The Journal of Experimental Medicine
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Published online 5 September 2000.
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© The Rockefeller University Press, 0022-1007/2000/9/719/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 5, September 5, 2000 719-728

Original Article

Essential Role of Signal Transducer and Activator of Transcription (Stat)5a but Not Stat5b for Flt3-dependent Signaling

Shuli Zhanga,c,d, Seiji Fukudaa,c,d, Younghee Leea,c,d, Giao Hangoca,c,d, Scott Coopera,c,d, Rosanne Spolskie, Warren J. Leonarde, and Hal E. Broxmeyera,b,c,d
a Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202
b Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202
c Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202
d Walther Cancer Institute, Indianapolis, Indiana 46206
e Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892

Correspondence to: Hal E. Broxmeyer, Department of Microbiology/Immunology and the Walther Oncology Center, Indiana University School of Medicine, Bldg. R4, Rm. 302, 1044 West Walnut St., Indianapolis, IN 46202-5254. Tel:317-274-7510 Fax:317-274-7592 E-mail:hbroxmey{at}iupui.edu.

The receptor tyrosine kinase Flt3 plays an important role in proliferation and survival of hematopoietic stem and progenitor cells. Although some post-receptor signaling events of Flt3 have been characterized, the involvement of the Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway in Flt3 signaling has not been thoroughly evaluated. To this aim, we examined whether Flt3 activates the Jak/Stat pathway in Baf3/Flt3 cells, a line stably expressing human Flt3 receptor. Stat5a, but not Stats 1–4, 5b, or 6, was potently activated by Flt3 ligand (FL) stimulation. Interestingly, FL did not activate any Jaks. Activation of Stat5a required the kinase activity of Flt3. A selective role for Stat5a in the proliferative response of primary hematopoietic progenitor cells to FL was documented, as FL did not act on progenitors from marrows of Stat5a-/- mice, but did stimulate/costimulate proliferation of these cells from Stat5a+/+, Stat5b-/-, and Stat5b+/+ mice. Thus, Stat5a is essential for at least certain effects of FL. Moreover, our data confirm that Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function.

Key Words: Flt3, signal transducer and activator of transfection 5, signal transduction, hematopoiesis, gene knockout


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