Endocytosis allows cells to transport particles and molecules across the plasma membrane. In addition, it is involved in the termination of signalling through receptor downmodulation and degradation. This traditional outlook has been substantially modified in recent years by discoveries that endocytosis and subsequent trafficking routes have a profound impact on the positive regulation and propagation of signals, being key for the spatiotemporal regulation of signal transmission in cells. Accordingly, endocytosis and membrane trafficking regulate virtually every aspect of cell physiology and are frequently subverted in pathological conditions. Two key aspects of endocytic control over signalling are coming into focus: context-dependency and long-range effects. First, endocytic-regulated outputs are not stereotyped but heavily dependent on the cell-specific regulation of endocytic networks. Second, endocytic regulation has an impact not only on individual cells but also on the behaviour of cellular collectives. Herein, we will discuss recent advancements in these areas, highlighting how endocytic trafficking impacts complex cell properties, including cell polarity and collective cell migration, and the relevance of these mechanisms to disease, in particular cancer.
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We thank Maria Grazia Malabarba for support in figure design and Rosalind Gunby for critically editing the manuscript before submission. Work in the authors’ labs is supported by: Associazione Italiana per la Ricerca sul Cancro (AIRC IG 24415 to SS, AIRC IG 22811 to LL, AIRC IG 18621 and 5XMille 22759 to GS, and AIRC IG 18988, AIRC IG 23060 and MCO 10000 to PPDF); the Worldwide Cancer Research (20-0094 to SS), the Italian Ministry of University and Scientific Research (PRIN 2017, Prot. 2017E5L5P3 to SS; Prot. 2017HWTP2K to GS; PRIN 2015 Prot. 2015XS92CC to PPDF); the University of Milan (PSR2019 to SS); the FPRC 5×1000 Ministero Salute 2017 (to LL); the Italian Ministry of Health (RF-2016-02361540 to PPDF).
We apologize to the many colleagues whose excellent work could not be reviewed or cited for lack of space. An additional number of primary research papers and reviews is included in the Supplementary Information.
The authors declare no competing interests.
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- Receptor tyrosine kinases
(RTKs). A family of plasma membrane proteins (~60 genes in humans) that function as high affinity binding sites for growth factors and cytokines and transduce signals intracellularly through their intrinsic tyrosine kinase activity.
- G protein-coupled receptors
(GPCRs). A vast family of plasma membrane receptors (more than 800 genes in humans) characterized by seven transmembrane regions. They transduce signals through a variety of modes, among which the best characterized is the coupling with heterotrimeric G proteins.
A family of proteins that act as multifunctional scaffolding proteins, regulating the trafficking and signalling of transmembrane receptors, particularly of GPCRs. They are involved in receptor desensitization, endocytosis and ubiquitylation. They can also function as positive effectors of GPCRs through their scaffolding abilities. The arrestin family comprises visual arrestins, β-arrestins (non-visual arrestins) and α-arrestins.
- AKT kinase
The three members of the human AKT serine-threonine protein kinase family are often referred to as protein kinase Bα (PKBα), PKBβ and PKBγ. These proteins are phosphorylated by phosphoinositide 3-kinase (PI3K). AKT–PI3K forms a key component of many signalling pathways that involves the binding of membrane-bound ligands such as RTKs.
- Epsin family of endocytic adaptor proteins
A family of endocytic proteins composed of three paralogs: EPN1, EPN2 and EPN3, characterized by the presence of an epsin N-terminal homology domain involved in phosphoinositide binding at the plasma membrane, ubiquitin binding motifs and motifs that bind to clathrin, AP2 and other endocytic proteins. They are involved in both clathrin-mediated endocytosis, where they play a role in clathrin-coat assembly and cargo recruitment, and in the non-clathrin endocytosis of epidermal growth factor receptor.
- Epithelial–mesenchymal transition
(EMT). A process, of great relevance in embryogenesis, through which epithelial cells lose polarity and cell–cell adhesion contacts (sessile state) to acquire characteristics of migratory mesenchymal-like cells. In physiology, typically, after migrating, these cells re-acquire an epithelial phenotype through the opposite process of mesenchymal–epithelial transition.
- Death receptors
Type I transmembrane proteins belonging to the tumour necrosis factor/nerve growth factor superfamily. They are activated upon binding to various agonists (such as FASLG, TNFA or TRAIL). They typically trigger the so-called apoptotic extrinsic pathway, yet they can also activate multiple alternative signalling pathways with opposing outcomes (survival/proliferation versus cell death) depending on the cell context.
