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

doi:10.1084/jem.192.5.719

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 Zhang^a^,c^,d, Seiji Fukuda^a^,c^,d, Younghee Lee^a^,c^,d, Giao Hangoc^a^,c^,d, Scott Cooper^a^,c^,d, Rosanne Spolski^e, Warren J. Leonard^e, and Hal E. Broxmeyer^a^,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
Department of Microbiology/Immunology and the Walther Oncology Center, Indiana University School of Medicine, Bldg. R4, Rm. 302, 1044 West Walnut St., Indianapolis, IN 46202-5254.317-274-7592317-274-7510

hbroxmey{at}iupui.edu

The receptor tyrosine kinase Flt3 plays an important role inproliferation and survival of hematopoietic stem and progenitorcells. Although some post-receptor signaling events of Flt3have been characterized, the involvement of the Janus kinase/signaltransducer and activator of transcription (Jak/Stat) pathwayin Flt3 signaling has not been thoroughly evaluated. To thisaim, we examined whether Flt3 activates the Jak/Stat pathwayin Baf3/Flt3 cells, a line stably expressing human Flt3 receptor.Stat5a, but not Stats 1–4, 5b, or 6, was potently activatedby Flt3 ligand (FL) stimulation. Interestingly, FL did not activateany Jaks. Activation of Stat5a required the kinase activityof Flt3. A selective role for Stat5a in the proliferative responseof 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 cellsfrom 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, butrather are at least partially distinctive in their function.

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

Abbreviations used in this paper: FL, Flt3 ligand; Jak, Januskinase; PDGF, platelet-derived growth factor; RTK, receptortyrosine kinase; SLF, Steel factor; Stat, signal transducerand activator of kinase.

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