Skip to main content

Molecular Mechanisms of Apical and Basolateral Sorting in Polarized Epithelial Cells

  • Chapter
  • First Online:
Ion Channels and Transporters of Epithelia in Health and Disease

Part of the book series: Physiology in Health and Disease ((PIHD))

Abstract

The proper localization of ion channels and transporters to the apical or basolateral membrane domains is essential for correct ion transport through epithelia. Polarized sorting is achieved through elaborate intracellular sorting pathways encompassing the trans-Golgi network, early endosomes, and recycling endosomes that are fine-tuned for epithelial function and thus different from the secretory and endocytic systems in non-polarized cells. Polarized cells express epithelial cell-specific molecules, including sorting adaptors like the cytosolic clathrin adaptor AP-1B, that are required for efficient segregation and targeting of proteins to specific plasma membrane domains. In this book chapter, we will first discuss the various sorting stations in the cells followed by a review of apical and basolateral sorting signals and their interpretation at different compartments. Specific emphasis is placed on the trafficking of ion transporters.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AEE:

Apical early endosome

ARE:

Apical RE

BEE:

Basolateral early endosome

CRE:

Common RE

RE:

Recycling endosome

TGN:

trans-Golgi network

TJ:

Tight junction

References

  • Adair-Kirk TL, Cox KH, Cox JV (1999) Intracellular trafficking of variant chicken kidney AE1 anion exchangers: Role of alternative NH2 termini in polarized sorting and Golgi recycling. J Cell Biol 147:1237–1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Almomani EY, King JC, Netsawang J, Yenchitsomanus PT, Malasit P, Limjindaporn T, Alexander RT, Cordat E (2012) Adaptor protein 1 complexes regulate intracellular trafficking of the kidney anion exchanger 1 in epithelial cells. Am J Physiol Cell Physiol 303:C554–C566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ang AL, Taguchi T, Francis S, Fölsch H, Murrells LJ, Pypaert M, Warren G, Mellman I (2004) Recycling endosomes can serve as intermediates during transport from the Golgi to the plasma membrane of MDCK cells. J Cell Biol 167:531–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ang SF, Fölsch H (2012) The role of secretory and endocytic pathways in the maintenance of cell polarity. Essays Biochem 53:29–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Antalffy G, Mauer AS, Paszty K, Hegedus L, Padanyi R, Enyedi A, Strehler EE (2012) Plasma membrane calcium pump (PMCA) isoform 4 is targeted to the apical membrane by the w-splice insert from PMCA2. Cell Calcium 51:171–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ares GR, Ortiz PA (2012) Dynamin2, clathrin, and lipid rafts mediate endocytosis of the apical Na/K/2Cl cotransporter NKCC2 in thick ascending limbs. J Biol Chem 287:37824–37834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arnspang EC, Sundbye S, Nelson WJ, Nejsum LN (2013) Aquaporin-3 and aquaporin-4 are sorted differently and separately in the trans-Golgi network. PLoS ONE 8, e73977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bandler PE, Westlake CJ, Grant CE, Cole SP, Deeley RG (2008) Identification of regions required for apical membrane localization of human multidrug resistance protein 2. Mol Pharmacol 74:9–19

    Article  CAS  PubMed  Google Scholar 

  • Bartles JR, Feracci HM, Stieger B, Hubbard AL (1987) Biogenesis of the rat hepatocyte plasma membrane in vivo: comparison of the pathways taken by apical and basolateral proteins using subcellular fractionation. J Cell Biol 105:1241–1251

    Article  CAS  PubMed  Google Scholar 

  • Bibee KP, Augustin R, Gazit V, Moley KH (2013) The apical sorting signal for human GLUT9b resides in the N-terminus. Mol Cell Biochem 376:163–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bigay J, Antonny B (2012) Curvature, lipid packing, and electrostatics of membrane organelles: defining cellular territories in determining specificity. Dev Cell 23:886–895

    Article  CAS  PubMed  Google Scholar 

  • Boehm M, Bonifacino JS (2001) Adaptins: the final recount. Mol Biol Cell 12:2907–2920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bomsel M, Parton R, Kuznetsov SA, Schroer TA, Gruenberg J (1990) Microtubule- and motor-dependent fusion in vitro between apical and basolateral endocytic vesicles from MDCK cells. Cell 62:719–731

    Article  CAS  PubMed  Google Scholar 

  • Bonifacino JS (2014) Adaptor proteins involved in polarized sorting. J Cell Biol 204:7–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bravo-Zehnder M, Orio P, Norambuena A, Wallner M, Meera P, Toro L, Latorre R, Gonzalez A (2000) Apical sorting of a voltage- and Ca2 + −activated K+ channel alpha -subunit in Madin-Darby canine kidney cells is independent of N-glycosylation. Proc Natl Acad Sci USA 97:13114–13119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brone B, Eggermont J (2005) PDZ proteins retain and regulate membrane transporters in polarized epithelial cell membranes. Am J Physiol Cell Physiol 288:C20–C29

