Cellular and Molecular Life Sciences

, Volume 69, Issue 11, pp 1755–1771

The role of endocytosis in activating and regulating signal transduction

Review

Abstract

Endocytosis is increasingly understood to play crucial roles in most signaling pathways, from determining which signaling components are activated, to how the signal is subsequently transduced and/or terminated. Whether a receptor-ligand complex is internalized via a clathrin-dependent or clathrin-independent endocytic route, and the complexes’ subsequent trafficking through specific endocytic compartments, to then be recycled or degraded, has profound effects on signaling output. This review discusses the roles of endocytosis in three markedly different signaling pathways: the Wnt, Notch, and Eph/Ephrin pathways. These offer fundamentally different signaling systems: (1) diffusible ligands inducing signaling in one cell, (2) membrane-tethered ligands inducing signaling in a contacting receptor cell, and (3) bi-directional receptor-ligand signaling in two contacting cells. In each of these systems, endocytosis controls signaling in fascinating ways, and comparison of their similarities and dissimilarities will help to expand our understanding of endocytic control of signal transduction across multiple signaling pathways.

Keywords

Endocytosis Clathrin Dynamin Caveolin Primary cilium Signaling Wnt Notch Eph Ephrin EGF 

Abbreviations

ADAM

A disintegrin and metallo-protease

AP1/2

Adaptor protein one or two

Arf

ADP-ribosylation factor

Arp2/3

Actin-related protein 2/3

Cav1/2

Caveolin one or two

CCP

Clathrin-coated pit

CCV

Clathrin-coated vesicle

CDR

Circular dorsal ruffles (also known as waves)

CE

Convergent extension

CLASP

Clathrin-associated sorting proteins

CLIC-GEEC

Clathrin-independent carrier/GPI-anchored protein-enriched early endosomal compartment

CME

Clathrin-mediated endocytosis

CSL

CBF1/Suppressor of Hairless/LAG-1

Dll1/3/4

Delta-like one, three or four (Notch ligands)

Dsh/Dvl

Disheveled

EEA1

Early endosomal antigen one

EGF

Epidermal growth factor

EGFR

Epidermal growth factor receptor

Fc

Fragment crystallizable region (tail region of antibody)

Flot1/2

Flotillin one or two

GPI

Glycosylphosphatidylinositol

GTPase

Guanosine triphosphate hydrolase enzyme

Hek cells

Human embryonic kidney cells

HeLa cells

Cervical cancer cells from Henrietta Lacks

HGF

Hepatocyte growth factor

Jag1/2

Jagged one or two (Notch ligands)

LacZ

Beta-d-galactosidase

LDL

Low-denstity lipoprotein

Lef1

Lymphoid enhancer-binding factor 1

Lqf

Liquid facets (Drosophila epsin homolog)

NECD

Notch extracellular domain

NEXT

Notch extracellular truncation

NICD

Notch intracellular domain

N-WASP

Neural Wiskott-Aldrich syndrome protein (aka WASL, Wiskott-Aldrich syndrome-like)

PCP

Planar cell polarity

PDGF

Platelet-derived growth factor

PKC

Protein kinase C

PM

Plasma membrane

Ptc

Patched (Shh receptor)

