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J Cell Sci. 2015 Oct 15;128(20):3781-95. doi: 10.1242/jcs.170969. Epub 2015 Aug 25.

Essential role of endocytosis for interleukin-4-receptor-mediated JAK/STAT signalling.

Author information

1
Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstr. 105, Dresden 01307, Germany.
2
BIOTEC/Biophysics, Technische Universität Dresden, Tatzberg 47-51, Dresden 01307, Germany.
3
BIOTEC/Biophysics, Technische Universität Dresden, Tatzberg 47-51, Dresden 01307, Germany weidemann@biochem.mpg.de christian.boekel@crt-dresden.de.
4
Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstr. 105, Dresden 01307, Germany weidemann@biochem.mpg.de christian.boekel@crt-dresden.de.

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.

KEYWORDS:

Cytokine receptor; Dimerization; IL-13; IL-13Rα1; IL-2Rγ; IL-4; IL-4Rα; JAK3; Pak1; Pak2; Rac1

PMID:
26306492
DOI:
10.1242/jcs.170969
[Indexed for MEDLINE]
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