    Article  CAS  PubMed  Google Scholar 

  • Burgos PV, Mardones GA, Rojas AL, daSilva LL, Prabhu Y, Hurley JH, Bonifacino JS (2010) Sorting of the Alzheimer’s disease amyloid precursor protein mediated by the AP-4 complex. Dev Cell 18:425–436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butterworth MB, Edinger RS, Silvis MR, Gallo LI, Liang X, Apodaca G, Frizzell RA, Johnson JP (2012) Rab11b regulates the trafficking and recycling of the epithelial sodium channel (ENaC). Am J Physiol Renal Physiol 302:F581–F590

    Article  CAS  PubMed  Google Scholar 

  • Caceres PS, Mendez M, Ortiz PA (2014) Vesicle-associated Membrane Protein 2 (VAMP2) but Not VAMP3 Mediates cAMP-stimulated Trafficking of the Renal Na + −K + −2Cl Co-transporter NKCC2 in Thick Ascending Limbs. J Biol Chem 289:23951–23962

    Google Scholar 

  • Casanova JE, Mishumi Y, Ikehara Y, Hubbard AL, Mostov KE (1991) Direct apical sorting of rat liver dipeptidylpeptidase IV expressed in Madin-Darby canine kidney cells. J Biol Chem 266:24428–24432

    CAS  PubMed  Google Scholar 

  • Chen G, Howe AG, Xu G, Frohlich O, Klein JD, Sands JM (2011) Mature N-linked glycans facilitate UT-A1 urea transporter lipid raft compartmentalization. FASEB J 25:4531–4539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng CL, Glover G, Banker G, Amara SG (2002) A novel sorting motif in the glutamate transporter excitatory amino acid transporter 3 directs its targeting in Madin-Darby canine kidney cells and hippocampal neurons. J Neurosci 22:10643–10652

    CAS  PubMed  Google Scholar 

  • Chicka MC, Strehler EE (2003) Alternative splicing of the first intracellular loop of plasma membrane Ca2 + −ATPase isoform 2 alters its membrane targeting. J Biol Chem 278:18464–18470

    Article  CAS  PubMed  Google Scholar 

  • Clemens Grisham R, Kindt K, Finger-Baier K, Schmid B, Nicolson T (2013) Mutations in ap1b1 cause mistargeting of the Na+/K+-ATPase pump in sensory hair cells. PLoS ONE 8, e60866

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cresawn KO, Potter BA, Oztan A, Guerriero CJ, Ihrke G, Goldenring JR, Apodaca G, Weisz OA (2007) Differential involvement of endocytic compartments in the biosynthetic traffic of apical proteins. EMBO J 26:3737–3748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dehmelt L, Bastiaens PI (2010) Spatial organization of intracellular communication: insights from imaging. Nat Rev 11:440–452

    Article  CAS  Google Scholar 

  • Delacour D, Cramm-Behrens CI, Drobecq H, Le Bivic A, Naim HY, Jacob R (2006) Requirement for galectin-3 in apical protein sorting. Curr Biol 16:408–414

    Article  CAS  PubMed  Google Scholar 

  • Delacour D, Gouyer V, Zanetta JP, Drobecq H, Leteurtre E, Grard G, Moreau-Hannedouche O, Maes E, Pons A, Andre S, Le Bivic A, Gabius HJ, Manninen A, Simons K, Huet G (2005) Galectin-4 and sulfatides in apical membrane trafficking in enterocyte-like cells. J Cell Biol 169:491–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delacour D, Greb C, Koch A, Salomonsson E, Leffler H, Le Bivic A, Jacob R (2007) Apical sorting by galectin-3-dependent glycoprotein clustering. Traffic 8:379–388

    Article  CAS  PubMed  Google Scholar 

  • Delacour D, Koch A, Jacob R (2009) The role of galectins in protein trafficking. Traffic 10:1405–1413

    Article  CAS  PubMed  Google Scholar 

  • Dell’Angelica EC, Mullins C, Bonifacino JS (1999) AP-4, a novel protein complex related to clathrin adaptors. J Biol Chem 274:7278–7285

    Article  PubMed  Google Scholar 

  • Deora AA, Gravotta D, Kreitzer G, Hu J, Bok D, Rodriguez-Boulan E (2004) The basolateral targeting signal of CD147 (EMMPRIN) consists of a single leucine and is not recognized by retinal pigment epithelium. Mol Biol Cell 15:4148–4165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Distel B, Bauer U, Le Borgne R, Hoflack B (1998) Basolateral sorting of the cation-dependent mannose 6-phosphate receptor in Madin-Darby canine kidney cells. Identification of a basolateral determinant unrelated to clathrin-coated pit localization signals. J Biol Chem 273:186–193

