Abstract
Our view of endocytosis and membrane trafficking of transmembrane receptors has dramatically changed over the last 20 years. Several new endocytic routes have been discovered and mechanistically characterized in mammalian cells. Long considered as a passive means to terminate signaling through down-regulation of the number of activated receptors at the plasma membrane, it is now established that receptor endocytosis and endosomal sorting can be directly linked to the regulation of intracellular signaling pathways. The functional links between membrane trafficking of interferon receptors and JAK/STAT signaling have recently begun to be unraveled. These studies raise the exciting possibility that a certain level of signal specificity can be achieved through endocytosis and selective localization of the activated complexes within cellular membranes. The ongoing development of high-resolution cell imaging techniques with better spatial and temporal resolution gives new means of deciphering the inherent complexity of membrane trafficking and signaling. This should help to better comprehend the molecular mechanisms by which endocytosis and endosomal sorting of interferon receptors can orchestrate signaling selectivity within the JAK/STAT pathway that can be activated by as many as 60 different cytokines, growth factors, and hormones.
Highlights
ENDOCYTIC PROCESSES IN MAMMALIAN CELLS Endocytosis is a highly dynamic and tightly regulated process by which solutes and macromolecules enter the cell and are distributed within intracellular compartments
Long seen as a passive means to control the number of signaling receptors at the plasma membrane, it is clear that endocytosis and endosomal sorting can play a more direct control on the signaling outputs of several transmembrane receptors involved in fundamental cellular processes
The deletion of the corresponding LI motif on IFNGR2 does not result in a strong inhibition of its endocytosis, implying that the tyrosinebased endocytic motifs are required for efficient uptake [15]
Summary
Trafficking and signaling of IFNGR (RTK) such as the EGF-R, and of G-protein coupled receptors (GPCR) that undergo endocytosis upon binding to their agonist [10, 11]. The deletion of the corresponding LI motif on IFNGR2 does not result in a strong inhibition of its endocytosis, implying that the tyrosinebased endocytic motifs are required for efficient uptake [15]. It was shown in 2006 that RNAi-mediated silencing of clathrin and dynamin led to the accumulation of IFNGR1 at the plasma membrane and inhibition of IFN-γ endocytosis in several cell types [19]. CLATHRIN-INDEPENDENT ENDOCYTOSIS It has been confirmed that in addition to the canonical clathrin-dependent endocytosis, several distinct endocytic pathways can simultaneously operate in mammalian cells (Figure 1) [21,22,23]. Cargo molecules are trafficked to the sorting endosome where they are either targeted to the lysosome for degradation or recycled back to the plasma membrane through recycling endosomes
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