Rab11

Rab-protein 11

Rac1

RAS-related C3 botulinum substrate 1

Rin1

Ras and Rab interactor one

Ror1/2

Receptor tyrosine kinase-like orphan receptor one or two

Ryk

Receptor-like tyrosine kinase

Shh

Sonic hedgehog

TCF

T-cell factor

TGF-β

Transforming growth factor beta

Vav2

Vav 2 guanine nucleotide exchange factor

References

  1. 1.
    Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902PubMedGoogle Scholar
  2. 2.
    Vieira AV, Lamaze C, Schmid SL (1996) Control of EGF receptor signaling by clathrin-mediated endocytosis. Science 274:2086–2089PubMedGoogle Scholar
  3. 3.
    Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P, Di Fiore PP, Polo S (2005) Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci USA 102:2760–2765PubMedGoogle Scholar
  4. 4.
    Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC et al (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449–2452PubMedGoogle Scholar
  5. 5.
    Galbiati F, Engelman JA, Volonte D, Zhang XL, Minetti C, Li M, Hou H Jr, Kneitz B, Edelmann W, Lisanti MP (2001) Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and t-tubule abnormalities. J Biol Chem 276:21425–21433PubMedGoogle Scholar
  6. 6.
    Hagiwara Y, Sasaoka T, Araishi K, Imamura M, Yorifuji H, Nonaka I, Ozawa E, Kikuchi T (2000) Caveolin-3 deficiency causes muscle degeneration in mice. Hum Mol Genet 9:3047–3054PubMedGoogle Scholar
  7. 7.
    Razani B, Engelman JA, Wang XB, Schubert W, Zhang XL, Marks CB, Macaluso F, Russell RG, Li M, Pestell RG et al (2001) Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J Biol Chem 276:38121–38138PubMedGoogle Scholar
  8. 8.
    Razani B, Wang XB, Engelman JA, Battista M, Lagaud G, Zhang XL, Kneitz B, Hou H Jr, Christ GJ, Edelmann W et al (2002) Caveolin-2-deficient mice show evidence of severe pulmonary dysfunction without disruption of caveolae. Mol Cell Biol 22:2329–2344PubMedGoogle Scholar
  9. 9.
    Mattsson CL, Andersson ER, Nedergaard J (2010) Differential involvement of caveolin-1 in brown adipocyte signaling: impaired beta3-adrenergic, but unaffected LPA, PDGF and EGF receptor signaling. Biochim Biophys Acta 1803:983–989PubMedGoogle Scholar
  10. 10.
    Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL (2003) Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol 5:410–421PubMedGoogle Scholar
  11. 11.
    Pearse BM (1976) Clathrin: a unique protein associated with intracellular transfer of membrane by coated vesicles. Proc Natl Acad Sci USA 73:1255–1259PubMedGoogle Scholar
  12. 12.
    Kirchhausen T (2000) Clathrin. Annu Rev Biochem 69:699–727PubMedGoogle Scholar
  13. 13.
    Reider A, Wendland B (2011) Endocytic adaptors-social networking at the plasma membrane. J Cell Sci 124:1613–1622PubMedGoogle Scholar
  14. 14.
    Pearse BM, Robinson MS (1984) Purification and properties of 100-kd proteins from coated vesicles and their reconstitution with clathrin. EMBO J 3:1951–1957PubMedGoogle Scholar
  15. 15.
    Chen H, Fre S, Slepnev VI, Capua MR, Takei K, Butler MH, Di Fiore PP, De Camilli P (1998) Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis. Nature 394:793–797PubMedGoogle Scholar
  16. 16.
    Itoh T, Koshiba S, Kigawa T, Kikuchi A, Yokoyama S, Takenawa T (2001) Role of the ENTH domain in phosphatidylinositol-4, 5-bisphosphate binding and endocytosis. Science 291:1047–1051PubMedGoogle Scholar
  17. 17.
    Overstreet E, Fitch E, Fischer JA (2004) Fat facets and liquid facets promote delta endocytosis and delta signaling in the signaling cells. Development 131:5355–5366PubMedGoogle Scholar
  18. 18.
    Gurevich EV, Gurevich VV (2006) Arrestins: ubiquitous regulators of cellular signaling pathways. Genome Biol 7:236PubMedGoogle Scholar
  19. 19.
    Dho SE, French MB, Woods SA, McGlade CJ (1999) Characterization of four mammalian Numb protein isoforms. Identification of cytoplasmic and membrane-associated variants of the phosphotyrosine binding domain. J Biol Chem 274:33097–33104PubMedGoogle Scholar
