IL-5 receptor-mediated tyrosine phosphorylation of SH2/SH3-containing proteins and activation of Bruton's tyrosine and Janus 2 kinases.
Interleukin 5 (IL-5) induces proliferation and differentiation of B cells and eosinophils by interacting with its receptor (IL-5R) which consists of two distinct polypeptide chains, alpha and beta (beta c). Although both IL-5R alpha and beta c lack a kinase catalytic domain, IL-5 is capable of inducing tyrosine phosphorylation of cellular proteins. We investigated the role of IL-5R alpha in tyrosine phosphorylation of molecules involved in IL-5 signal transduction, using an IL-5-dependent early B cell line, Y16 and transfectants expressing intact or mutant IL-5R alpha together with intact beta c. The results revealed that the transfectants expressing truncated IL-5R alpha, which entirely lacks a cytoplasmic domain, together with beta c, showed neither protein-tyrosine phosphorylation nor proliferation in response to IL-5. This confirms that IL-5R alpha plays a critical role in protein-tyrosine phosphorylation which triggers cell growth. IL-5 stimulation results in rapid tyrosine phosphorylation of beta c and proteins containing Src homology 2 (SH2) and/or SH3 domains such as phosphatidyl-inositol-3 kinase, Shc, Vav, and HS1, suggesting their involvement in IL-5-mediated signal transduction. IL-5 stimulation significantly enhanced activities of Janus 2 and B cell-specific Bruton's tyrosine kinases (JAK2 and Btk) and increased the tyrosine phosphorylation of JAK2 kinase. These results and recent data on signaling of growth factors taken together, multiple biochemical pathways driven by tyrosine kinases such as JAK2 and Btk are involved in IL-5 signal transduction.
Sato
S
S
Department of Immunology, University of Tokyo, Japan.
Katagiri
T
T
Takaki
S
S
Kikuchi
Y
Y
Hitoshi
Y
Y
Yonehara
S
S
Tsukada
S
S
Kitamura
D
D
Watanabe
T
T
Witte
O
O
Takatsu
K
K
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000911:Antibodies, Monoclonal; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D016227:Benzoquinones; D002460:Cell Line; D006224:Cricetinae / Q000276:immunology; D004789:Enzyme Activation; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D007700:Kinetics; D047029:Lactams, Macrocyclic; D008213:Lymphocyte Activation / Q000187:drug effects; D046911:Macromolecular Substances; D051379:Mice / Q000276:immunology; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D011809:Quinones / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000502:physiology*; D053649:Receptors, Interleukin-5; D017828:Rifabutin / Q000031:analogs & derivatives; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D000911:Antibodies, Monoclonal; D016227:Benzoquinones; D015848:Interleukin-5; D047029:Lactams, Macrocyclic; D046911:Macromolecular Substances; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011809:Quinones; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D017828:Rifabutin; D019000:Phosphotyrosine; D014443:Tyrosine; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2