Reactome: A Curated Pathway Database

Clathrin-mediated endocytosis

Stable Identifier
Homo sapiens
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Clathrin-mediated endocytosis (CME) is one of a number of process that control the uptake of material from the plasma membrane, and leads to the formation of clathrin-coated vesicles (Pearse et al, 1975; reviewed in Robinson, 2015; McMahon and Boucrot, 2011; Kirchhausen et al, 2014). CME contributes to signal transduction by regulating the cell surface expression and signaling of receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs). Most RTKs exhibit a robust increase in internalization rate after binding specific ligands; however, some RTKs may also exhibit significant ligand-independent internalization (reviewed in Goh and Sorkin, 2013). CME controls RTK and GPCR signaling by organizing signaling both within the plasma membrane and on endosomes (reviewed in Eichel et al, 2016; Garay et al, 2015; Vieira et al, 1996; Sorkin and von Zastrow, 2014; Di Fiori and von Zastrow, 2014; Barbieri et al, 2016). CME also contributes to the uptake of material such as metabolites, hormones and other proteins from the extracellular space, and regulates membrane composition by recycling membrane components and/or targeting them for degradation.

Clathrin-mediated endocytosis involves initiation of clathrin-coated pit (CCP) formation, cargo selection, coat assembly and stabilization, membrane scission and vesicle uncoating. Although for simplicity in this pathway, the steps leading to a mature CCP are represented in a linear and temporally distinct fashion, the formation of a clathrin-coated vesicle is a highly heterogeneous process and clear temporal boundaries between these processes may not exist (see for instance Taylor et al, 2011; Antonescu et al, 2011; reviewed in Kirchhausen et al, 2014). Cargo selection in particular is a critical aspect of the formation of a mature and stable CCP, and many of the proteins involved in the initiation and maturation of a CCP contribute to cargo selection and are themselves stabilized upon incorporation of cargo into the nascent vesicle (reviewed in Kirchhausen et al, 2014; McMahon and Boucrot, 2011).

Although the clathrin triskelion was identified early as a major component of the coated vesicles, clathrin does not bind directly to membranes or to the endocytosed cargo. Vesicle formation instead relies on many proteins and adaptors that can bind the plasma membrane and interact with cargo molecules. Cargo selection depends on the recognition of endocytic signals in cytoplasmic tails of the cargo proteins by adaptors that interact with components of the vesicle's inner coat. The classic adaptor for clathrin-coated vesicles is the tetrameric AP-2 complex, which along with clathrin was identified early as a major component of the coat. Some cargo indeed bind directly to AP-2, but subsequent work has revealed a large family of proteins collectively known as CLASPs (clathrin- associated sorting proteins) that mediate the recruitment of diverse cargo into the emerging clathrin-coated vesicles (reviewed in Traub and Bonifacino, 2013). Many of these CLASP proteins themselves interact with AP-2 and clathrin, coordinating cargo recruitment with coat formation (Schmid et al, 2006; Edeling et al, 2006; reviewed in Traub and Bonifacino, 2013; Kirchhausen et al, 2014).

Initiation of CCP formation is also influenced by lipid composition, regulated by clathrin-associated phosphatases and kinases (reviewed in Picas et al, 2016). The plasma membrane is enriched in PI(4,5)P2. Many of the proteins involved in initiating clathrin-coated pit formation bind to PI(4,5)P2 and induce membrane curvature through their BAR domains (reviewed in McMahon and Boucrot, 2011; Daumke et al, 2014). Epsin also contributes to early membrane curvature through its Epsin N-terminal homology (ENTH) domain, which promotes membrane curvature by inserting into the lipid bilayer (Ford et al, 2002).

Following initiation, some CCPs progress to formation of vesicles, while others undergo disassembly at the cell surface without producing vesicles (Ehrlich et al, 2004; Loerke et al, 2009; Loerke et al, 2011; Aguet et al, 2013; Taylor et al, 2011). The assembly and stabilization of nascent CCPs is regulated by several proteins and lipids (Mettlen et al, 2009; Antonescu et al, 2011).