  20. 20.
    Santolini E, Puri C, Salcini AE, Gagliani MC, Pelicci PG, Tacchetti C, Di Fiore PP (2000) Numb is an endocytic protein. J Cell Biol 151:1345–1352PubMedGoogle Scholar
  21. 21.
    Ghossoub R, Molla-Herman A, Bastin P, Benmerah A (2011) The ciliary pocket: a once-forgotten membrane domain at the base of cilia. Biol Cell 103:131–144PubMedGoogle Scholar
  22. 22.
    Molla-Herman A, Ghossoub R, Blisnick T, Meunier A, Serres C, Silbermann F, Emmerson C, Romeo K, Bourdoncle P, Schmitt A et al (2010) The ciliary pocket: an endocytic membrane domain at the base of primary and motile cilia. J Cell Sci 123:1785–1795PubMedGoogle Scholar
  23. 23.
    Field MC, Carrington M (2009) The trypanosome flagellar pocket. Nat Rev Microbiol 7:775–786PubMedGoogle Scholar
  24. 24.
    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 329:436–439PubMedGoogle Scholar
  25. 25.
    Michaud EJ, Yoder BK (2006) The primary cilium in cell signaling and cancer. Cancer Res 66:6463–6467PubMedGoogle Scholar
  26. 26.
    Tang Z, Scherer PE, Okamoto T, Song K, Chu C, Kohtz DS, Nishimoto I, Lodish HF, Lisanti MP (1996) Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle. J Biol Chem 271:2255–2261PubMedGoogle Scholar
  27. 27.
    Hill MM, Bastiani M, Luetterforst R, Kirkham M, Kirkham A, Nixon SJ, Walser P, Abankwa D, Oorschot VM, Martin S et al (2008) PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function. Cell 132:113–124PubMedGoogle Scholar
  28. 28.
    Liu L, Pilch PF (2008) A critical role of cavin (polymerase I and transcript release factor) in caveolae formation and organization. J Biol Chem 283:4314–4322PubMedGoogle Scholar
  29. 29.
    Hansen CG, Bright NA, Howard G, Nichols BJ (2009) SDPR induces membrane curvature and functions in the formation of caveolae. Nat Cell Biol 11:807–814PubMedGoogle Scholar
  30. 30.
    McMahon KA, Zajicek H, Li WP, Peyton MJ, Minna JD, Hernandez VJ, Luby-Phelps K, Anderson RG (2009) SRBC/cavin-3 is a caveolin adapter protein that regulates caveolae function. EMBO J 28:1001–1015PubMedGoogle Scholar
  31. 31.
    Oh P, McIntosh DP, Schnitzer JE (1998) Dynamin at the neck of caveolae mediates their budding to form transport vesicles by GTP-driven fission from the plasma membrane of endothelium. J Cell Biol 141:101–114PubMedGoogle Scholar
  32. 32.
    Le PU, Nabi IR (2003) Distinct caveolae-mediated endocytic pathways target the Golgi apparatus and the endoplasmic reticulum. J Cell Sci 116:1059–1071PubMedGoogle Scholar
  33. 33.
    Minshall RD, Tiruppathi C, Vogel SM, Niles WD, Gilchrist A, Hamm HE, Malik AB (2000) Endothelial cell-surface gp60 activates vesicle formation and trafficking via G(i)-coupled Src kinase signaling pathway. J Cell Biol 150:1057–1070PubMedGoogle Scholar
  34. 34.
    Parton RG, Molero JC, Floetenmeyer M, Green KM, James DE (2002) Characterization of a distinct plasma membrane macrodomain in differentiated adipocytes. J Biol Chem 277:46769–46778PubMedGoogle Scholar
  35. 35.
    Naslavsky N, Weigert R, Donaldson JG (2003) Convergence of non-clathrin- and clathrin-derived endosomes involves Arf6 inactivation and changes in phosphoinositides. Mol Biol Cell 14:417–431PubMedGoogle Scholar
  36. 36.
    Pelkmans L, Burli T, Zerial M, Helenius A (2004) Caveolin-stabilized membrane domains as multifunctional transport and sorting devices in endocytic membrane traffic. Cell 118:767–780PubMedGoogle Scholar
  37. 37.
    Meyer C, Zizioli D, Lausmann S, Eskelinen EL, Hamann J, Saftig P, von Figura K, Schu P (2000) mu1A-adaptin-deficient mice: lethality, loss of AP-1 binding and rerouting of mannose 6-phosphate receptors. EMBO J 19:2193–2203PubMedGoogle Scholar
  38. 38.
    Mitsunari T, Nakatsu F, Shioda N, Love PE, Grinberg A, Bonifacino JS, Ohno H (2005) Clathrin adaptor AP-2 is essential for early embryonal development. Mol Cell Biol 25:9318–9323PubMedGoogle Scholar
  39. 39.