    Article  CAS  PubMed  Google Scholar 

  • Donoso M, Cancino J, Lee J, van Kerkhof P, Retamal C, Bu G, Gonzalez A, Caceres A, Marzolo MP (2009) Polarized traffic of LRP1 involves AP1B and SNX17 operating on Y-dependent sorting motifs in different pathways. Mol Biol Cell 20:481–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doray B, Ghosh P, Griffith J, Geuze HJ, Kornfeld S (2002) Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network. Science 297:1700–1703

    Article  CAS  PubMed  Google Scholar 

  • Doray B, Lee I, Knisely J, Bu G, Kornfeld S (2007) The gamma/sigma1 and alpha/sigma2 hemicomplexes of clathrin adaptors AP-1 and AP-2 harbor the dileucine recognition site. Mol Biol Cell 18:1887–1896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duffield A, Fölsch H, Mellman I, Caplan MJ (2004) Sorting of H,K-ATPase beta-subunit in MDCK and LLC-PK cells is independent of mu1B adaptin expression. Traffic 5:449–461

    Article  CAS  PubMed  Google Scholar 

  • Dunbar LA, Aronson P, Caplan MJ (2000) A transmembrane segment determines the steady-state localization of an ion-transporting adenosine triphosphatase. J Cell Biol 148:769–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emi Y, Yasuda Y, Sakaguchi M (2012) A cis-acting five-amino-acid motif controls targeting of ABCC2 to the apical plasma membrane domain. J Cell Sci 125:3133–3143

    Article  CAS  PubMed  Google Scholar 

  • Fang L, Garuti R, Kim BY, Wade JB, Welling PA (2009) The ARH adaptor protein regulates endocytosis of the ROMK potassium secretory channel in mouse kidney. J Clin Invest 119:3278–3289

    CAS  PubMed  PubMed Central  Google Scholar 

  • Farr GA, Hull M, Mellman I, Caplan MJ (2009) Membrane proteins follow multiple pathways to the basolateral cell surface in polarized epithelial cells. J Cell Biol 186:269–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fields IC, King SM, Shteyn E, Kang RS, Fölsch H (2010) Phosphatidylinositol 3,4,5-trisphosphate localization in recycling endosomes is necessary for AP-1B-dependent sorting in polarized epithelial cells. Mol Biol Cell 21:95–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fields IC, Shteyn E, Pypaert M, Proux-Gillardeaux V, Kang RS, Galli T, Fölsch H (2007) v-SNARE cellubrevin is required for basolateral sorting of AP-1B-dependent cargo in polarized epithelial cells. J Cell Biol 177:477–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fölsch H (2008) Regulation of membrane trafficking in polarized epithelial cells. Curr Opin Cell Biol 20:208–213

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Fölsch H, Mattila PE, Weisz OA (2009) Taking the scenic route: biosynthetic traffic to the plasma membrane in polarized epithelial cells. Traffic 10:972–981

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Fölsch H, Ohno H, Bonifacino JS, Mellman I (1999) A novel clathrin adaptor complex mediates basolateral targeting in polarized epithelial cells. Cell 99:189–198

    Article  PubMed  Google Scholar 

  • Fölsch H, Pypaert M, Maday S, Pelletier L, Mellman I (2003) The AP-1A and AP-1B clathrin adaptor complexes define biochemically and functionally distinct membrane domains. J Cell Biol 163:351–362

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Fölsch H, Pypaert M, Schu P, Mellman I (2001) Distribution and function of AP-1 clathrin adaptor complexes in polarized epithelial cells. J Cell Biol 152:595–606

    Article  PubMed  PubMed Central  Google Scholar 

  • Francis SS, Sfakianos J, Lo B, Mellman I (2011) A hierarchy of signals regulates entry of membrane proteins into the ciliary membrane domain in epithelial cells. J Cell Biol 193:219–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fry AC, Su Y, Yiu V, Cuthbert AW, Trachtman H, Frankl FEK (2012) Mutation conferring apical-targeting motif on AE1 exchanger causes autosomal dominant distal RTA. J Am Soc Nephrol 23:1238–1249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galli T, Zahraoui A, Vaidyanathan VV, Raposo G, Tian JM, Karin M, Niemann H, Louvard D (1998) A novel tetanus neurotoxin-insensitive vesicle-associated membrane protein in SNARE complexes of the apical plasma membrane of epithelial cells. Mol Biol Cell 9:1437–1448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gan Y, McGraw TE, Rodriguez-Boulan E (2002) The epithelial-specific adaptor AP1B mediates post-endocytic recycling to the basolateral membrane. Nat Cell Biol 4:605–609

    CAS  PubMed  Google Scholar 

  • Gephart JD, Singh B, Higginbotham JN, Franklin JL, Gonzalez A, Fölsch H, Coffey RJ (2011) Identification of a novel mono-leucine basolateral sorting motif within the cytoplasmic domain of amphiregulin. Traffic 12:1793–1804

