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Cargo Sorting in the Endocytic Pathway: a Key Regulator of Cell Polarity and Tissue Dynamics

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Cargo Sorting in the Endocytic Pathway: a Key Regulator of Cell Polarity and Tissue Dynamics Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Cargo Sorting in the Endocytic Pathway: A Key Regulator of Cell Polarity and Tissue Dynamics Suzanne Eaton1 and Fernando Martin-Belmonte2 1Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany 2Centro de Biologı´a Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı´ficas (CSIC), Madrid 28049, Spain Correspondence: [email protected]; [email protected] The establishment and maintenance of polarized plasma membrane domains is essential for cellular function and proper development of organisms. Epithelial cells polarize along two fundamental axes, the apicobasal and the planar, both depending on finely regulated protein trafficking mechanisms. Newly synthesized proteins destined for either surface domain are processed along the biosynthetic pathway and segregated into distinct subsets of transport carriers emanating from the trans-Golgi network or endosomes. This exocytic trafficking has been identified as essential for proper epithelial polarization. Accumulating evidence now reveals that endocytosis and endocytic recycling play an equally important role in epithelial polarization and the appropriate localization of key polarity proteins. Here, we review recent work in metazoan systems illuminating the connections between endocytosis, postendocytic trafficking, and cell polarity, both apicobasal and planar, in the formation of differentiated epithelial cells, and how these processes regulate tissue dynamics. ENDOCYTOSIS REGULATES APICOBASAL either membrane domain. Thus, endocytosis EPITHELIAL POLARITY and recycling from both surface domains are essential to maintain the composition of the embrane traffic does not simply reinforce different membrane domains. Recent work has Mpolarity but is critical for the generation of implicated the RE as a polarized sorting center cortical epithelial cell asymmetry. Newly syn- that seems instrumental in the establishment, thesized plasma membrane components sorted maintenance, and plasticity of epithelial polar- in the trans-Golgi network (TGN) use exocytot- ity and separated membrane domains (for re- ic pathways to be delivered to specific domains view, see Golachowska et al. 2010). of the plasma membrane in epithelial cells (Rod- Most of the evidence for the importance riguez-Boulan et al. 2005). Then, endocytosed of endocytosis in regulating cell polarity has apical and basolateral cargoes are either sorted come from several genetic screens in Drosophila to late endosomes (LEs) and lysosomes for deg- (for review, see Shivas et al. 2010). These stud- radation, or converge in recycling endosomes ies have shown that endocytic pathways are re- (REs) and are segregated and recycled back to quired for general apicobasal polarity in embry- Editors: Sandra L. Schmid, Alexander Sorkin, and Marino Zerial Additional Perspectives on Endocytosis available at www.cshperspectives.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a016899 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016899 1 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press S. Eaton and F. Martin-Belmonte onic and different adult Drosophila epithelial patterns are maintained both by regulatory in- tissues. Endocytic transport has been proposed teractions between the protein components, to regulate epithelial polarity through the con- such as mutual antagonism (for more in- trol of the levels of certain transmembrane pro- formation, see St Johnston and Ahringer 2010; teins that act as “master regulators” of polarized McCaffrey and Macara 2011), as well as inter- domains such as Crumbs, or signaling events action with additional factors, namely, small downstream from Crumbs, and the proteins GTPases (Iden and Collard 2008) and phos- that regulate cell adhesion such as E-cadherin. phoinositides (PIs) (Martin-Belmonte and Additionally, endocytosis and recycling of sur- Mostov 2007). face cargo are necessary for polarity because Crumbs was first identified as an apical de- they allow the proper relocation of apical and terminant in Drosophila melanogaster embryon- basolateral proteins that require transcytosis to ic epithelia, where it is required for the mainte- reach their correct membrane domain. These nance of apicobasal polarity and promotes the processes are also important for relocalization formation of the apical membrane domain (Te- of proteins that become wrongly distributed as a pass et al. 1990; Tepassand Knust 1993; Wodarz consequence of sorting defects or protein diffu- et al. 