title: Essential role of endocytosis for interleukin-4-receptor-mediated JAK/STAT signalling.
abstract: Many important signalling cascades operate through specialized signalling endosomes, but a corresponding mechanism has as yet not been described for hematopoietic cytokine receptors. Based on live-cell affinity measurements, we recently proposed that ligand-induced interleukin-4 receptor (IL-4R) complex formation and thus JAK/STAT pathway activation requires a local subcellular increase in receptor density. Here, we show that this concentration step is provided by the internalization of IL-4R subunits through a constitutive, Rac1-, Pak- and actin-mediated endocytosis route that causes IL-4R subunits to become enriched by about two orders of magnitude within a population of cortical endosomes. Consistently, ligand-induced receptor dimers are preferentially detected within these endosomes. IL-4 signalling can be blocked by pharmacological inhibitors targeting the actin polymerization machinery driving receptor internalization, placing endocytosis unambigously upstream of receptor activation. Taken together, these observations demonstrate a role for endocytosis that is mechanistically distinct from the scaffolding function of signalling endosomes in other pathways.
authors: Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstr. 105, Dresden 01307, Germany.
authors: Kristina
authors: K
authors: Kurgonaite
authors: BIOTEC/Biophysics, Technische Universität Dresden, Tatzberg 47-51, Dresden 01307, Germany.
authors: Hetvi
authors: H
authors: Gandhi
authors: Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstr. 105, Dresden 01307, Germany.
authors: Thomas
authors: T
authors: Kurth
authors: Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstr. 105, Dresden 01307, Germany.
authors: Sophie
authors: S
authors: Pautot
authors: BIOTEC/Biophysics, Technische Universität Dresden, Tatzberg 47-51, Dresden 01307, Germany.
authors: Petra
authors: P
authors: Schwille
authors: BIOTEC/Biophysics, Technische Universität Dresden, Tatzberg 47-51, Dresden 01307, Germany weidemann@biochem.mpg.de christian.boekel@crt-dresden.de.
authors: Thomas
authors: T
authors: Weidemann
authors: Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstr. 105, Dresden 01307, Germany weidemann@biochem.mpg.de christian.boekel@crt-dresden.de.
authors: Christian
authors: C
authors: Bökel
mesh_terms: D004705:Endocytosis / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C504000:IL4R protein, human; D053662:Interleukin-4 Receptor alpha Subunit; D050791:STAT Transcription Factors; D053612:Janus Kinases
keywords: Cytokine receptor; Dimerization; IL-13; IL-13Rα1; IL-2Rγ; IL-4; IL-4Rα; JAK3; Pak1; Pak2; Rac1