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Signal transduction and endocytosis: close encounters of many kinds

Key Points

  • Many receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs) are rapidly endocytosed after ligand-induced activation, and then move through a series of endosomal compartments. Receptors can be recycled to the plasma membrane after endocytosis or can be retained in multivesicular bodies (MVBs), trapped in the MVB interior and delivered to lysosomes.

  • Endocytosis has an essential role in controlling the amounts of signalling receptors and their ligands on the cell surface and extracellular medium, thereby reducing or elevating the intensity of receptor signalling. During development, the endocytic machinery acts in various ways to regulate signalling by soluble factors and membrane factors by establishing gradients and regulating growth-factor accessibility.

  • Many growth factors remain bound to endocytosed receptors, which maintains the activity of the receptors in endosomes. This sustained activation allows signalling proteins to bind receptors in endosomes. Several downstream signalling proteins that are involved in MAPK pathways are also found in endosomes that contain internalized RTKs and GPCRs.

  • In neuronal cells, endocytosed TrkA receptors remain activated in endosomes. TrkA receptors that are activated and internalized in the axonal terminals signal to MAPKs not only locally in axons but also in the cell body in which they can be transported in endosomes.

  • Inhibition of endocytosis of RTKs or GPCRs by dominant-negative mutants of endocytic proteins causes impaired activation of MAPK pathways in some experimental systems, which indicates that endocytosis is essential for MAPK activation.

  • Activation of signalling receptors leads to phosphorylation and ubiquitylation of several components of the clathrin coat. These modifications might contribute to the specific mechanisms of ligand-induced endocytosis of RTKs and GPCRs.

  • Signal-induced ubiquitylation of endosomal proteins and activation of endosomal enzymes have an essential role in the sorting of RTKs and GPCRs to the lysosomal degradation pathway. In MVBs, ubiquitylated receptors interact with proteins carrying ubiquitin-interacting motifs, which leads to trapping the receptors into internal vesicles of MVBs.

Abstract

Binding of hormones, growth factors and other cell modulators to cell-surface receptors triggers a complex array of signal-transduction events. The activation of many receptors also accelerates their endocytosis. Endocytic transport is important in regulating signal transduction and in mediating the formation of specialized signalling complexes. Conversely, signal-transduction events modulate specific components of the endocytic machinery. Recent studies of protein tyrosine kinases and G-protein-coupled receptors have shed new light on the mechanisms and functional consequences of this bidirectional interplay between signalling and membrane-transport networks.

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Figure 1: Endocytic transport itineraries of receptor tyrosine kinases.
Figure 2: Endocytic transport itineraries of G-protein-coupled receptors.
Figure 3: Desensitization and resensitization of G-protein-coupled receptors during endocytosis.
Figure 4: Role of endocytosis in Notch signalling in Drosophila.
Figure 5: Termination of receptor-tyrosine-kinase signalling in multivesicular bodies.
Figure 6: Hypothetical model of signalling complexes in endosomes.
Figure 7: Retrograde transport of endosomes containing TrkA signalling complexes in neurons.
Figure 8: Endocytic protein complexes modified by signalling receptors.
Figure 9: Protein complexes modified by signalling receptors in endosomes.

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Acknowledgements

A.S. was supported by grants from the National Cancer Institute, National Institute on Drug Abuse, National Science Foundation and the American Cancer Society. M.v.Z. was supported by grants from the National Institute on Drug Abuse.

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DATABASES

FlyBase

RN-tre

Delta

dor

dpp

engrailed

Neuralized

Notch

SOS

Wg

LocusLink

B-Raf

C3G

CrkL

EGF

EGF receptor

ERK5

Gab2

PI3K

Rab5

Rap1

RIN1

TrkA

Swiss-Prot

β-adrenergic receptor

c-Raf-1

Grb2

MEK

Shc

Glossary

SH2 DOMAIN

(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

PTB DOMAIN

(Phosphotyrosine-binding domain). Also known as a phosphotyrosine interaction domain (PID), this motif is similar to an SH2 domain in that it binds tyrosine-phosphorylated sequences, and thereby mediates signal transduction.

