Uncoupling of proliferation and Stat5 activation in thymic stromal lymphopoietin-mediated signal transduction.
Thymic stromal lymphopoietin (TSLP) is a cytokine that facilitates B lymphocyte differentiation and costimulates T cells. Previous studies have demonstrated that a functional TSLP receptor complex is a heterodimer consisting of the TSLP receptor and the IL-7R alpha-chain. TSLP-mediated signaling is unique among members of the cytokine receptor family in that activation of the transcription factor Stat5 occurs without detectable Janus kinase activation. Using a variety of biological systems we demonstrate here that TSLP-mediated Stat5 activation can be uncoupled from proliferation. We also show that the single tyrosine residue in the cytoplasmic domain of the TSLP receptor is critical for TSLP-mediated proliferation, but is dispensable for Stat5 activation. Our data demonstrate that TSLP-mediated Stat5 activation is insufficient for cell proliferation and identifies residues within the TSLP receptor complex required to mediate these downstream events.
Isaksen
Deborah E
DE
Virginia Mason Research Center, Seattle, WA 98101, USA.
Baumann
Heinz
H
Zhou
Baohua
B
Nivollet
Sebastien
S
Farr
Andrew G
AG
Levin
Steven D
SD
Ziegler
Steven F
SF
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D003593:Cytoplasm / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008894:Milk Proteins; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000502:physiology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D017154:Stromal Cells / Q000502:physiology; D013950:Thymus Gland / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000235:genetics / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D004268:DNA-Binding Proteins; D015851:Interleukin-7; D008894:Milk Proteins; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D019061:src-Family Kinases; D000094632:Thymic Stromal Lymphopoietin