1993; Grawe et al. 1996; Tepass 1996). Ac- sion. cumulated evidence suggests that membrane Crumbs is constantly internalized to maintain the level of surface expression that allows appro- Endocytosis Serves to Maintain the priate overall apicobasal polarity. Crumbs is en- Appropriate Levels of Different Surface docytosed at the basolateral membrane to avoid Proteins apical expansion apparently through an AP2/ Endocytosis of receptors is a common strategy clathrin pathway regulated by Lgl (Fletcher et al. for regulating the activity of many types of cell- 2012). However, in order to maintain the prop- signaling pathways and is thought to sensitively er levels of Crumbs in the apical domain, the control their kinetics, as well as functioning as endocytic uptake of Crumbs at this domain biological switches (see Di Fiore and von Zas- must be also finely regulated. Almost a decade trow 2014). Similarly, cell polarity requires con- ago, David Bilder’s laboratory using a mosaic trolled plasma membrane levels of certain trans- genetic screen showed that inhibition of exo- membrane proteins that act as master regulators cytic machinery has little effect on apicobasal of apicobasal polarity. Endocytosis could func- protein localization. However, mutating ava- tion to restrict surface levels of these proteins lanche (avl), a protein required for apical inter- by mediating their transport to lysosomes for nalization of Crumbs and Notch, caused a de- degradation or recycling. Interestingly, polarity fect in apicobasal polarity in follicle cells similar regulators have been recently identified as im- to that produced by aPKC or Scrib mutations portant controllers of endocytosis and posten- (Lu and Bilder 2005). Interestingly, avl is a docytic trafficking (for a recent review, see Shi- syntaxin (homologous to human Stx 7, local- vas et al. 2010). ized in late endosomes, and Stx 12) and colo- Polarity regulators are those proteins that calizes with early (Rab5-positive) and recycling show conserved roles in polarizing different (Rab11-positive) endosomes. Furthermore, the cell types. Three key polarity modules are Rab5-null deletion mutant showed multilay- the Crumbs (Crumbs/Stardust/PatJ), Scribble ered, overproliferative phenotypes very similar (Scribble/Discs Large/Lethal Giant Larva), and to that of avl. Thus, apical Crumbs appears to be PAR (Par6/Par3/aPKC) modules (St Johnston internalized, via Avl and Rab5, to maintain a and Sanson 2011), which in epithelial cells po- level of surface expression that allows appropri- larize along the apicobasal axis; the PAR and ate overall apicobasal polarity. Taken together, Crumbs complexes localize to the apical do- these data are consistent with a model in which main, whereas the Scribble complex localizes increased Crumbs levels resulting from defec- to the basolateral domain. These segregation tive apical endocytosis directly contribute to 2 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016899 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Cell Polarity and Tissue Dynamics the avl defect in apicobasal polarity and neo- the AJs of the ventral neuroectoderm of Dro- plastic phenotype (Fig. 1A). However, cells also sophila. A constitutive active form of aPKC re- need to prevent an excessive uptake of Crumbs stores the normal phenotype. Recent results, for normal polarization. however, suggest that Crumbs regulation could The small GTPase Cdc42 acting through its be different in other Drosophila epithelial tissues effector, the Par complex, seems to play an es- (Fletcher et al. 2012). Results from this work sential role in preventing the endocytosis of define an apical positive feedback loop that cen- Crumbs and other apical proteins from the ters on endocytic regulation of Crumbs, indi- plasma membrane in the Drosophila neuroecto- cating that aPKC phosphorylation is central to derm (Fig. 1) (Harris and Tepass 2008). Loss of stabilizing Crumbs at the plasma membrane in Cdc42 caused the endocytosis of Crumbs, a de- the Drosophila follicle cell epithelium. Indeed, fect that, in turn, causes the disorganization of Crumbs is endocytosed when it fails to interact AB WT Loss of Avl or Rab5WT Loss of Cdc42 or Par complex Crumbs Crumbs Crumbs P P P EE Cdc42 Par/ P AJ AJAvl AJ AJ Avl EE aPKC EE Rab5 AJ Rab5 EE EE AJ RE RE Golgi Golgi Golgi Golgi Lys Lys Lys Lys NUC NUC NUC NUC Crumbs levels Apical membrane Crumbs levels Junction stability CD WT Crumbs Loss of Par complex or Ex/Kibra WT Loss of retromer Crumbs Crumbs P P Crumbs P Crumbs Par/ P aPKC AJ Cdc42 AJ Retromer? AJ AJ Ex/kibra AJ Cdc42 Retromer? EE EE EE EE EE Retromer? RE Lys Golgi Golgi Golgi Golgi Lys Lys NUC NUC NUC NUC Crumbs levels Junction stability Crumbs levels Junction stability Figure 1.
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