Critical cytoplasmic domains of human interleukin-9 receptor alpha chain in interleukin-9-mediated cell proliferation and signal transduction.
Interleukin-9 receptor (IL-9R) complex consists of a ligand-specific alpha chain and IL-2R gamma chain. In this study, two regions in the cytoplasmic domain of human IL-9Ralpha were found to be important for IL-9-mediated cell growth. A membrane-proximal region that contains the BOX1 consensus sequence is required for IL-9-induced cell proliferation and tyrosine phosphorylation of Janus kinases (JAKs). Deletion of this region or internal deletion of the BOX1 motif abrogated IL-9-induced cell proliferation and signal transduction. However, substitution of the Pro-X-Pro in the BOX1 motif with Ala-X-Ala failed to abolish IL-9-induced cell proliferation but decreased IL-9-mediated tyrosine phosphorylation of JAK kinases, insulin receptor substrate-2, and signal transducer and activator of transcription 3 (STAT3) and expression of c-myc and junB. Another important region is downstream of the BOX1 motif and contains a STAT3 binding motif YLPQ. Deletion of this region significantly impaired IL-9-induced cell growth, activation of JAK kinases, insulin receptor substrate-2, and STAT3 and expression of early response genes. A point mutation changing YLPQ into YLPA greatly reduced IL-9-induced activation of STAT3 and expression of c-myc but did not affect cell proliferation. These results suggest that cooperation or cross-talk of signaling molecules associated with different domains of IL-9Ralpha other than STAT3 is essential for IL-9-mediated cell growth.
Zhu
Y X
YX
Department of Medicine (Hematology/Oncology), Indianapolis, Indiana 46202, USA.
Sun
H B
HB
Tsang
M L
ML
McMahel
J
J
Grigsby
S
S
Yin
T
T
Yang
Y C
YC
D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D016259:Genes, myc; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D016906:Interleukin-9 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000502:physiology; D053651:Receptors, Interleukin-9; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D017384:Sequence Deletion; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection
D004268:DNA-Binding Proteins; C508045:IL9R protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D016906:Interleukin-9; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D018123:Receptors, Interleukin; D053651:Receptors, Interleukin-9; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3