    Chinkers M, McKanna JA, Cohen S (1979) Rapid induction of morphological changes in human carcinoma cells A-431 by epidermal growth factors. J Cell Biol 83:260–265PubMedGoogle Scholar
  40. 40.
    Dowrick P, Kenworthy P, McCann B, Warn R (1993) Circular ruffle formation and closure lead to macropinocytosis in hepatocyte growth factor/scatter factor-treated cells. Eur J Cell Biol 61:44–53PubMedGoogle Scholar
  41. 41.
    Mellstrom K, Heldin CH, Westermark B (1988) Induction of circular membrane ruffling on human fibroblasts by platelet-derived growth factor. Exp Cell Res 177:347–359PubMedGoogle Scholar
  42. 42.
    Mellstroom K, Hoglund AS, Nister M, Heldin CH, Westermark B, Lindberg U (1983) The effect of platelet-derived growth factor on morphology and motility of human glial cells. J Muscle Res Cell Motil 4:589–609PubMedGoogle Scholar
  43. 43.
    Peleg B, Disanza A, Scita G, Gov N (2011) Propagating cell-membrane waves driven by curved activators of actin polymerization. PLoS One 6:e18635PubMedGoogle Scholar
  44. 44.
    Orth JD, McNiven MA (2006) Get off my back! Rapid receptor internalization through circular dorsal ruffles. Cancer Res 66:11094–11096PubMedGoogle Scholar
  45. 45.
    Weaver AM, Karginov AV, Kinley AW, Weed SA, Li Y, Parsons JT, Cooper JA (2001) Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation. Curr Biol 11:370–374PubMedGoogle Scholar
  46. 46.
    Hasegawa J, Tokuda E, Tenno T, Tsujita K, Sawai H, Hiroaki H, Takenawa T, Itoh T (2011) SH3YL1 regulates dorsal ruffle formation by a novel phosphoinositide-binding domain. J Cell Biol 193:901–916PubMedGoogle Scholar
  47. 47.
    Legg JA, Bompard G, Dawson J, Morris HL, Andrew N, Cooper L, Johnston SA, Tramountanis G, Machesky LM (2007) N-WASP involvement in dorsal ruffle formation in mouse embryonic fibroblasts. Mol Biol Cell 18:678–687PubMedGoogle Scholar
  48. 48.
    Huang M, Satchell L, Duhadaway JB, Prendergast GC, Laury-Kleintop LD (2011) RhoB links PDGF signaling to cell migration by coordinating activation and localization of Cdc42 and Rac. J Cell Biochem 112:1572–1584PubMedGoogle Scholar
  49. 49.
    Glebov OO, Bright NA, Nichols BJ (2006) Flotillin-1 defines a clathrin-independent endocytic pathway in mammalian cells. Nat Cell Biol 8:46–54PubMedGoogle Scholar
  50. 50.
    Affentranger S, Martinelli S, Hahn J, Rossy J, Niggli V (2011) Dynamic reorganization of flotillins in chemokine-stimulated human T-lymphocytes. BMC Cell Biol 12:28PubMedGoogle Scholar
  51. 51.
    Langhorst MF, Solis GP, Hannbeck S, Plattner H, Stuermer CA (2007) Linking membrane microdomains to the cytoskeleton: regulation of the lateral mobility of reggie-1/flotillin-2 by interaction with actin. FEBS Lett 581:4697–4703PubMedGoogle Scholar
  52. 52.
    Kirkham M, Nixon SJ, Howes MT, Abi-Rached L, Wakeham DE, Hanzal-Bayer M, Ferguson C, Hill MM, Fernandez-Rojo M, Brown DA et al (2008) Evolutionary analysis and molecular dissection of caveola biogenesis. J Cell Sci 121:2075–2086PubMedGoogle Scholar
  53. 53.
    Babuke T, Ruonala M, Meister M, Amaddii M, Genzler C, Esposito A, Tikkanen R (2009) Hetero-oligomerization of reggie-1/flotillin-2 and reggie-2/flotillin-1 is required for their endocytosis. Cell Signal 21:1287–1297PubMedGoogle Scholar
  54. 54.
    Saslowsky DE, Cho JA, Chinnapen H, Massol RH, Chinnapen DJ, Wagner JS, De Luca HE, Kam W, Paw BH, Lencer WI (2010) Intoxication of zebrafish and mammalian cells by cholera toxin depends on the flotillin/reggie proteins but not derlin-1 or -2. J Clin Invest 120:4399–4409PubMedGoogle Scholar
  55. 55.
    Henley JR, Krueger EW, Oswald BJ, McNiven MA (1998) Dynamin-mediated internalization of caveolae. J Cell Biol 141:85–99PubMedGoogle Scholar
  56. 56.
    Schnitzer JE, Oh P, McIntosh DP (1996) Role of GTP hydrolysis in fission of caveolae directly from plasma membranes. Science 274:239–242PubMedGoogle Scholar
  57. 57.
