Interleukin-9 induces tyrosine phosphorylation of insulin receptor substrate-1 via JAK tyrosine kinases.
Interleukin (IL)-9 stimulates the proliferation of a variety of hematopoietic lineages through its interaction with a receptor of the cytokine receptor superfamily. In the studies presented here, we have begun to characterize the downstream signaling pathways activated by IL-9. In addition to the activation of JAK1 and JAK3 tyrosine kinases, IL-9, unlike most hematopoietic cytokines but similar to IL-4, induces the tyrosine phosphorylation of a 170-kDa protein that is related to the insulin receptor substrate-1 (IRS-1). We further demonstrate for the first time that IRS-1 is not only associated with JAK1 but also tyrosine phosphorylated and functionally involved in IL-9 signaling in TS1 lymphocytes transfected with the murine IRS-1 cDNA. Cotransfection studies and in vitro experiments directly demonstrate that JAK1, JAK2, or JAK3 is capable of tyrosine phosphorylating IRS-1, suggesting a functional role for these kinases in vivo. Lastly, we demonstrate that IL-9 induces the tyrosine phosphorylation of Stat3 and in this regard differs from IL-4, which triggers tyrosine phosphorylation of Stat6. Taken together, these results strongly suggest that IL-9 and IL-4 utilize common and unique signaling pathways via inducing the similar and distinct tyrosine-phosphorylated proteins.
Yin
T
T
Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46202, USA.
Keller
S R
SR
Quelle
F W
FW
Witthuhn
B A
BA
Tsang
M L
ML
Lienhard
G E
GE
Ihle
J N
JN
Yang
Y C
YC
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D055504:Insulin Receptor Substrate Proteins; D015847:Interleukin-4 / Q000494:pharmacology; D016906:Interleukin-9 / Q000494:pharmacology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D007700:Kinetics; D051379:Mice; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes; D053634:TYK2 Kinase; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D055504:Insulin Receptor Substrate Proteins; D016906:Interleukin-9; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D015847:Interleukin-4; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse