Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling.
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.
Zhang
S
S
Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Fukuda
S
S
Lee
Y
Y
Hangoc
G
G
Cooper
S
S
Spolski
R
R
Leonard
W J
WJ
Broxmeyer
H E
HE
D000818:Animals; D019556:COS Cells; D002455:Cell Division; D002460:Cell Line; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D051941:fms-Like Tyrosine Kinase 3
D003115:Colony-Stimulating Factors; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2