title: Ectodomain shedding of interleukin-2 receptor beta and generation of an intracellular functional fragment.
abstract: Interleukin-2 (IL-2) regulates different functions of various lymphoid cell subsets. These are mediated by its binding to the IL-2 receptor (IL-2R) composed of three subunits (IL2-Ralpha, -beta, and -gamma(c)). IL-2Rbeta is responsible for the activation of several signaling pathways. Ectodomain shedding of membrane receptors is thought to be an important mechanism for down-regulation of cell surface receptor abundance but is also emerging as a mechanism that cell membrane-associated molecules require for proper action in vivo. Here, we demonstrate that IL-2Rbeta is cleaved in cell lines of different origin, including T cells, generating an intracellular 37-kDa fragment (37beta ic) that comprises the full intracellular C-terminal and transmembrane domains. Ectodomain shedding of IL-2Rbeta decreases in a mutant deleted of the juxtamembrane region, where cleavage is predicted to occur, and is inhibited by tissue inhibitor of metalloproteases-3. 37Beta ic is tyrosine-phosphorylated and associates with STAT-5, a canonic signal transducer of IL-2R. Finally, lymphoid cell transfection with a truncated form of IL-2Rbeta mimicking 37beta ic increases their proliferation. These data indicate that IL-2Rbeta is subject to ectodomain shedding generating an intracellular fragment biologically functional, because (i) it is phosphorylated, (ii) it associates with STAT5A, and (iii) it increases cell proliferation.
authors.affiliation: Institut Pasteur, Biologie des Interactions Cellulaires, CNRS URA2582, 25 rue du Dr. Roux, 75015 Paris, France. pavel73@hotmail.com
authors.forename: Pavel
authors.initials: P
authors.lastname: Montes de Oca
authors.forename: Valerie
authors.initials: V
authors.lastname: Malardé
authors.forename: Richard
authors.initials: R
authors.lastname: Proust
authors.forename: Alice
authors.initials: A
authors.lastname: Dautry-Varsat
authors.forename: Franck
authors.initials: F
authors.lastname: Gesbert
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D053646:Interleukin-2 Receptor beta Subunit / Q000737:chemistry* / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins
chemical_list: D053646:Interleukin-2 Receptor beta Subunit; D010446:Peptide Fragments; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D025521:Tumor Suppressor Proteins; D019000:Phosphotyrosine; D002738:Chloroquine