    Article  CAS  PubMed  Google Scholar 

  • Gravotta D, Deora A, Perret E, Oyanadel C, Soza A, Schreiner R, Gonzalez A, Rodriguez-Boulan E (2007) AP1B sorts basolateral proteins in recycling and biosynthetic routes of MDCK cells. Proc Natl Acad Sci USA 104:1564–1569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grindstaff KK, Yeaman C, Anandasabapathy N, Hsu SC, Rodriguez-Boulan E, Scheller RH, Nelson WJ (1998) Sec6/8 complex is recruited to cell-cell contacts and specifies transport vesicle delivery to the basal-lateral membrane in epithelial cells. Cell 93:731–740

    Article  CAS  PubMed  Google Scholar 

  • Guerriero CJ, Lai Y, Weisz OA (2008) Differential sorting and Golgi export requirements for raft-associated and raft-independent apical proteins along the biosynthetic pathway. J Biol Chem 283:18040–18047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hill WG, Butterworth MB, Wang H, Edinger RS, Lebowitz J, Peters KW, Frizzell RA, Johnson JP (2007) The epithelial sodium channel (ENaC) traffics to apical membrane in lipid rafts in mouse cortical collecting duct cells. J Biol Chem 282:37402–37411

    Article  CAS  PubMed  Google Scholar 

  • Hirst J, Robinson MS (1998) Clathrin and adaptors. Biochim Biophys Acta 1404:173–193

    Article  CAS  PubMed  Google Scholar 

  • Hu Q, Milenkovic L, Jin H, Scott MP, Nachury MV, Spiliotis ET, Nelson WJ (2010) A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution. Science 329:436–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hunziker W, Harter C, Matter K, Mellman I (1991) Basolateral sorting in MDCK cells requires a distinct cytoplasmic domain determinant. Cell 66:907–920

    Article  CAS  PubMed  Google Scholar 

  • Imjeti NS, Lebreton S, Paladino S, de la Fuente E, Gonzalez A, Zurzolo C (2011) N-Glycosylation instead of cholesterol mediates oligomerization and apical sorting of GPI-APs in FRT cells. Mol Biol Cell 22:4621–4634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ito M, Sakurai A, Hayashi K, Ohi A, Kangawa N, Nishiyama T, Sugino S, Uehata Y, Kamahara A, Sakata M, Tatsumi S, Kuwahata M, Taketani Y, Segawa H, Miyamoto K (2010) An apical expression signal of the renal type IIc Na + −dependent phosphate cotransporter in renal epithelial cells. Am J Physiol Renal Physiol 299:F243–F254

    Article  CAS  PubMed  Google Scholar 

  • Jacob R, Naim HY (2001) Apical membrane proteins are transported in distinct vesicular carriers. Curr Biol 11:1444–1450

    Article  CAS  PubMed  Google Scholar 

  • Janvier K, Kato Y, Boehm M, Rose JR, Martina JA, Kim BY, Venkatesan S, Bonifacino JS (2003) Recognition of dileucine-based sorting signals from HIV-1 Nef and LIMP-II by the AP-1 gamma-sigma1 and AP-3 delta-sigma3 hemicomplexes. J Cell Biol 163:1281–1290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Junking M, Sawasdee N, Duangtum N, Cheunsuchon B, Limjindaporn T, Yenchitsomanus PT (2014) Role of adaptor proteins and clathrin in the trafficking of human kidney anion exchanger 1 (kAE1) to the cell surface. Traffic 15:788–802

    Article  CAS  PubMed  Google Scholar 

  • Kang RS, Fölsch H (2011) ARH cooperates with AP-1B in the exocytosis of LDLR in polarized epithelial cells. J Cell Biol 193:51–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kinlough CL, Poland PA, Gendler SJ, Mattila PE, Mo D, Weisz OA, Hughey RP (2011) Core-glycosylated mucin-like repeats from MUC1 are an apical targeting signal. J Biol Chem 286:39072–39081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kirchhausen T (2002) Single-handed recognition of a sorting traffic motif by the GGA proteins. Nat Struct Biol 9:241–244

    Article  CAS  PubMed  Google Scholar 

  • Kizhatil K, Yoon W, Mohler PJ, Davis LH, Hoffman JA, Bennett V (2007) Ankyrin-G and beta2-spectrin collaborate in biogenesis of lateral membrane of human bronchial epithelial cells. J Biol Chem 282:2029–2037

    Article  CAS  PubMed  Google Scholar 

  • Kwon SH, Guggino WB (2004) Multiple sequences in the C terminus of MaxiK channels are involved in expression, movement to the cell surface, and apical localization. Proc Natl Acad Sci USA 101:15237–15242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lapierre LA, Dorn MC, Zimmerman CF, Navarre J, Burnette JO, Goldenring JR (2003) Rab11b resides in a vesicular compartment distinct from Rab11a in parietal cells and other epithelial cells. Exp Cell Res 290:322–331