    Cremona ML, Matthies HJ, Pau K, Bowton E, Speed N, Lute BJ, Anderson M, Sen N, Robertson SD, Vaughan RA et al (2011) Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT. Nat Neurosci 14:469–477PubMedGoogle Scholar
  58. 58.
    Stuermer CA (2011) Microdomain-forming proteins and the role of the reggies/flotillins during axon regeneration in zebrafish. Biochim Biophys Acta 1812:415–422PubMedGoogle Scholar
  59. 59.
    Cornfine S, Himmel M, Kopp P, El Azzouzi K, Wiesner C, Kruger M, Rudel T, Linder S (2011) The kinesin KIF9 and reggie/flotillin proteins regulate matrix degradation by macrophage podosomes. Mol Biol Cell 22:202–215PubMedGoogle Scholar
  60. 60.
    Schneider A, Rajendran L, Honsho M, Gralle M, Donnert G, Wouters F, Hell SW, Simons M (2008) Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons. J Neurosci 28:2874–2882PubMedGoogle Scholar
  61. 61.
    Neumann-Giesen C, Fernow I, Amaddii M, Tikkanen R (2007) Role of EGF-induced tyrosine phosphorylation of reggie-1/flotillin-2 in cell spreading and signaling to the actin cytoskeleton. J Cell Sci 120:395–406PubMedGoogle Scholar
  62. 62.
    Katanaev VL, Solis GP, Hausmann G, Buestorf S, Katanayeva N, Schrock Y, Stuermer CA, Basler K (2008) Reggie-1/flotillin-2 promotes secretion of the long-range signalling forms of wingless and hedgehog in Drosophila. EMBO J 27:509–521PubMedGoogle Scholar
  63. 63.
    Chadda R, Howes MT, Plowman SJ, Hancock JF, Parton RG, Mayor S (2007) Cholesterol-sensitive Cdc42 activation regulates actin polymerization for endocytosis via the GEEC pathway. Traffic 8:702–717PubMedGoogle Scholar
  64. 64.
    Kirkham M, Fujita A, Chadda R, Nixon SJ, Kurzchalia TV, Sharma DK, Pagano RE, Hancock JF, Mayor S, Parton RG (2005) Ultrastructural identification of uncoated caveolin-independent early endocytic vehicles. J Cell Biol 168:465–476PubMedGoogle Scholar
  65. 65.
    Sabharanjak S, Sharma P, Parton RG, Mayor S (2002) GPI-anchored proteins are delivered to recycling endosomes via a distinct cdc42-regulated, clathrin-independent pinocytic pathway. Dev Cell 2:411–423PubMedGoogle Scholar
  66. 66.
    Geli MI, Riezman H (1996) Role of type I myosins in receptor-mediated endocytosis in yeast. Science 272:533–535PubMedGoogle Scholar
  67. 67.
    Rao TP, Kuhl M (2010) An updated overview on Wnt signaling pathways: a prelude for more. Circ Res 106:1798–1806PubMedGoogle Scholar
  68. 68.
    van Amerongen R, Nusse R (2009) Towards an integrated view of Wnt signaling in development. Development 136:3205–3214PubMedGoogle Scholar
  69. 69.
    Inoue T, Oz HS, Wiland D, Gharib S, Deshpande R, Hill RJ, Katz WS, Sternberg PW (2004) C. elegans LIN-18 is a Ryk ortholog and functions in parallel to LIN-17/frizzled in Wnt signaling. Cell 118:795–806PubMedGoogle Scholar
  70. 70.
    Lu W, Yamamoto V, Ortega B, Baltimore D (2004) Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell 119:97–108PubMedGoogle Scholar
  71. 71.
    Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC et al (2003) The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8:645–654PubMedGoogle Scholar
  72. 72.
    Schambony A, Wedlich D (2007) Wnt-5A/Ror2 regulate expression of XPAPC through an alternative noncanonical signaling pathway. Dev Cell 12:779–792PubMedGoogle Scholar
  73. 73.
    Roszko I, Sawada A, Solnica-Krezel L (2009) Regulation of convergence and extension movements during vertebrate gastrulation by the Wnt/PCP pathway. Semin Cell Dev Biol 20:986–997PubMedGoogle Scholar
  74. 74.
    Gao C, Chen YG (2010) Dishevelled: the hub of Wnt signaling. Cell Signal 22:717–727PubMedGoogle Scholar
  75. 75.
    Dubois L, Lecourtois M, Alexandre C, Hirst E, Vincent JP (2001) Regulated endocytic routing modulates wingless signaling in Drosophila embryos. Cell 105:613–624PubMedGoogle Scholar
  76. 76.
    Seto ES, Bellen HJ (2006) Internalization is required for proper wingless signaling in Drosophila melanogaster. J Cell Biol 173:95–106PubMedGoogle Scholar
  77. 77.
