Endosomal crosstalk: meeting points for signaling pathways - PubMed (original) (raw)

Endosomal crosstalk: meeting points for signaling pathways

Máté Pálfy et al. Trends Cell Biol. 2012 Sep.

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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1

Endosome-associated adaptors/scaffolds mediate signaling specificity, localization, and crosstalk. Green color shows scaffold proteins; orange and yellow shows scaffold-interacting proteins; brown shows endosome-related proteins; blue arrows represent crosstalk; white arrows represent other post-translational modifications; black squares represent output functions. (a) Crosstalk between two pathways may be localized to endosomes as physical platforms through crosstalk mediating scaffolds that bind to the endosome. EL denotes Endosome Localization domains (Box 1). (b) In zebrafish embryos, the endosomal adaptor APPL mediates crosstalk between glycogen synthase 3 beta (GSK3-β) and AKT, but is not required for TSC2 activation by AKT. (c) On angiotensin-II signaling, early endosome antigen 1 (EEA1) recruits signaling components to endosomes and mediates the crosstalk between p38 and AKT. (d) In bone morphogenetic protein (BMP) signaling, the endosomal scaffold hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) facilitates the crosstalk between SMADs and the TAK1 kinase. This phosphorylation event is HGS dependent.

Figure 2

Figure 2

Two scaffolds that could potentially mediate crosstalk on endosomes. (a) A hypothetical arrangement showing AXIN as an endosomal scaffold able to connect multiple pathways (not all known AXIN binding proteins are shown). Based on the AXIN binding partners from and the interaction between AXIN and the endosomal adaptor Endophilin A2 . (b) A predicted picture of the β-catenin–SMAD3 interaction mediated by the endosome-bound SARA.

Figure I

Figure I

Phosphoinositide-specific binding of proteins to distinct endosomal populations. The change of phosphoinositides (PtdIns) on endosomes is reflected in their protein composition, because their associated protein factors often bind to endosomal membranes via modular domains (e.g., PH, FYVE, PX, or PROPPIN) that can specifically interact with distinct forms of PtdIns. Note that WIPI49 is one of the few PROPPIN domain-containing proteins and we hypothesize that it could bind to the membrane of late endosomes, though experimental validation is needed to prove its late endosomal localization.

Figure I

Figure I

Overlapping classes and lists of the 76 endosome-associated scaffolds based on their binding properties. In humans, we identified 10 scaffolds that can bind to endosomal membrane (blue), 20 scaffolds that bind to endosome-related proteins (red), and 16 indirect endosomal scaffolds that interact with directly binding endosomal scaffolds (green). In addition, 29 scaffolds can bind both to endosome-related proteins and to directly binding endosomal scaffolds (red–green overlap). Only one scaffold hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) can bind both the endosomal membrane and endosome-related proteins (blue–red overlap). Scaffolds that are mentioned in the main text are highlighted.

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References

    1. Wiley H.S. The role of tyrosine kinase activity in endocytosis, compartmentation, and down-regulation of the epidermal growth factor receptor. J. Biol. Chem. 1991;266:11083–11094. - PubMed
    1. Bo S.K. Regulatory mechanisms that modulate signalling by G-protein-coupled receptors. Biochem. J. 1997;322:1–18. - PMC - PubMed
    1. Miaczynska M. Not just a sink: endosomes in control of signal transduction. Curr. Opin. Cell Biol. 2004;16:400–406. - PubMed
    1. Howe C.L., Mobley W.C. Signaling endosome hypothesis: a cellular mechanism for long distance communication. J. Neurobiol. 2004;58:207–216. - PubMed
    1. Le Roy C., Wrana J.L. Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling. Nat. Rev. Mol. Cell Biol. 2005;6:112–126. - PubMed

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