    Article  CAS  PubMed  Google Scholar 

  • Lauffer BE, Melero C, Temkin P, Lei C, Hong W, Kortemme T, von Zastrow M (2010) SNX27 mediates PDZ-directed sorting from endosomes to the plasma membrane. J Cell Biol 190:565–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le Bivic A, Quaroni A, Nichols B, Rodriguez-Boulan E (1990) Biogenetic pathways of plasma membrane proteins in Caco-2, a human intestinal epithelial cell line. J Cell Biol 111:1351–1361

    Article  PubMed  Google Scholar 

  • Le Maout S, Welling PA, Brejon M, Olsen O, Merot J (2001) Basolateral membrane expression of a K+ channel, Kir 2.3, is directed by a cytoplasmic COOH-terminal domain. Proc Natl Acad Sci USA 98:10475–10480

    Article  PubMed  PubMed Central  Google Scholar 

  • Lerner M, Lemke D, Bertram H, Schillers H, Oberleithner H, Caplan MJ, Reinhardt J (2006) An extracellular loop of the human non-gastric H, K-ATPase alpha-subunit is involved in apical plasma membrane polarization. Cell Physiol Biochem 18:75–84

    Article  CAS  PubMed  Google Scholar 

  • Li C, Franklin JL, Graves-Deal R, Jerome WG, Cao Z, Coffey RJ (2004) Myristoylated Naked2 escorts transforming growth factor alpha to the basolateral plasma membrane of polarized epithelial cells. Proc Natl Acad Sci USA 101:5571–5576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li C, Hao M, Cao Z, Ding W, Graves-Deal R, Hu J, Piston DW, Coffey RJ (2007) Naked2 acts as a cargo recognition and targeting protein to ensure proper delivery and fusion of TGF-alpha containing exocytic vesicles at the lower lateral membrane of polarized MDCK cells. Mol Biol Cell 18:3081–3093

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Li L, Omata W, Kojima I, Shibata H (2001) Direct interaction of Rab4 with syntaxin 4. J Biol Chem 276:5265–5273

    Article  CAS  PubMed  Google Scholar 

  • Ling K, Bairstow SF, Carbonara C, Turbin DA, Huntsman DG, Anderson RA (2007) Type Igamma phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with mu1B adaptin. J Cell Biol 176:343–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lisanti MP, Caras IW, Davitz MA, Rodriguez-Boulan E (1989) A glycophospholipid membrane anchor acts as an apical targeting signal in polarized epithelial cells. J Cell Biol 109:2145–2156

    Article  CAS  PubMed  Google Scholar 

  • Maday S, Anderson E, Chang HC, Shorter J, Satoh A, Sfakianos J, Fölsch H, Anderson JM, Walther Z, Mellman I (2008) A PDZ-binding motif controls basolateral targeting of syndecan-1 along the biosynthetic pathway in polarized epithelial cells. Traffic 9:1915–1924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madrid R, Le Maout S, Barrault MB, Janvier K, Benichou S, Merot J (2001) Polarized trafficking and surface expression of the AQP4 water channel are coordinated by serial and regulated interactions with different clathrin-adaptor complexes. EMBO J 20:7008–7021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marrs JA, Andersson-Fisone C, Jeong MC, Cohen-Gould L, Zurzolo C, Nabi IR, Rodriguez-Boulan E, Nelson WJ (1995) Plasticity in epithelial cell phenotype: modulation by expression of different cadherin cell adhesion molecules. J Cell Biol 129:507–519

    Article  CAS  PubMed  Google Scholar 

  • Matter K, Brauchbar M, Bucher K, Hauri HP (1990) Sorting of endogenous plasma membrane proteins occurs from two sites in cultured human intestinal epithelial cells (Caco-2). Cell 60:429–437

    Article  CAS  PubMed  Google Scholar 

  • Matter K, Whitney JA, Yamamoto EM, Mellman I (1993) Common signals control low density lipoprotein receptor sorting in endosomes and the Golgi complex of MDCK cells. Cell 74:1053–1064

    Article  CAS  PubMed  Google Scholar 

  • Mattera R, Boehm M, Chaudhuri R, Prabhu Y, Bonifacino JS (2011) Conservation and diversification of dileucine signal recognition by adaptor protein (AP) complex variants. J Biol Chem 286:2022–2030

    Article  CAS  PubMed  Google Scholar 

  • Mattila PE, Raghavan V, Rbaibi Y, Baty CJ, Weisz OA (2014) Rab11a-positive compartments in proximal tubule cells sort fluid-phase and membrane cargo. Am J Physiol Cell Physiol 306:C441–C449

    Article  CAS  PubMed  Google Scholar 

  • Mattila PE, Youker RT, Mo D, Bruns JR, Cresawn KO, Hughey RP, Ihrke G, Weisz OA (2012) Multiple biosynthetic trafficking routes for apically secreted proteins in MDCK cells. Traffic 13:433–442