    Blitzer JT, Nusse R (2006) A critical role for endocytosis in Wnt signaling. BMC Cell Biol 7:28PubMedGoogle Scholar
  78. 78.
    Chen W, Hu LA, Semenov MV, Yanagawa S, Kikuchi A, Lefkowitz RJ, Miller WE (2001) beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins. Proc Natl Acad Sci USA 98:14889–14894PubMedGoogle Scholar
  79. 79.
    Bryja V, Gradl D, Schambony A, Arenas E, Schulte G (2007) Beta-arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo. Proc Natl Acad Sci USA 104:6690–6695PubMedGoogle Scholar
  80. 80.
    Yamamoto H, Komekado H, Kikuchi A (2006) Caveolin is necessary for Wnt-3a-dependent internalization of LRP6 and accumulation of beta-catenin. Dev Cell 11:213–223PubMedGoogle Scholar
  81. 81.
    Bilic J, Huang YL, Davidson G, Zimmermann T, Cruciat CM, Bienz M, Niehrs C (2007) Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science 316:1619–1622PubMedGoogle Scholar
  82. 82.
    Li Y, Lu W, King TD, Liu CC, Bijur GN, Bu G (2010) Dkk1 stabilizes Wnt co-receptor LRP6: implication for Wnt ligand-induced LRP6 down-regulation. PLoS One 5:e11014PubMedGoogle Scholar
  83. 83.
    Kim GH, Her JH, Han JK (2008) Ryk cooperates with frizzled 7 to promote Wnt11-mediated endocytosis and is essential for Xenopus laevis convergent extension movements. J Cell Biol 182:1073–1082PubMedGoogle Scholar
  84. 84.
    Kim GH, Han JK (2007) Essential role for beta-arrestin 2 in the regulation of Xenopus convergent extension movements. EMBO J 26:2513–2526PubMedGoogle Scholar
  85. 85.
    Chen W, ten Berge D, Brown J, Ahn S, Hu LA, Miller WE, Caron MG, Barak LS, Nusse R, Lefkowitz RJ (2003) Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5a-stimulated endocytosis of Frizzled 4. Science 301:1391–1394PubMedGoogle Scholar
  86. 86.
    Yu A, Rual JF, Tamai K, Harada Y, Vidal M, He X, Kirchhausen T (2007) Association of dishevelled with the clathrin AP-2 adaptor is required for frizzled endocytosis and planar cell polarity signaling. Dev Cell 12:129–141PubMedGoogle Scholar
  87. 87.
    Andersson ER, Prakash N, Cajanek L, Minina E, Bryja V, Bryjova L, Yamaguchi TP, Hall AC, Wurst W, Arenas E (2008) Wnt5a regulates ventral midbrain morphogenesis and the development of A9–A10 dopaminergic cells in vivo. PLoS One 3:e3517PubMedGoogle Scholar
  88. 88.
    Sato A, Yamamoto H, Sakane H, Koyama H, Kikuchi A (2010) Wnt5a regulates distinct signalling pathways by binding to Frizzled2. EMBO J 29:41–54PubMedGoogle Scholar
  89. 89.
    Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138:3593–3612PubMedGoogle Scholar
  90. 90.
    Poulson D (1937) Chromosomal deficiencies and the embryonic development of Drosophila melanogaster. PNAS 23:133–137PubMedGoogle Scholar
  91. 91.
    Chen MS, Obar RA, Schroeder CC, Austin TW, Poodry CA, Wadsworth SC, Vallee RB (1991) Multiple forms of dynamin are encoded by shibire, a Drosophila gene involved in endocytosis. Nature 351:583–586PubMedGoogle Scholar
  92. 92.
    Poodry CA (1990) Shibire, a neurogenic mutant of Drosophila. Dev Biol 138:464–472PubMedGoogle Scholar
  93. 93.
    Seugnet L, Simpson P, Haenlin M (1997) Requirement for dynamin during Notch signaling in Drosophila neurogenesis. Dev Biol 192:585–598PubMedGoogle Scholar
  94. 94.
    Parks AL, Stout JR, Shepard SB, Klueg KM, Dos Santos AA, Parody TR, Vaskova M, Muskavitch MA (2006) Structure-function analysis of delta trafficking, receptor binding and signaling in Drosophila. Genetics 174:1947–1961PubMedGoogle Scholar
  95. 95.
    Glittenberg M, Pitsouli C, Garvey C, Delidakis C, Bray S (2006) Role of conserved intracellular motifs in Serrate signalling, cis-inhibition and endocytosis. EMBO J 25:4697–4706PubMedGoogle Scholar
  96. 96.
    Haglund K, Di Fiore PP, Dikic I (2003) Distinct monoubiquitin signals in receptor endocytosis. Trends Biochem Sci 28:598–603PubMedGoogle Scholar
  97. 97.
    Deblandre GA, Lai EC, Kintner C (2001) Xenopus neuralized is a ubiquitin ligase that interacts with XDelta1 and regulates notch signaling. Dev Cell 1:795–806PubMedGoogle Scholar
