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

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Kurgonaite, K., Gandhi, H., Kurth, T., Pautot, S., Schwille, P., Weidemann, T., et al. (2015). Essential role of endocytosis for interleukin-4-receptor-mediated JAK/STAT signalling. Journal of Cell Science, 128(20), 3781-3795. doi:10.1242/jcs.170969.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0029-35FA-8
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.