Elsevier

Current Opinion in Cell Biology

Volume 35, August 2015, Pages 137-143
Current Opinion in Cell Biology

Effects of endocytosis on receptor-mediated signaling

https://doi.org/10.1016/j.ceb.2015.05.005Get rights and content

Cellular mechanisms of membrane traffic and signal transduction are deeply interconnected. The present review discusses how membrane trafficking in the endocytic pathway impacts receptor-mediated signaling. Examples of recent progress are highlighted, focusing on the endocytosis-signaling nexus in mammals.

Introduction

Close relationships between endocytosis and receptor-mediated cellular signaling have been recognized since early investigations of ligand-induced down-regulation of epidermal growth factor receptors (EGFRs, reviewed in [1]), and the identification of endosomes as discrete membrane compartments containing internalized growth factors and activated growth factor receptors [2•, 3, 4•, 5•]. Subsequent studies have verified and extended this relationship in many systems, as reviewed previously (e.g. [6, 7, 8, 9]). The present discussion seeks to minimize duplication by focusing on recent developments and restricting scope to results from mammalian systems.

We will begin with a brief review of mechanisms determining the molecular sorting of signaling receptors in endosomes, and the role of these mechanisms in modulating long-term cellular signaling responsiveness. We will then discuss the hypothesis that endosomes serve, additionally, as sites of active signal initiation. There are other interesting examples of intracellular signaling that do not require receptor endocytosis per se (such as nutrient sensing by lysosomes); these are not discussed here but excellent reviews have appeared elsewhere (e.g. [10]).

Section snippets

Endosomes as sorting stations determining long-term cellular signaling responsiveness

Endocytosis of signaling receptors is widely recognized to confer long-term homeostatic control on cellular signaling responsiveness by adjusting the total cellular receptor complement, or surface-accessible complement, in accord with the cell's history of cognate ligand exposure or overall activation state. Ligand-induced activation typically increases receptor endocytic rate, and internalized receptors engage molecular sorting machineries that specify subsequent transport via divergent

Endosomes as sites of receptor-mediated signal initiation

As noted above, it was proposed from the earliest investigations that endosomes may themselves function as active signaling sites. This idea, formalized in the ‘signaling endosome’ hypothesis, has been supported by many subsequent studies. However, two fundamental questions remain incompletely resolved. First, are endosomes bona fide sites of significant signal initiation under normal physiological conditions? Second, does the endosome signal confer functional effects different from the plasma

Recent progress in the study of endosome signaling and its consequences

Significant advances have been made recently toward determining the subcellular location of defined receptor-mediated signaling mechanisms directly. As noted above, this is a key limitation of many studies in this area, and directly detecting signal initiation would seem feasible for growth factor signaling because pathway activation is associated with receptor phosphorylation and physical association of receptors with a signaling adaptor. Indeed, energy transfer methods have yielded arguably

Outlook

Accumulating evidence strongly supports the general idea that receptor-mediated signaling and membrane trafficking processes are intimately interconnected (Figure 1). One connection, which is now well established, is that endocytic trafficking modulates long-term cellular responsiveness by dynamically adjusting the number of receptors accessible to extracellular ligands in the plasma membrane (or relevant domains thereof, such as synapses). Multiple endosomal sorting machineries contribute to

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank present and former members of the von Zastrow lab, as well as many other colleagues and collaborators at UCSF and elsewhere, for contributions of data, reagents, ideas and critical discussion. We regret being able to cite only a subset of important papers in this area. Work in the authors’ laboratory is supported by the U.S. National Institutes of Health. R.I. is supported by a K99/R00 Pathway to Independence Award from the NIH/NHLBI. N.T. is supported by a postdoctoral

References (52)

  • F. Jean-Alphonse et al.

    Spatially restricted G protein-coupled receptor activity via divergent endocytic compartments

    J Biol Chem

    (2014)
  • A. Sorkin et al.

    Interaction of EGF receptor and grb2 in living cells visualized by fluorescence resonance energy transfer (FRET) microscopy

    Curr Biol

    (2000)
  • A. Fortian et al.

    Live-cell fluorescence imaging reveals high stoichiometry of Grb2 binding to the EGF receptor sustained during endocytosis

    J Cell Sci

    (2014)
  • J. Steyaert et al.

    Nanobody stabilization of G protein-coupled receptor conformational states

    Curr Opin Struct Biol

    (2011)
  • N.G. Tsvetanova et al.

    Spatial encoding of cyclic AMP signaling specificity by GPCR endocytosis

    Nat Chem Biol

    (2014)
  • S.K. Shenoy et al.

    β-Arrestin-mediated receptor trafficking and signal transduction

    Trends Pharmacol Sci

    (2011)
  • J.D. Urban et al.

    Functional selectivity and classical concepts of quantitative pharmacology

    J Pharmacol Exp Ther

    (2007)
  • H.T. Haigler et al.

    Direct visualization of the binding and internalization of a ferritin conjugate of epidermal growth factor in human carcinoma cells A-431

    J Cell Biol

    (1979)
  • M. Marsh et al.

    Penetration of Semliki Forest virus from acidic prelysosomal vacuoles

    Cell

    (1983)
  • W.A. Dunn et al.

    Receptor-mediated endocytosis of epidermal growth factor by hepatocytes in the perfused rat liver: ligand and receptor dynamics

    J Cell Biol

    (1984)
  • L.K. Goh et al.

    Endocytosis of receptor tyrosine kinases

    Cold Spring Harbor Perspect Biol

    (2013)
  • K.E. Cosker et al.

    Neuronal signaling through endocytosis

    Cold Spring Harbor Perspect Biol

    (2014)
  • R. Irannejad et al.

    GPCR signaling along the endocytic pathway

    Curr Opin Cell Biol

    (2014)
  • R. Zoncu et al.

    mTOR: from growth signal integration to cancer, diabetes and ageing

    Nat Rev Mol Cell Biol

    (2011)
  • L.M. Traub et al.

    Cargo recognition in clathrin-mediated endocytosis

    Cold Spring Harbor Perspect Biol

    (2013)
  • S. Mayor et al.

    Clathrin-independent pathways of endocytosis

    Cold Spring Harbor Perspect Biol

    (2014)
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