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 ligandinduced 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.

Nanoconjugation prolongs endosomal signaling of the epidermal growth factor receptor and enhances apoptosis

“…Our findings are consistent with the hypothesis that spatial regulation of intracellular signaling through trafficking represents an important control mechanism, 16, 28, 29, 86–88 and that nanoconjugation represents an alternative strategy for manipulating endosomal signaling. One conceivable application of this approach is the treatment of apoptosis evasion of cancer cells 89 through NPs loaded with EGF that efficiently enrich at the tumor site due to the enhanced permeability and retention effect (EPR) 90–92 .…”

“…While the former influences and regulates the interplay of the receptor with intracellular effector molecules 27 , the latter modulates signaling through cooperative interactions between co-localized receptors 28, 29 . Due to these spatial aspects of the signaling regulation, the disruption of the trafficking of EGF-pEGFR can lead to dramatic changes in the outcome.…”

Cytokine Receptor Endocytosis: New Kinase Activity-Dependent and -Independent Roles of PI3K

“…Endocytosis concentrates receptors in clathrin-coated pits or in endosomes, and the resulting increase in receptor density can promote receptor dimerization and activation (8, 16, 17). Examples of such activation include the enhanced activation of JAK/STAT signaling from granulocyte macrophage colony-stimulating factor (GM-CSF) receptors in clathrin-coated pits (18), and the requirement of endocytosis and concentration in endosomes for proper activation of JAK/STAT signaling by IL4 receptors (19). Endocytic compartments can also serve as signaling platforms to facilitate interaction of cytokine receptors with different signaling modules, thereby changing the signal output from those that occur at the plasma membrane (8, 16, 17).…”

“…Both CME and CIE are involved in endocytosis of cytokine receptors (15, 19, 38–40). CME mediates endocytosis of gp130, the shared receptor for IL6 family cytokines, and receptors for prolactin, thrombopoietin, erythropoietin, interferon, IL5 (IL5Rα), IL7 (IL7Rα), and IL36 (18, 39, 41–48).…”

“…CME mediates endocytosis of gp130, the shared receptor for IL6 family cytokines, and receptors for prolactin, thrombopoietin, erythropoietin, interferon, IL5 (IL5Rα), IL7 (IL7Rα), and IL36 (18, 39, 41–48). CIE mediates endocytosis of the common γ chain receptor, and IL2Rβ, IL4Rα, and IL15Rα receptors (19, 49–53). The same receptor can sometimes utilize both CME and CIE pathways.…”