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J. Biol. Chem., Vol. 283, Issue 48, 33569-33577, November 28, 2008

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Ligand-independent Homomeric and Heteromeric Complexes between Interleukin-2 or -9 Receptor Subunits and the Chain^*

Yaniv Malka, Tekla Hornakova¹², Yohan Royer¹³, Laurent Knoops, Jean-Christophe Renauld, Stefan N. Constantinescu⁴, and Yoav I. Henis⁵

From the Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel and the Ludwig Institute for Cancer Research and de Duve Institute, Université Catholique de Louvain, Brussels B-1200, Belgium

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 chain (_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-2Rβ, IL-9R, and _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-Rβ or IL-9R with _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-2R does not affect the hetero-oligomerization of IL-2Rβ and _c. Recruitment of _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 _c and IL-2Rβ or IL-9R 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.

Received for publication, April 23, 2008 , and in revised form, September 18, 2008.

^* This research was supported in part by a grant from the Israeli Ministry of Health Chief Scientist's Office (to Y. I. H.). This work was also supported by the Fonds National de la Recherche Scientifique (Belgium), the Salus Sanguinis Foundation, the Action de Recherche Concertée MEXP31C1 (University Catholique de Louvain), the Fondation Contre le Cancer (Brussels), PAI Program BCHM61B5 (Belgium), and the Atlantic Philantropies, New York (to S. N. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors were equal contributors.

² Supported by Télévie.

³ Supported by a Mandat d'Aspirant of the Fonds National de la Recherche Scientifique, Belgium.

⁴ A Research Associate of the Fonds National de la Recherche Scientifique, Belgium. To whom correspondence may be addressed: Ludwig Institute for Cancer Research, Brussels B-1200, Belgium. Tel.: 32-2-764-7540; Fax: 32-2-764-6566; E-mail: stefan.constantinescu{at}bru.licr.org.

⁵ An incumbent of the Zalman Weinberg Chair in Cell Biology. To whom correspondence may be addressed. Tel.: 972-3-640-9053; Fax: 972-3-640-7643; E-mail: henis{at}post.tau.ac.il.

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