Small flask-shaped invaginations of the plasma membrane (50–80 nm) that can be morphologically identified by the presence of coat-like proteins (caveolins) and that are particularly abundant in tissues involved in lipid homeostasis or subjected to mechanical challenges like adipocytes, muscle cells and endothelial cells.
A protein involved in the formation of focal adhesions that links surface structures (integrins) to the actin cytoskeleton (through binding to F-actin).
- Focal adhesions
Cell-to-matrix adhesion structures involved in the transmission and regulation of signals between the extracellular matrix and the intracellular environment. They are large and dynamic protein complexes established through integrins (which bind to the extracellular matrix), vinculin, F-actin and several regulatory components (up to 100 different proteins, according to the state of the cell). Focal adhesions have roles in signal transduction, cell motility, cell cycle regulation and several other cellular phenotypes. They represent one of the main sensors/effectors in cellular mechanosensing.
A class of proteins that bind specifically to β-galactoside sugars such as N-acetyl-lactosamine. Galectins are secreted in the extracellular space, where they encounter galactose-containing glycoproteins and glycolipids. The binding of galectins to glycosylated proteins, such as CD44 and α5β1 integrin, triggers galectin oligomerization, which allows their interaction with glycosphingolipids and the generation of plasma membrane curvature, leading to the formation of clathrin-independent endocytic carriers.
- Tip cells
During angiogenesis, new vessels that sprout from existing ones are guided by a leader cell that drives the extension of the sprout and senses the environment for guidance cues.
- ERK signalling
Signalling mediated by the activation of the extracellular signal-regulated kinases (ERKs, also called mitogen-activated protein kinases or MAPKs). This signalling is mediated by the sequential activation of the small GTPase RAS and a cascade of kinases (RAF, MEK and ERK1,2) that transduce a signal from a receptor, located on the cell surface or on endosomes, to regulate a number of fundamental biological functions, including cell proliferation, differentiation and migration.
A family of serine/threonine protein kinases that includes six members in mammals. They serve as targets for the small GTPases CDC42 and RAC and have been implicated in a wide range of biological activities.
A lipid phosphatase (phosphatidylinositol 3,4,5 triphosphate 3-phosphatase). It catalyses the conversion of PI(3,4,5)P3 to PI(4,5)P2, thereby antagonizing the action of PI3K and the activation of AKT. It represents one of the most frequently lost tumour suppressors in human cancers.
AMP-activated protein kinase or 5’ adenosine monophosphate-activated protein kinase. It is a heterotrimeric protein complex endowed with serine/threonine kinase activity that regulates the energy metabolism, mostly acting on glucose and fatty acid metabolism.
A member of RHO subfamily of small GTPases that plays a central role in controlling the activity of protein complexes that are necessary to remodel the actin cytoskeleton during migration.
A member of a class of MAPKs that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy.
JNK (or c-Jun N-terminal Kinase) is a member of a family of protein kinases, which play a central role in stress signalling pathways implicated in gene expression, neuronal plasticity, regeneration, cell death and regulation of cellular senescence.
- RAB GTPases
A subfamily of small GTPases that includes more than 70 members in mammals and regulates several key steps of membrane trafficking, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion.
This term broadly defines a vast group of proteins (frequently unrelated) that all possess Guanine Nucleotide Exchange Factor activity, that is, the ability to convert G proteins from an inactive GDP-bound to an active GTP-bound form.
- Jammed epithelial monolayers
The dynamics of epithelia has been described in terms of jamming transitions. During this transition, collective motion ceases, cells can no longer exchange neighbours, and monolayers become static and rigid, displaying a behaviour similar to that of ensembles of dense and packed inactive particles such as coffee in a chute or sand in a pile.
Central region of the thin cytoplasmic bridge that connects cells at the end of cytokinesis. It consists mostly of microtubules, together with various other types of proteins (400–500). It functions as a platform to mediate abscission, the process of severing the intercellular bridge. It is also endowed with numerous other functions, including the determination of cell fate and asymmetric post-abscission signal transduction.
A key component of a pentameric actin nucleation promoting complex that acts downstream of the GTPase RAC and is necessary for activating the Arp2/3 complex for the generation of branched actin networks.