    Article  CAS  PubMed  Google Scholar 

  • Milewski MI, Forrest JK, Mickle JE, Stanton B, Cutting GR (2000) The role of PDZ-binding motif in polarized distribution of CFTR and other apical or basolateral membrane proteins. Am J Hum Genet 67:198–198

    Google Scholar 

  • Mishra R, Grzybek M, Niki T, Hirashima M, Simons K (2010) Galectin-9 trafficking regulates apical-basal polarity in Madin-Darby canine kidney epithelial cells. Proc Natl Acad Sci USA 107:17633–17638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mo D, Costa SA, Ihrke G, Youker RT, Pastor-Soler N, Hughey RP, Weisz OA (2012) Sialylation of N-linked glycans mediates apical delivery of endolyn in MDCK cells via a galectin-9-dependent mechanism. Mol Biol Cell 23:3636–3646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mohrmann K, Leijendekker R, Gerez L, van Der Sluijs P (2002) rab4 regulates transport to the apical plasma membrane in Madin-Darby canine kidney cells. J Biol Chem 277:10474–10481

    Article  CAS  PubMed  Google Scholar 

  • Mostov K, Su T, ter Beest M (2003) Polarized epithelial membrane traffic: conservation and plasticity. Nat Cell Biol 5:287–293

    Article  CAS  PubMed  Google Scholar 

  • Moyer BD, Denton J, Karlson KH, Reynolds D, Wang S, Mickle JE, Milewski M, Cutting GR, Guggino WB, Li M, Stanton BA (1999) A PDZ-interacting domain in CFTR is an apical membrane polarization signal. J Clin Invest 104:1353–1361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muniz M, Zurzolo C (2014) Sorting of GPI-anchored proteins from yeast to mammals - common pathways at different sites? J Cell Sci 127:2793–2801

    Article  CAS  PubMed  Google Scholar 

  • Muth TR, Gottardi CJ, Roush DL, Caplan MJ (1998) A basolateral sorting signal is encoded in the alpha-subunit of Na-K-ATPase. Am J Physiol Cell Physiol 274:C688–C696

    CAS  Google Scholar 

  • Nabi IR, Le Bivic A, Fambrough D, Rodriguez-Boulan E (1991) An endogenous MDCK lysosomal membrane glycoprotein is targeted basolaterally before delivery to lysosomes. J Cell Biol 115:1573–1584

    Article  CAS  PubMed  Google Scholar 

  • Nies AT, Konig J, Cui YH, Brom M, Spring H, Keppler D (2002) Structural requirements for the apical sorting of human multidrug resistance protein 2 (ABCC2). Eur J Biochem 269:1866–1876

    Article  CAS  PubMed  Google Scholar 

  • Nokes RL, Fields IC, Collins RN, Fölsch H (2008) Rab13 regulates membrane trafficking between TGN and recycling endosomes in polarized epithelial cells. J Cell Biol 182:845–853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohno H, Tomemori T, Nakatsu F, Okazaki Y, Aguilar RC, Fölsch H, Mellman I, Saito T, Shirasawa T, Bonifacino JS (1999) Mu1B, a novel adaptor medium chain expressed in polarized epithelial cells. FEBS Lett 449:215–220

    Article  CAS  PubMed  Google Scholar 

  • Olsen O, Liu H, Wade JB, Merot J, Welling PA (2002) Basolateral membrane expression of the Kir 2.3 channel is coordinated by PDZ interaction with Lin-7/CASK complex. Am J Physiol Cell Physiol 282:C183–C195

    Article  CAS  PubMed  Google Scholar 

  • Ozaslan D, Wang S, Ahmed BA, Kocabas AM, McCastlain JC, Bene A, Kilic F (2003) Glycosyl modification facilitates homo- and hetero-oligomerization of the serotonin transporter. A specific role for sialic acid residues. J Biol Chem 278:43991–44000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paladino S, Lebreton S, Tivodar S, Campana V, Tempre R, Zurzolo C (2008) Different GPI-attachment signals affect the oligomerisation of GPI-anchored proteins and their apical sorting. J Cell Sci 121:4001–4007

    Article  CAS  PubMed  Google Scholar 

  • Paladino S, Sarnataro D, Pillich R, Tivodar S, Nitsch L, Zurzolo C (2004) Protein oligomerization modulates raft partitioning and apical sorting of GPI-anchored proteins. J Cell Biol 167:699–709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perego C, Vanoni C, Massari S, Longhi R, Pietrini G (2000) Mammalian LIN-7 PDZ proteins associate with beta-catenin at the cell-cell junctions of epithelia and neurons. EMBO J 19:3978–3989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perego C, Vanoni C, Villa A, Longhi R, Kaech SM, Frohli E, Hajnal A, Kim SK, Pietrini G (1999) PDZ-mediated interactions retain the epithelial GABA transporter on the basolateral surface of polarized epithelial cells. EMBO J 18:2384–2393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pocard T, Le Bivic A, Galli T, Zurzolo C (2007) Distinct v-SNAREs regulate direct and indirect apical delivery in polarized epithelial cells. J Cell Sci 120:3309–3320