Maturation of the emerging clathrin-coated vesicle is accompanied by further changes in the lipid composition of the membrane and increased membrane curvature, promoted by the recruitment of N-BAR domain containing proteins (reviewed in Daumke et al, 2014; Ferguson and De Camilli, 2012; Picas et al, 2016). Some N-BAR domain containing proteins also contribute to the recruitment of the large GTPase dynamin, which is responsible for scission of the mature vesicle from the plasma membrane (Koh et al, 2007; Lundmark and Carlsson, 2003; Soulet et al, 2005; David et al, 1996; Owen et al, 1998; Shupliakov et al, 1997; Taylor et al, 2011; Ferguson et al, 2009; Aguet et al, 2013; Posor et al, 2013; Chappie et al, 2010; Shnyrova et al, 2013; reviewed in Mettlen et al, 2009; Daumke et al, 2014). After vesicle scission, the clathrin coat is dissociated from the new vesicle by the ATPase HSPA8 (also known as HSC70) and its DNAJ cofactor auxilin, priming the vesicle for fusion with a subsequent endocytic compartment and releasing clathrin for reuse (reviewed in McMahon and Boucrot, 2011; Sousa and Laufer, 2015).

Literature References
PubMed ID Title Journal Year
9736607 Crystal structure of the amphiphysin-2 SH3 domain and its role in the prevention of dynamin ring formation EMBO J. 1998
26872272 Endocytic control of signaling at the plasma membrane Curr. Opin. Cell Biol. 2016
19696798 Endocytosis and signalling: intertwining molecular networks Nat. Rev. Mol. Cell Biol. 2009
15339664 Endocytosis by random initiation and stabilization of clathrin-coated pits Cell 2004
26042225 The role of molecular chaperones in clathrin mediated vesicular trafficking Front Mol Biosci 2015
23823722 Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate Nature 2013
8552632 A role of amphiphysin in synaptic vesicle endocytosis suggested by its binding to dynamin in nerve terminals Proc. Natl. Acad. Sci. U.S.A. 1996
19754444 Dissecting dynamin's role in clathrin-mediated endocytosis Biochem. Soc. Trans. 2009
16516836 Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly Dev. Cell 2006
19458185 Endocytic accessory proteins are functionally distinguished by their differential effects on the maturation of clathrin-coated pits Mol. Biol. Cell 2009
23891661 Advances in analysis of low signal-to-noise images link dynamin and AP2 to the functions of an endocytic checkpoint Dev. Cell 2013
26246598 Epidermal growth factor-stimulated Akt phosphorylation requires clathrin or ErbB2 but not receptor endocytosis Mol. Biol. Cell 2015
22233676 Dynamin, a membrane-remodelling GTPase Nat. Rev. Mol. Cell Biol. 2012
25085911 Endocytosis, signaling, and beyond Cold Spring Harb Perspect Biol 2014
23637288 Endocytosis of receptor tyrosine kinases Cold Spring Harb Perspect Biol 2013
21445324 A high precision survey of the molecular dynamics of mammalian clathrin-mediated endocytosis PLoS Biol. 2011
24581490 BAR domain scaffolds in dynamin-mediated membrane fission Cell 2014
17620409 Eps15 and Dap160 control synaptic vesicle membrane retrieval and synapse development J. Cell Biol. 2007
21447041 Measuring the hierarchy of molecular events during clathrin-mediated endocytosis Traffic 2011
21613550 Phosphatidylinositol-(4,5)-bisphosphate regulates clathrin-coated pit initiation, stabilization, and size Mol. Biol. Cell 2011
20059951 Coordinated actions of actin and BAR proteins upstream of dynamin at endocytic clathrin-coated pits Dev. Cell 2009
26829388 ?-Arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation Nat. Cell Biol. 2016
9092476 Synaptic vesicle endocytosis impaired by disruption of dynamin-SH3 domain interactions Science 1997
16903783 Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly PLoS Biol. 2006
20428113 G domain dimerization controls dynamin's assembly-stimulated GTPase activity Nature 2010
26403691 Forty Years of Clathrin-coated Vesicles Traffic 2015
27092250 The emerging role of phosphoinositide clustering in intracellular trafficking and signal transduction F1000Res 2016
1177317 Coated vesicles from pig brain: purification and biochemical characterization J. Mol. Biol. 1975
19296720 Cargo and dynamin regulate clathrin-coated pit maturation PLoS Biol. 2009
15703209 SNX9 regulates dynamin assembly and is required for efficient clathrin-mediated endocytosis Mol. Biol. Cell 2005
21779028 Molecular mechanism and physiological functions of clathrin-mediated endocytosis Nat. Rev. Mol. Cell Biol. 2011
19092055 SNX9 - a prelude to vesicle release J. Cell. Sci. 2009
12353027 Curvature of clathrin-coated pits driven by epsin Nature 2002
24186068 Cargo recognition in clathrin-mediated endocytosis Cold Spring Harb Perspect Biol 2013
24789820 Molecular structure, function, and dynamics of clathrin-mediated membrane traffic Cold Spring Harb Perspect Biol 2014
8953040 Control of EGF receptor signaling by clathrin-mediated endocytosis Science 1996
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