Ligand-independent homomeric and heteromeric complexes between interleukin-2 or -9 receptor subunits and the gamma chain.
Signaling via interleukin-2 (IL-2) and interleukin-9 receptors (IL-2R and IL-9R) involves heteromeric interactions between specific interleukin receptor subunits, which bind Janus kinase 1 (JAK1) and the JAK3 binding common gamma chain (gamma c). The potential existence and roles of homomeric and heteromeric complexes before ligand binding and their modulation by ligand and JAK3 are unclear. Using computerized antibody-mediated immunofluorescence co-patching of epitope-tagged receptors at the surface of live cells, we demonstrate that IL-2Rbeta, IL-9Ralpha, and gamma c each display a significant fraction of ligand-independent homomeric complexes (24-28% co-patching), whereas control co-patching levels with unrelated receptors are very low (7%). Heteromeric complex formation of IL2-Rbeta or IL-9Ralpha with gamma c is also observed in the absence of ligand (15-30%). Ligand binding increases this hetero-oligomerization 2-fold but does not affect homo-oligomerization. Co-expression of IL-2Ralpha does not affect the hetero-oligomerization of IL-2Rbeta and gamma c. Recruitment of gamma c into heterocomplexes is partly at the expense of its homo-oligomerization, suggesting that a functional role of the latter may be to keep the receptors inactive in the absence of ligand. At the same time, the preformed complexes between gamma c and IL-2Rbeta or IL-9Ralpha promote signaling by the JAK3 A572V mutant without ligand, supporting a pathophysiological role for the constitutive oligomerization in triggering ligand-independent activation of JAK3 (and perhaps other JAK mutants) mutants identified in several human cancers.
Malka
Yaniv
Y
Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Hornakova
Tekla
T
Royer
Yohan
Y
Knoops
Laurent
L
Renauld
Jean-Christophe
JC
Constantinescu
Stefan N
SN
Henis
Yoav I
YI
D019943:Amino Acid Substitution; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D053651:Receptors, Interleukin-9 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
C508017:IL2RA protein, human; C508020:IL2RB protein, human; C507941:IL2RG protein, human; C508045:IL9R protein, human; D053631:Interleukin Receptor Common gamma Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; D008024:Ligands; D046912:Multiprotein Complexes; D053651:Receptors, Interleukin-9; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3