    Article  CAS  PubMed  Google Scholar 

  • Potter BA, Hughey RP, Weisz OA (2006a) Role of N- and O-glycans in polarized biosynthetic sorting. Am J Physiol Cell Physiol 290:C1–C10

    Article  CAS  PubMed  Google Scholar 

  • Potter BA, Weixel KM, Bruns JR, Ihrke G, Weisz OA (2006b) N-glycans mediate apical recycling of the sialomucin endolyn in polarized MDCK cells. Traffic 7:146–154

    Article  CAS  PubMed  Google Scholar 

  • Rai T, Sasaki S, Uchida S (2006) Polarized trafficking of the aquaporin-3 water channel is mediated by an NH2-terminal sorting signal. Am J Physiol Cell Physiol 290:C298–C304

    Article  CAS  PubMed  Google Scholar 

  • Reales E, Sharma N, Low SH, Fölsch H, Weimbs T (2011) Basolateral sorting of syntaxin 4 is dependent on its N-terminal domain and the AP1B clathrin adaptor, and required for the epithelial cell polarity. PLoS ONE 6, e21181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riquier AD, Lee DH, McDonough AA (2009) Renal NHE3 and NaPi2 partition into distinct membrane domains. Am J Physiol Cell Physiol 296:C900–C910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodriguez-Boulan E, Kreitzer G, Musch A (2005) Organization of vesicular trafficking in epithelia. Nat Rev 6:233–247

    Article  CAS  Google Scholar 

  • Rodriguez-Boulan E, Perez-Bay A, Schreiner R, Gravotta D (2013) Response: the “tail” of the twin adaptors. Dev Cell 27:247–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roush DL, Gottardi CJ, Naim HY, Roth MG, Caplan MJ (1998) Tyrosine-based membrane protein sorting signals are differentially interpreted by polarized Madin-Darby canine kidney and LLC-PK1 epithelial cells. J Biol Chem 273:26862–26869

    Article  CAS  PubMed  Google Scholar 

  • Ryan S, Verghese S, Cianciola NL, Cotton CU, Carlin CR (2010) Autosomal recessive polycystic kidney disease epithelial cell model reveals multiple basolateral epidermal growth factor receptor sorting pathways. Mol Biol Cell 21:2732–2745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sai Y, Nies AT, Arias IM (1999) Bile acid secretion and direct targeting of mdr1-green fluorescent protein from Golgi to the canalicular membrane in polarized WIF-B cells. J Cell Sci 112:4535–4545

    CAS  PubMed  Google Scholar 

  • Schreiner R, Frindt G, Diaz F, Carvajal-Gonzalez JM, Perez Bay AE, Palmer LG, Marshansky V, Brown D, Philp NJ, Rodriguez-Boulan E (2010) The absence of a clathrin adapter confers unique polarity essential to proximal tubule function. Kidney Int 78:382–388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheff DR, Kroschewski R, Mellman I (2002) Actin dependence of polarized receptor recycling in Madin-Darby canine kidney cell endosomes. Mol Biol Cell 13:262–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shoshani L, Contreras RG, Roldan ML, Moreno J, Lazaro A, Balda MS, Matter K, Cereijido M (2005) The polarized expression of Na+, K + −ATPase in epithelia depends on the association between beta-subunits located in neighboring cells. Mol Biol Cell 16:1071–1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shteyn E, Pigati L, Fölsch H (2011) Arf6 regulates AP-1B-dependent sorting in polarized epithelial cells. J Cell Biol 194:873–887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silvis MR, Bertrand CA, Ameen N, Golin-Bisello F, Butterworth MB, Frizzell RA, Bradbury NA (2009) Rab11b regulates the apical recycling of the cystic fibrosis transmembrane conductance regulator in polarized intestinal epithelial cells. Mol Biol Cell 20:2337–2350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387:569–572

    Article  CAS  PubMed  Google Scholar 

  • Stechly L, Morelle W, Dessein AF, Andre S, Grard G, Trinel D, Dejonghe MJ, Leteurtre E, Drobecq H, Trugnan G, Gabius HJ, Huet G (2009) Galectin-4-regulated delivery of glycoproteins to the brush border membrane of enterocyte-like cells. Traffic 10:438–450

    Article  CAS  PubMed  Google Scholar 

  • Stiegler AL, Zhang R, Liu W, Boggon TJ (2014) Structural determinants for binding of sorting nexin 17 (SNX17) to the cytoplasmic adaptor protein Krev interaction trapped 1 (KRIT1). J Biol Chem 289:25362–25373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Straube T, von Mach T, Honig E, Greb C, Schneider D, Jacob R (2013) pH-dependent recycling of galectin-3 at the apical membrane of epithelial cells. Traffic 14:1014–1027

