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  • Review Article
  • Published:

Signal dispersal and transduction through the endocytic pathway

Nature Reviews Molecular Cell Biology volume 4, pages 213–224 (2003)Cite this article

Key Points

  • uring cell signalling, information that is conveyed by ligands travels from one place, the source, to another, the target, where signals are transduced by receptors. The predominant view of the role of endocytosis in cell signalling used to be that it downregulates signal responses by internalizing the receptors.

  • Recent data indicate, however, that ligands traffic through the endocytic pathway before being released. Some ligands seem to be released together with the membrane that surrounds them. Two types of pathways have being proposed that might explain this process: exosomal transport and transendocytosis.

  • Some ligands, such as the Decapentaplegic (Dpp) morphogen, have been proposed to spread across target tissues by trafficking through cells using the endocytic pathway, instead of by diffusing between cells. Dpp forms a concentration gradient that endows cells with positional information. Endocytosis at the receiving cells is essential for gradient formation and determines the morphogen gradient range.

  • In other cases, for example Wingless (Wg), the ligand spreads by diffusion, and the range of morphogen dispersal is restricted by ligand degradation and recycling through the endocytic pathway.

  • Signal transduction from the endosome (the 'signalling endosome') takes place during epidermal growth factor receptor (EGFR) signalling, nerve growth factor (NGF) and TGF-β signalling. How and why signalling from endosomes occurs are still controversial issues and will be the focus of an increasing number of studies on signalling.

Abstract

During cell signalling, information that is encoded by ligands travels from one place, the source, to another, the target, where signals are transduced by receptors. Evidence has emerged recently that uncovers a role for the endocytic pathway in the secretion of ligands at the source, their dispersion through developing target tissues and the transduction of the signals from endocytic compartments. As a result, endosomes have become the focus of attention in cell–cell communication studies.

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Figure 1: Dispersal of membrane-bound ligands.
Figure 2: Morphogenetic signalling and dispersal of morphogens.
Figure 3: A possible rationale for signalling from endosomes.
Figure 4: SARA mediates endosomal signalling.

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Acknowledgements

I would like to thank C. Böckel, N. Foster, M. Brand and C. Klämbt for their comments on the manuscript.

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  1. Max-Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, Dresden, D01307, Germany

    Marcos González-Gaitán

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  1. Marcos González-Gaitán
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DATABASES

Swiss-Prot

Boss

Cbl

Dally

Dally-like

Delta

Dispatched

Dor

Dpp

Eps15

Hh

Nedd4

Ptc

SARA

Serrate

Shh

Smad2

Smad4

Smo

Tkv

FURTHER INFORMATION

Marcos González-Gaitán's laboratory

Glossary

PRIMORDIUM

Undifferentiated developing tissue.

MORPHOGEN

A molecule, the concentration of which endows cells with positional information that determines the fate of a developing cell.

HEPARAN-SULPHATE PROTEOGLYCAN

(HSPG). A protein that is bound to a complex polysaccharide (heparan-sulphate glycosaminoglycan) present at the cell surface or the extracellular matrix. When bound to ligand, it can have a key signalling role.

HEDGEHOG

(Hh). A morphogenetic ligand that is involved in patterning during development.

GPI

(Glycosylphosphatidylinositol). A lipid species that is characteristic of lipid rafts.

MULTIVESICULAR BODY

A vesicular compartment that contains membrane vesicles and that is an intermediate in the lysosomal degradative pathway. It can also be an intermediate in exosome formation.

TETRASPANINS

A family of proteins that have four transmembrane domains and are associated with lipid rafts.

CLATHRIN

The main component of the endocytic vesicle coat.

WINGLESS

(Wg). A morphogenetic ligand that is involved in patterning during development.

DECAPENTAPLEGIC

A TGF-β-like morphogenetic ligand that is involved in patterning during development.

DYNAMIN

A GTPase that is involved in the fission of the coated pit.

RAB PROTEIN FAMILY

A family of small GTPases that function as key, specific regulators of membrane trafficking.

RAB7

A small GTPase that controls the targeting of endocytic cargo to the lysosome.

RAB5

A small GTPase that controls clathrin-coated pit formation from the plasma membrane and fusion to the early endosome.

RAB11

A small GTPase that controls the targeting of endocytic cargo to the recycling endosome.

DENTICLE

A specialization of the cuticle of the ventral hypodermis of the Drosophila larva, which has been used as a diagnostic marker of the segmentation of the embryo.

DEEP-ORANGE

(Dor). A component of the homotypic fusion and vacuole protein sorting (HOPS) complex that controls the fusion of multivesicular bodies to lysosomes.

AP2

An adaptor complex that interacts with the cytosolic tail of plasma-membrane receptors and recruits the clathrin coat.

EPS15

An adaptor protein that binds to AP2 when phosphorylated by the EGF receptor and recruits clathrin to the endocytic vesicle coat.

β-ARRESTIN

An adaptor protein that binds to clathrin on interaction with phosphorylated β-adrenergic receptor.

HEPATIC GROWTH FACTOR-REGULATED TYROSINE KINASE SUBSTRATE

(Hrs). A FYVE-domain protein that controls the invagination of the membrane to form multivesicular bodies.

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González-Gaitán, M. Signal dispersal and transduction through the endocytic pathway. Nat Rev Mol Cell Biol 4, 213–224 (2003). https://doi.org/10.1038/nrm1053

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