- Tight junction
A cell-to-cell junction formed by a multiprotein complex. This type of junction is established through homotypic interactions between adhesion molecules (occludins, claudins, JAMs) present on the surface of abutting cells. Tight junctions mark the border between the apical and the basolateral surfaces in epithelial cells and control the formation of functionally distinct apical domains. They are also present in endothelial cells and astrocytes and establish the blood–brain barrier. One of their major function is to seal the epithelia by preventing the leakage of water and small molecular weight solutes.
- Arp2/3 complex
A seven-subunit complex that, upon activation, promotes the branched elongation of the actin network by binding to the side of mother filaments.
- Crumbs polarity complex
A multiprotein complex composed of three members originally identified in Drosophila melanogaster, Crumbs, Pals1 and PatJ. This complex plays a key role in specifying the apical plasma membrane domain of epithelial cells and in controlling cell shape in both invertebrates and vertebrates.
A process in which molecules are transported across cellular barriers. It involves the endocytosis of molecules (typically plasma membrane proteins or extracellular molecules captured through interaction with surface receptors) at one side of the cell and their vesicle-mediated transport to another side, where they are released through exocytosis. It contributes to the establishment of apical–basal cell polarity by transferring transmembrane proteins between distinct plasma membrane domains. It is involved in many other processes, for instance, in the crossing of the blood–brain barrier.
An octameric protein complex involved in vesicle trafficking, specifically in the tethering and spatial targeting of vesicles to the plasma membrane prior to vesicle fusion.
- Annexin 2
A 36-kDa calcium-dependent, phospholipid-binding protein that functions in promoting the exocytosis of intracellular proteins to the extracellular space.
- CDC42 apical polarity complex
CDC42 is a highly conserved RHO-family GTPase that regulates cell polarity in many eukaryotes. It directly interacts with PAR6 and regulates, through this protein, the activity of the atypical protein kinase C (aPKC).
- I-BAR domain
BAR domains are banana-shaped protein domains capable of sensing membrane curvature by binding preferentially to positively curved membranes and named after three proteins in which they were originally identified: BIN1 (bridging interactor 1), AMPH (amphiphysin) and Rvs167 (the yeast homolog of amphiphysin). In contrast to the banana-shaped BAR domains, the I-BAR (which stand for inverse BAR) domain is a zeppelin-shaped structure with convex geometry, thus generating negative membrane curvature.
- Adherens junctions
Cadherin-based cell-to-cell junctions present in epithelial and endothelial cells, frequently in a more basal position with respect to tight junctions.
A process in which the volume of a closed system does not change. It is synonym of isovolumetric.
In Drosophila melanogaster, the ventral part of the embryo that forms during gastrulation and gives rise to the segmented trunk of the animal (gnathal, thoracic, abdominal segments). It includes the mesoderm, ventral ectoderm and dorsal epidermis but excludes the dorsal-most tissue of the embryo, the amnioserosa.
In Drosophila melanogaster, a short-lived extraembryonic tissue with a critical role in dorsal closure and other early developmental morphogenetic events.
- Border cells
A cluster of cells that migrate from the anterior tip of the Drosophila melanogaster egg chamber to the border of the oocyte at stage 9 of oogenesis. These cells perform a stereotypical collective migration on the intervening nurse cells and reach the oocyte. They are required for the formation of the micropyle, the eggshell structure through which sperm enters the egg.
Thin membrane protrusion present at the leading edge of migrating cells, mostly constituted by a flat network of actin.
A process characterizing filamentous multimeric protein structures within the cell and mostly used in reference to filamentous actin (F-actin). When actin subunits (G-actin) are constantly added at one end of the filament and removed from the opposite one, the net effect is the treadmilling of the filament which is used, for instance, to generate motion. The term is also used, more generally, for other biological processes in which the treadmilling of molecules or organelles occurs.
- Neural crest
A temporary group of cells established during vertebrate development, which forms after gastrulation at the border between the neural plate and the surrounding ectoderm. After closure of the neural tube (due to the folding of the neural plate into itself), the neural crest runs along the roof plate of the neural tube. At this stage, neural crest cells undergo EMT and migrate to the periphery, where they give origin to various cell lineages.
- Ascitic fluid
An abnormal accumulation of fluid in the abdominal cavity frequently caused by liver disease or cirrhosis, cancers (specifically ovarian and colon cancer), and heart failure.
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Sigismund, S., Lanzetti, L., Scita, G. et al. Endocytosis in the context-dependent regulation of individual and collective cell properties. Nat Rev Mol Cell Biol 22, 625–643 (2021). https://doi.org/10.1038/s41580-021-00375-5