Ectodomain shedding of interleukin-2 receptor beta and generation of an intracellular functional fragment.
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.
Montes de Oca
Pavel
P
Institut Pasteur, Biologie des Interactions Cellulaires, CNRS URA2582, 25 rue du Dr. Roux, 75015 Paris, France. pavel73@hotmail.com
Malardé
Valerie
V
Proust
Richard
R
Dautry-Varsat
Alice
A
Gesbert
Franck
F
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
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