  98. 98.
    Lai EC, Deblandre GA, Kintner C, Rubin GM (2001) Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta. Dev Cell 1:783–794PubMedGoogle Scholar
  99. 99.
    Pavlopoulos E, Pitsouli C, Klueg KM, Muskavitch MA, Moschonas NK, Delidakis C (2001) Neuralized encodes a peripheral membrane protein involved in delta signaling and endocytosis. Dev Cell 1:807–816PubMedGoogle Scholar
  100. 100.
    Yeh E, Dermer M, Commisso C, Zhou L, McGlade CJ, Boulianne GL (2001) Neuralized functions as an E3 ubiquitin ligase during Drosophila development. Curr Biol 11:1675–1679PubMedGoogle Scholar
  101. 101.
    Chen W, Casey Corliss D (2004) Three modules of zebrafish mind bomb work cooperatively to promote delta ubiquitination and endocytosis. Dev Biol 267:361–373PubMedGoogle Scholar
  102. 102.
    Itoh M, Kim CH, Palardy G, Oda T, Jiang YJ, Maust D, Yeo SY, Lorick K, Wright GJ, Ariza-McNaughton L et al (2003) Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by delta. Dev Cell 4:67–82PubMedGoogle Scholar
  103. 103.
    Overstreet E, Chen X, Wendland B, Fischer JA (2003) Either part of a Drosophila epsin protein, divided after the ENTH domain, functions in endocytosis of delta in the developing eye. Curr Biol 13:854–860PubMedGoogle Scholar
  104. 104.
    Tian X, Hansen D, Schedl T, Skeath JB (2004) Epsin potentiates Notch pathway activity in Drosophila and C. elegans. Development 131:5807–5815PubMedGoogle Scholar
  105. 105.
    Wang W, Struhl G (2004) Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch. Development 131:5367–5380PubMedGoogle Scholar
  106. 106.
    Chen H, Ko G, Zatti A, Di Giacomo G, Liu L, Raiteri E, Perucco E, Collesi C, Min W, Zeiss C et al (2009) Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice. Proc Natl Acad Sci USA 106:13838–13843PubMedGoogle Scholar
  107. 107.
    Windler SL, Bilder D (2010) Endocytic internalization routes required for delta/notch signaling. Curr Biol 20:538–543PubMedGoogle Scholar
  108. 108.
    Le Borgne R, Schweisguth F (2003) Notch signaling: endocytosis makes delta signal better. Curr Biol 13:R273–R275PubMedGoogle Scholar
  109. 109.
    Gyorgy B, Szabo TG, Pasztoi M, Pal Z, Misjak P, Aradi B, Laszlo V, Pallinger E, Pap E, Kittel A et al (2011) Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68:2667–2688PubMedGoogle Scholar
  110. 110.
    Sheldon H, Heikamp E, Turley H, Dragovic R, Thomas P, Oon CE, Leek R, Edelmann M, Kessler B, Sainson RC et al (2010) New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. Blood 116:2385–2394PubMedGoogle Scholar
  111. 111.
    Rajan A, Tien AC, Haueter CM, Schulze KL, Bellen HJ (2009) The Arp2/3 complex and WASp are required for apical trafficking of delta into microvilli during cell fate specification of sensory organ precursors. Nat Cell Biol 11:815–824PubMedGoogle Scholar
  112. 112.
    Emery G, Hutterer A, Berdnik D, Mayer B, Wirtz-Peitz F, Gaitan MG, Knoblich JA (2005) Asymmetric Rab 11 endosomes regulate delta recycling and specify cell fate in the Drosophila nervous system. Cell 122:763–773PubMedGoogle Scholar
  113. 113.
    Jafar-Nejad H, Andrews HK, Acar M, Bayat V, Wirtz-Peitz F, Mehta SQ, Knoblich JA, Bellen HJ (2005) Sec15, a component of the exocyst, promotes Notch signaling during the asymmetric division of Drosophila sensory organ precursors. Dev Cell 9:351–363PubMedGoogle Scholar
  114. 114.
    Heuss SF, Ndiaye-Lobry D, Six EM, Israel A, Logeat F (2008) The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity. Proc Natl Acad Sci USA 105:11212–11217PubMedGoogle Scholar
  115. 115.
    Parr-Sturgess CA, Rushton DJ, Parkin ET (2010) Ectodomain shedding of the Notch ligand Jagged1 is mediated by ADAM17, but is not a lipid-raft-associated event. Biochem J 432:283–294PubMedGoogle Scholar
  116. 116.
