title: A tyrosine kinase physically associates with the beta-subunit of the human IL-2 receptor.
abstract: Cell surface expression of the high affinity IL-2R regulates, in part, the proliferative response occurring in Ag- or mitogen-activated T cells. The functional high affinity IL-2R is composed of at least two distinct ligand-binding components, IL-2R alpha (Tac, p55) and IL-2R beta (p70/75). The IL-2R beta polypeptide appears to be essential for growth signal transduction, whereas the IL-2R alpha protein participates in the regulation of receptor affinity. We have prepared and characterized two mAb, DU-1 and DU-2, that specifically react with IL-2R beta. In vitro kinase assays performed with DU-2 immunoprecipitates, but not anti-IL-2R alpha or control antibody immunoprecipitates, have revealed co-precipitation of a tyrosine kinase enzymatic activity that mediates phosphorylation of IL-2R beta. Because both IL-2R alpha and IL-2R beta lack tyrosine kinase enzymatic domains, these findings strongly suggest that noncovalent association of a tyrosine kinase with the high affinity IL-2R complex. Deletion mutants of the intracellular region of IL-2R beta, lacking either a previously described "critical domain" between amino acids 267 and 322 or the carboxyl-terminal 198 residues (IL-2R beta 88), lacked the ability to co-precipitate this tyrosine kinase activity, as measured by phosphorylation of IL-2R beta in vitro. Both of these mutants also failed to transduce growth-promoting signals in response to IL-2 in vivo. Analysis of the IL-2R beta 88 mutant receptor suggested that a second protein kinase mediating phosphorylation on serine and threonine residues physically interacts with the carboxyl terminus of IL-2R beta. This kinase may be necessary but, alone, appears to be insufficient to support a full IL-2-induced proliferative response. These studies highlight the physical association of protein kinases with the cytoplasmic domain of IL-2R beta and their likely role in IL-2-induced growth signaling mediated through the multimeric high affinity IL-2R complex.
authors.affiliation: Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710.
authors.forename: M R
authors.initials: MR
authors.lastname: Fung
authors.forename: R M
authors.initials: RM
authors.lastname: Scearce
authors.forename: J A
authors.initials: JA
authors.lastname: Hoffman
authors.forename: N J
authors.initials: NJ
authors.lastname: Peffer
authors.forename: S R
authors.initials: SR
authors.lastname: Hammes
authors.forename: J B
authors.initials: JB
authors.lastname: Hosking
authors.forename: R
authors.initials: R
authors.lastname: Schmandt
authors.forename: W A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: B F
authors.initials: BF
authors.lastname: Haynes
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D004789:Enzyme Activation; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000032:analysis*; D015375:Receptors, Interleukin-2 / Q000032:analysis* / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011505:Protein-Tyrosine Kinases