    Article  CAS  PubMed  Google Scholar 

  • Subramanian VS, Marchant JS, Boulware MJ, Ma TY, Said HM (2009) Membrane targeting and intracellular trafficking of the human sodium-dependent multivitamin transporter in polarized epithelial cells. Am J Physiol Cell Physiol 296:C663–C671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Subramanian VS, Marchant JS, Boulware MJ, Said HM (2004) A C-terminal region dictates the apical plasma membrane targeting of the human sodium-dependent vitamin C transporter-1 in polarized epithelia. J Biol Chem 279:27719–27728

    Article  CAS  PubMed  Google Scholar 

  • Sugimoto H, Sugahara M, Fölsch H, Koide Y, Nakatsu F, Tanaka N, Nishimura T, Furukawa M, Mullins C, Nakamura N, Mellman I, Ohno H (2002) Differential recognition of tyrosine-based basolateral signals by AP-1B subunit mu1B in polarized epithelial cells. Mol Biol Cell 13:2374–2382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun AQ, Salkar R, Sachchidanand S, Xu L, Zeng MMZ, Suchy FJ (2003) A 14-amino acid sequence with a beta-turn structure is required for apical membrane sorting of the rat ileal bile acid transporter. J Biol Chem 278:4000–4009

    Article  CAS  PubMed  Google Scholar 

  • Torres J, Funk HM, Zegers MM, ter Beest MB (2011) The syntaxin 4 N terminus regulates its basolateral targeting by munc18c-dependent and -independent mechanisms. J Biol Chem 286:10834–10846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toye AM, Banting G, Tanner MJ (2004) Regions of human kidney anion exchanger 1 (kAE1) required for basolateral targeting of kAE1 in polarised kidney cells: mis-targeting explains dominant renal tubular acidosis (dRTA). J Cell Sci 117:1399–1410

    Article  CAS  PubMed  Google Scholar 

  • Traub LM (2003) Sorting it out: AP-2 and alternate clathrin adaptors in endocytic cargo selection. J Cell Biol 163:203–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vagin O, Turdikulova S, Sachs G (2005) Recombinant addition of N-glycosylation sites to the basolateral Na, K-ATPase beta1 subunit results in its clustering in caveolae and apical sorting in HGT-1 cells. J Biol Chem 280:43159–43167

    Article  CAS  PubMed  Google Scholar 

  • van de Graaf SF, Hoenderop JG, van der Kemp AW, Gisler SM, Bindels RJ (2006) Interaction of the epithelial Ca2+ channels TRPV5 and TRPV6 with the intestine- and kidney-enriched PDZ protein NHERF4. Pflugers Arch - Eur J Physiol 452:407–417

    Article  CAS  Google Scholar 

  • van Hoek AN, Ma T, Yang B, Verkman AS, Brown D (2000) Aquaporin-4 is expressed in basolateral membranes of proximal tubule S3 segments in mouse kidney. Am J Physiol Renal Physiol 278:F310–F316

    PubMed  Google Scholar 

  • Weisz OA, Rodriguez-Boulan E (2009) Apical trafficking in epithelial cells: signals, clusters and motors. J Cell Sci 122:4253–4266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yeaman C, Grindstaff KK, Wright JR, Nelson WJ (2001) Sec6/8 complexes on trans-Golgi network and plasma membrane regulate late stages of exocytosis in mammalian cells. J Cell Biol 155:593–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yeaman C, Le Gall AH, Baldwin AN, Monlauzeur L, Le Bivic A, Rodriguez-Boulan E (1997) The O-glycosylated stalk domain is required for apical sorting of neurotrophin receptors in polarized MDCK cells. J Cell Biol 139:929–940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoo D, Flagg TP, Olsen O, Raghuram V, Foskett JK, Welling PA (2004) Assembly and trafficking of a multiprotein ROMK (Kir 1.1) channel complex by PDZ interactions. J Biol Chem 279:6863–6873

    Article  CAS  PubMed  Google Scholar 

  • Youker RT, Bruns JR, Costa SA, Rbaibi Y, Lanni F, Kashlan OB, Teng H, Weisz OA (2013) Multiple motifs regulate apical sorting of p75 via a mechanism that involves dimerization and higher-order oligomerization. Mol Biol Cell 24:1996–2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We apologize to colleagues whose work we could not cite due to space constraints. Work in the Weisz lab is supported by NIH R01 DK100357, and work in the Fölsch lab is supported by NIH R01 GM0707036.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Heike Fölsch .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 American Physiological Society

About this chapter

Cite this chapter

Weisz, O.A., Fölsch, H. (2016). Molecular Mechanisms of Apical and Basolateral Sorting in Polarized Epithelial Cells. In: Hamilton, K., Devor, D. (eds) Ion Channels and Transporters of Epithelia in Health and Disease. Physiology in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3366-2_7

Download citation

Publish with us

Policies and ethics