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Endocytosis and signalling: intertwining molecular networks

Key Points

  • Signalling receptors are rapidly endocytosed following activation and then move through a series of endosomal compartments. A common property of signalling receptor endocytosis is the efficient sorting of receptors for lysosomal degradation, which is mediated by their ubiquitylation and sorting into intraluminal vesicles of multivesicular bodies.

  • Endocytosis attenuates signalling that is triggered from the plasma membrane by decreasing the number of receptors available to extracellular ligands and by segregating activated receptors from plasma membrane effectors and substrates.

  • Many types of receptor remain active in endosomes and interact with downstream effectors, which allows them to continue signalling after internalization.

  • In neuronal cells, endosomes containing active complexes of neurotrophin receptors are transported from axonal termini to the cell soma to support retrograde survival signalling.

  • Assembly of signalling complexes on the basis of endosome-specific components allows endosome-specific signalling to occur.

  • Activation of signalling receptors leads to modifications of the basic endocytic machinery and contributes to the receptor-specific changes in endocytic processes.

  • The traditional duality of signalling and endocytosis as two independent processes is beginning to give way to a view that these cellular processes are based on intertwining molecular networks.

Abstract

Cell signalling and endocytic membrane trafficking have traditionally been viewed as distinct processes. Although our present understanding is incomplete and there are still great controversies, it is now recognized that these processes are intimately and bidirectionally linked in animal cells. Indeed, many recent examples illustrate how endocytosis regulates receptor signalling (including signalling from receptor tyrosine kinases and G protein-coupled receptors) and, conversely, how signalling regulates the endocytic pathway. The mechanistic and functional principles that underlie the relationship between signalling and endocytosis in cell biology are becoming increasingly evident across many systems.

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Figure 1: Endocytosis regulates signalling from the plasma membrane.
Figure 2: Signalling processes that begin at the cell surface and continue in endosomes.
Figure 3: Signalling complexes specifically assembled in endosomes.

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Acknowledgements

We thank past and present members of our laboratories, and many colleagues in other laboratories, who have contributed valuable data and ideas. A.S. is supported by National Institutes of Health (NIH) grants CA089151, CA112219 and DA014204, and M.v.Z. by NIH grants DA000439 and DA012864.

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Glossary

Endosomal compartment

An intracellular acidic membrane compartment to which receptors are delivered after endocytosis, and from which receptors are sorted to different intracellular destinations.

Receptor tyrosine kinase

Transmembrane receptor that consists of extracellular ligand-binding domains, one helix membrane-spanning domain and a tyrosine kinase domain in the cytoplasmic part of the molecule.

G protein-coupled receptor

A transmembrane receptor containing seven membrane-spanning helical domains, which functions as a ligand-dependent guanine nucleotide exchange factor to activate trimeric G proteins to interact with other signalling proteins.

Clathrin-coated pit

The initial site of the recruitment of receptors destined for endocytosis and of the formation of a clathrin-coated vesicle.

Clathrin-dependent endocytosis

Endocytosis mediated by clathrin-coated pits and vesicles.

Clathrin-independent endocytosis

Endocytosis that does not require clathrin.

Clathrin heavy chain

The main structural protein of the clathrin coat (170 kD) consisting of the hub, distal and proximal legs and the terminal domains.

E3 ubiquitin ligase

The final enzyme complex in the ubiquitin-conjugation pathway that transfers ubiquitin from previous components of the pathway to the substrate protein to form a covalently linked ubiquitin–substrate conjugate.

RING domain

A cysteine-rich tandem zinc-finger domain of 40–60 amino acids that is often found in E3 ubiquitin ligases.

HECT domain

A domain that contains 350 amino acids and is highly conserved among a family of E3 enzymes. The name HECT for stands for homologous to E6-AP carboxyl terminus.

Multivesicular body

An endosomal intermediate containing small membrane vesicles that are formed by inward invagination and budding from the limiting membrane.

HRS–STAM

A ubiquitin-binding protein complex that functions as an adaptor for cargo sorting to the multivesicular body and lysosome pathway.

Intraluminal vesicle

A small vesicle located inside multivesicular bodies that are formed by ESCRT (endosomal sorting complex required for transport)-mediated invagination of the limiting membrane of these endosomes.

Trimeric G protein

A family of cytoplasmic signal mediators composed of an α-subunit containing a GTP-binding site and intrinsic GTPase activity, together with a hydrophobic and often acylated β- and γ-protein subcomplex. The β- and γ-protein subcomplex is activated by dissociation of α-GTP, which is initiated by GTP exchange on the α-subunit.

FYVE domain

Phosphatidylinositol 3-phosphate binding domain of 60–65 amino acids that is named after four cysteine-rich proteins — Fab1, YOTB/ZK632.12, Vac1, and early endosome antigen 1 — that it has been found in.

PX domain

A lipid- and protein-interaction domain that consists of 100–130 amino acids and is defined by sequences that are found in two components of the phagocyte NADPH oxidase (phox) complex.

Lysophosphatidic acid

A phospholipid derivative that acts as a potent signalling molecule owing to the fact that it activates several G protein-coupled receptors. It is often formed by phospholipase D, which removes the choline group from lysophosphatidylcholine.

Soma

Cell body portion of a neuron that contains the nucleus.

Retrograde signalling

The process by which ligands released from a post-synaptic cell regulate events in a neuron synapsing onto that cell.

Pheochromocytoma

A rare catecholamine-secreting tumour derived from chromaffin cells, which are neuroendocrine cells found in the medulla of the adrenal gland.

Macropinosome

A large vesicle filled with extracellular fluid and formed through macropinocytosis.

PH domain

A phosphoinositol-binding protein domain that is characteristic of the RNase PH family of bacterial phosphate-dependent ribonucleases.

Leucine zipper

A leucine-rich domain in a protein that binds to other proteins with a similar domain.

Metalloendopeptidase

An enzyme which functions as an metalloproteinase endopeptidase.

Depolarization

A change in a cell's membrane potential, making it less negative, which in neurons and other excitatory cells may result in an action potential.

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Sorkin, A., von Zastrow, M. Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol 10, 609–622 (2009). https://doi.org/10.1038/nrm2748

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