title: Fes mediates the IL-4 activation of insulin receptor substrate-2 and cellular proliferation.
abstract: Although Jak kinases are essential for initiating cytokine signaling, the role of other nonreceptor tyrosine kinases in this process remains unclear. We have examined the role of Fes in IL-4 signaling. Examination of Jak1-deficient cell lines demonstrates that Jak1 is required for the activation of Fes by IL-4. Experiments studying signaling molecules activated by IL-4 receptor suggest that IL-4 signaling can be subdivided into Fes-dependent and Fes-independent pathways. Overexpression of kinase-inactive Fes blocks the IL-4 activation of insulin receptor substrate-2, but not STAT6. Fes appears to be a downstream kinase from Jak1/Jak3 in this process. Further examination of downstream signaling demonstrates that kinase-inactive Fes inhibits the recruitment of phosphoinositide 3-kinase to the activated IL-4 receptor complex and decreases the activation of p70(S6k) kinase in response to IL-4. This inhibition correlates with a decrease in IL-4-induced proliferation. In contrast, mutant Fes does not inhibit the activation of Akt by IL-4. These data demonstrate that signaling pathways activated by IL-4 require different tyrosine kinases. This differential requirement predicts that specific kinase inhibitors may permit the disruption of specific IL-4-induced functions.
authors.affiliation: Department of Medicine and Microbiology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.forename: K
authors.initials: K
authors.lastname: Foltenyi
authors.forename: M
authors.initials: M
authors.lastname: Kashiwada
authors.forename: L
authors.initials: L
authors.lastname: Donahue
authors.forename: B
authors.initials: B
authors.lastname: Vuong
authors.forename: B
authors.initials: B
authors.lastname: Hehn
authors.forename: P
authors.initials: P
authors.lastname: Rothman
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D015847:Interleukin-4 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051578:Proto-Oncogene Proteins c-fes; D011972:Receptor, Insulin / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D055504:Insulin Receptor Substrate Proteins; D015847:Interleukin-4; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051578:Proto-Oncogene Proteins c-fes; D011972:Receptor, Insulin; D019893:Ribosomal Protein S6 Kinases; C526297:IRS2 protein, human; C526298:Irs2 protein, mouse; C496645:FES protein, human; C496646:Fes protein, mouse; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; C494918:AKT1 protein, human