GUANINE-NUCLEOTIDE EXCHANGE FACTOR

(GEF). A protein that facilitates the release of GDP from, and the binding of the more abundant GTP to, small GTP-binding proteins.

ENDOCYTOSIS

The uptake of extracellular materials by cells. The plasma membrane invaginates and vesicles that contain endocytosed molecules and plasma membrane components pinch off.

CLATHRIN

A large protein, which polymerizes into a triskelion, and comprises three heavy chains and three light chains. Triskelions assemble into polyhedral lattices to form clathrin coats.

MICROPINOCYTOSIS

An actin-dependent process, in which the pinosomes that are formed are very small and can only be visualized using the electron microscope.

LYSOSOME

A membrane-bounded organelle with a low internal pH (4–5) that contains hydrolytic enzymes and that is the site of the degradation of proteins in both the biosynthetic and the endocytic pathways.

MULTIVESICULAR BODIES

Endosomal intermediates in which small membrane vesicles are enclosed within a limiting membrane. The internal vesicles are thought to form by invagination and budding from the limiting membrane.

GREEN FLUORESCENT PROTEIN

(GFP). An autofluorescent protein that was originally isolated from the jellyfish Aequorea victoria. Can be genetically conjugated with proteins to make them fluorescent. The most widely used mutant, enhanced (E)GFP, has an emission maximum at 510 nm.

RAB PROTEINS

These form the largest subfamily of small GTPases of the Ras superfamily. They regulate budding, tethering, fusion and motility at various sites within cells.

IMAGINAL DISCS

Sac-like structures that are present in the larvae and are composed of cells destined to form the adult cuticular structures. They are named after the adult part that they make; for example, wing, leg, eye-antennal or genital.

RING

A cysteine-rich 'RING'-finger domain of 40–60 amino acids (also called the C3HC4 Zn finger), which binds two atoms of Zn and might mediate protein–protein interactions. Most RING-finger proteins have been shown to bind DNA.

SUBSTANCE P

Substance P is an 11-amino-acid tachykinin peptide neurotransmitter that binds preferentially to the NK1 receptor. A second tachykinin (NKA) also has high affinity for this receptor, which indicates that to refer to the NK1 receptor as 'the substance-P receptor' could be misleading.

ADAPTOR PROTEIN

A protein that augments cellular responses by recruiting other proteins to a complex. Adaptor proteins usually contain several protein–protein interaction domains.

PC12 CELLS

A clonal line of rat adrenal pheochromocytoma cells that responds to nerve growth factor and can synthesize, store and secrete catecholamines, much like sympathetic neurons. PC12 cells contain small, clear synaptic-like vesicles and larger, dense core granules.

PALMITOYL

The common name for hexadecanoyl, the acyl group that is derived from palmitic acid.

MYRISTOYL

The common name for tetradecanoyl, the acyl group that is derived from myristic acid.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). A technique in which a fluorophore donor molecule is excited and transfers the energy of an adsorbed photon to an acceptor molecule.

ENDOTHELIAL CELLS

Flattened cells that grow in a single layer and line blood vessels.

CREB

A transcription factor that functions in glucose homeostasis and growth-factor-dependent cell survival, and has also been implicated in learning and memory.

MICROTUBULE

A hollow tube, 25 nm in diameter, that is formed by the lateral association of 13 protofilaments, which are themselves polymers of α- and β-tubulin subunits.

EPS15

(Epidermal-growth-factor-receptor pathway substrate clone 15). A mammalian protein that is required for budding of clathrin-coated vesicles during endocytosis.

GTPASE ACTIVATING PROTEINS

(GAPs). Proteins that inactivate small GTP-binding proteins, such as Ras family members, by increasing their rate of GTP hydrolysis.

E3 UBIQUITIN PROTEIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that are responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.

UBIQUITYLATION

The attachment of the protein ubiquitin to lysine residues of other molecules, often as a tag for their rapid cellular degradation.

FYVE DOMAIN

A protein motif that binds phosphatidylinositol 3-phosphate and thereby mediates docking of cytosolic proteins to the membrane.

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Sorkin, A., von Zastrow, M. Signal transduction and endocytosis: close encounters of many kinds. Nat Rev Mol Cell Biol 3, 600–614 (2002). https://doi.org/10.1038/nrm883

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