title: Activation of JAK3, but not JAK1, is critical to interleukin-4 (IL4) stimulated proliferation and requires a membrane-proximal region of IL4 receptor alpha.
abstract: The tyrosine kinases JAK1 and JAK3 have been shown to undergo tyrosine phosphorylation in response to interleukin-2 (IL), IL4, IL7, and IL9, cytokines which share the common IL2 receptor gamma-chain (IL2R gamma), and evidence has been found for a preferential coupling of JAK3 to IL2R gamma and JAK1 to IL2R beta. Here we show, using human premyeloid TF-1 cells, that IL4 stimulates JAK3 to a larger extent than JAK1, based upon three different evaluation criteria. These include a more vigorous tyrosine phosphorylation of JAK3 as measured by anti-phosphotyrosine immunoblotting, a more marked activation of JAK3 as determined by in vitro tyrosine kinase assays and a more manifest presence of JAK3 in activated IL4-receptor complexes. These observations suggest that IL4 receptor signal transduction does not depend on equimolar heterodimerization of JAK1 and JAK3 following IL4-induced heterodimerization of IL4R alpha and IL2R gamma. Indeed, when human IL4R alpha was stably expressed in mouse BA/F3 cells, robust IL4-induced proliferation and JAK3 activation occurred without detectable involvement of JAK1, JAK2, or TYK2. The present study suggests that JAK1 plays a subordinate role in IL4 receptor signaling, and that in certain cells exclusive JAK3 activation may mediate IL4-induced cell growth. Moreover, mutational analysis of human IL4R alpha showed that a membrane-proximal cytoplasmic region was critical for JAK3 activation, while the I4R motif was not, which is compatible with a role of JAK3 upstream of the recruitment of the insulin receptor substrate-1/4PS signaling proteins by IL4 receptors.
authors.affiliation: Biological Carcinogenesis and Development Program, Program Resources Inc./DynCorp., National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Malabarba
authors.forename: R A
authors.initials: RA
authors.lastname: Kirken
authors.forename: H
authors.initials: H
authors.lastname: Rui
authors.forename: K
authors.initials: K
authors.lastname: Koettnitz
authors.forename: M
authors.initials: M
authors.lastname: Kawamura
authors.forename: J J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: F S
authors.initials: FS
authors.lastname: Kalthoff
authors.forename: W L
authors.initials: WL
authors.lastname: Farrar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011817:Rabbits; D018123:Receptors, Interleukin / Q000502:physiology*; D019948:Receptors, Interleukin-4; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D014443:Tyrosine; 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