yu, Teresa S Hawley, Robert G Hawley & Cheng-Kui Qu

  2. Flow Cytometry Facility, Jerome H Holland Laboratory for the Biomedical Sciences, American Red Cross, 15601 Crabbs Branch Way, Rockville, 20855, MD, USA

    Teresa S Hawley

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

    Robert G Hawley & Cheng-Kui Qu

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Correspondence to Cheng-Kui Qu.

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Yu, WM., Hawley, T., Hawley, R. et al. Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling. Oncogene 22, 5995–6004 (2003). https://doi.org/10.1038/sj.onc.1206846

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