Endosomal crosstalk: meeting points for signaling pathways

Abstract

Endocytosis participates in downregulating incoming signals, but ‘signaling endosomes’ may also serve as physical platforms for crosstalk between signaling pathways. Here, we briefly review the role of endosomes in signaling crosstalk and suggest that endosome-associated scaffold proteins mediate this crosstalk. In addition, using a proteome-wide in silico approach – in which we analyze endosome-binding properties and the capacity of candidates to recruit signaling proteins from more than one distinct pathway – we extend the list of putative crosstalk-mediating endosomal scaffolds. Because endosomal crosstalk may be an important systems-level regulator of pathway communication, scaffold proteins that mediate this crosstalk could be potential targets for pharmacological intervention and synthetic engineering.

Spatio‐Temporal Parameters of Endosomal Signaling in Cancer: Implications for New Treatment Options

“…In case of bone morphogenetic protein receptor (BMPR) another specific scaffold, endofin, organizes signaling from endosomes. These and many other scaffolds that make possible activation of their downstream targets at specific subcellular locations, were previously comprehensively summarized in [Palfy et al, 2012]. …”

“…The binding of ligands to specific receptors at the cell surface, such as Receptor Tyrosine Kinases (RTKs) or G protein—coupled receptors (GPCRs), triggers the activation of many downstream signaling pathways, which are important for normal tissue homeostasis. For integration and regulation of complex signaling networks the endo/lysosomal system is essential [Miaczynska et al, 2004; Gould and Lippincott‐Schwartz, 2009; Sorkin and von Zastrow, 2009; Platta and Stenmark, 2011; Palfy et al, 2012]. Endosomes contribute to regulation of signal transduction in several different ways to ensure the appropriate signaling output in the proper time and the right place.…”

Reciprocal cross-regulation between RNF41 and USP8 controls cytokine receptor sorting and processing

“…Following de novo synthesis and delivery to the plasma membrane receptors are internalized into early endosomes, irrespective of ligand binding. These endosomes operate as a signaling platform by coupling activated receptors to specific signaling pathways (Pálfy et al, 2012) and serve as a central sorting station (Clague et al, 2012). From here, receptors can either be recycled back to the plasma membrane or sorted out for lysosomal degradation via late endosomes or multivesicular bodies (MVB).…”

6BIO Enhances Oligonucleotide Activity in Cells: A Potential Combinatorial Anti-androgen Receptor Therapy in Prostate Cancer Cells

“…GSK-3, due to its regulation of the insulin response and of the Wnt/b-catenin and Hedgehog pathways, has also been implicated in the biogenesis of endosomes and lysosomes. 57 Thus, it is possible that the 6BIO stimulation of ASO activity occurs at the level of the late endosome, where ASOs appear to penetrate the endosomal membrane. 16,33 In fact, the small-molecule GSK-3 inhibitor CHIR99021 also increased SSO activity in HeLa-EGFP-654 cells ( Figure 7A).…”