The interleukin-4 receptor activates STAT5 by a mechanism that relies upon common gamma-chain.
Interleukin (IL)-4 signaling proceeds via cytoplasmic activation of the Janus kinases JAK1 and JAK3 and the signal transducer and activator of transcription STAT6. We show that the IL-4 receptor, like other cytokine receptor systems utilizing the common receptor gamma-chain (gammac), is also connected to a signaling pathway that involves STAT5. Both STAT5a and STAT5b become tyrosine-phosphorylated and acquire specific DNA-binding properties in response to IL-4 receptor stimulation in the murine pro-B cell line Ba/F3. In preactivated human T cells, STAT5 became activated in an IL-4-dependent fashion as assayed by IL-4-induced STAT5 translocation from the cytoplasm to the cell nucleus and by binding to cognate DNA. Moreover, stimulation of preactivated human T cells by IL-4 led to specific transcriptional up-regulation of STAT5 target genes. IL-4 receptor-mediated STAT5 activation is dependent on the presence of gammac and JAK3 within the receptor complex. In COS-7 cells, the JAK/STAT pathway leading from the IL-4 receptor to STAT5-dependent regulation of a reporter gene relied largely on coexpression of JAK3. In Ba/F3 cells, studies on signal transduction evoked by directed specific receptor homo- or heterodimerization revealed that STAT5 activation can be triggered exclusively by IL-4R heterodimers containing gammac.
Lischke
A
A
Theodor-Boveri-Institut für Biowissenschaften (Biozentrum), Physiologische Chemie II, Am Hubland, D-97074 Würzburg, Germany.
Moriggl
R
R
Brändlein
S
S
Berchtold
S
S
Kammer
W
W
Sebald
W
W
Groner
B
B
Liu
X
X
Hennighausen
L
L
Friedrich
K
K
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001692:Biological Transport; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D053616:Janus Kinase 3; D051379:Mice; D008894:Milk Proteins; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000737:chemistry / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D019948:Receptors, Interleukin-4; 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; D015847:Interleukin-4; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3