    Hansson EM, Lanner F, Das D, Mutvei A, Marklund U, Ericson J, Farnebo F, Stumm G, Stenmark H, Andersson ER et al (2010) Control of Notch-ligand endocytosis by ligand-receptor interaction. J Cell Sci 123:2931–2942PubMedGoogle Scholar
  117. 117.
    Nichols JT, Miyamoto A, Olsen SL, D’Souza B, Yao C, Weinmaster G (2007) DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J Cell Biol 176:445–458PubMedGoogle Scholar
  118. 118.
    Parks AL, Klueg KM, Stout JR, Muskavitch MA (2000) Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. Development 127:1373–1385PubMedGoogle Scholar
  119. 119.
    Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC (2007) Structural basis for autoinhibition of Notch. Nat Struct Mol Biol 14:295–300PubMedGoogle Scholar
  120. 120.
    Sanchez-Irizarry C, Carpenter AC, Weng AP, Pear WS, Aster JC, Blacklow SC (2004) Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Mol Cell Biol 24:9265–9273PubMedGoogle Scholar
  121. 121.
    Gupta-Rossi N, Six E, LeBail O, Logeat F, Chastagner P, Olry A, Israel A, Brou C (2004) Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor. J Cell Biol 166:73–83PubMedGoogle Scholar
  122. 122.
    Moretti J, Chastagner P, Gastaldello S, Heuss SF, Dirac AM, Bernards R, Masucci MG, Israel A, Brou C (2010) The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation. PLoS Biol 8:e1000545PubMedGoogle Scholar
  123. 123.
    Cayouette M, Raff M (2002) Asymmetric segregation of Numb: a mechanism for neural specification from Drosophila to mammals. Nat Neurosci 5:1265–1269PubMedGoogle Scholar
  124. 124.
    Gonczy P (2008) Mechanisms of asymmetric cell division: flies and worms pave the way. Nat Rev Mol Cell Biol 9:355–366PubMedGoogle Scholar
  125. 125.
    McGill MA, Dho SE, Weinmaster G, McGlade CJ (2009) Numb regulates post-endocytic trafficking and degradation of Notch1. J Biol Chem 284:26427–26438PubMedGoogle Scholar
  126. 126.
    Beres BJ, George R, Lougher EJ, Barton M, Verrelli BC, McGlade CJ, Rawls JA, Wilson-Rawls J (2011) Numb regulates Notch1, but not Notch3, during myogenesis. Mech Dev 128(5–6):247–257PubMedGoogle Scholar
  127. 127.
    Diederich RJ, Matsuno K, Hing H, Artavanis-Tsakonas S (1994) Cytosolic interaction between deltex and Notch ankyrin repeats implicates deltex in the Notch signaling pathway. Development 120:473–481PubMedGoogle Scholar
  128. 128.
    Hori K, Fostier M, Ito M, Fuwa TJ, Go MJ, Okano H, Baron M, Matsuno K (2004) Drosophila deltex mediates suppressor of hairless-independent and late-endosomal activation of Notch signaling. Development 131:5527–5537PubMedGoogle Scholar
  129. 129.
    Matsuno K, Diederich RJ, Go MJ, Blaumueller CM, Artavanis-Tsakonas S (1995) Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. Development 121:2633–2644PubMedGoogle Scholar
  130. 130.
    Wilkin M, Tongngok P, Gensch N, Clemence S, Motoki M, Yamada K, Hori K, Taniguchi-Kanai M, Franklin E, Matsuno K et al (2008) Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of notch in the endosomal trafficking pathway. Dev Cell 15:762–772PubMedGoogle Scholar
  131. 131.
    Yamada K, Fuwa TJ, Ayukawa T, Tanaka T, Nakamura A, Wilkin MB, Baron M, Matsuno K (2011) Roles of Drosophila deltex in Notch receptor endocytic trafficking and activation. Genes Cells 16:261–272PubMedGoogle Scholar
  132. 132.
    Fuwa TJ, Hori K, Sasamura T, Higgs J, Baron M, Matsuno K (2006) The first deltex null mutant indicates tissue-specific deltex-dependent Notch signaling in Drosophila. Mol Genet Genomics 275:251–263PubMedGoogle Scholar
  133. 133.
    Matsuno K, Ito M, Hori K, Miyashita F, Suzuki S, Kishi N, Artavanis-Tsakonas S, Okano H (2002) Involvement of a proline-rich motif and RING-H2 finger of deltex in the regulation of Notch signaling. Development 129:1049–1059PubMedGoogle Scholar
  134. 134.
    Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakonas S (2005) Regulation of Notch signalling by non-visual beta-arrestin. Nat Cell Biol 7:1191–1201PubMedGoogle Scholar
  135. 135.
    Sestan N, Artavanis-Tsakonas S, Rakic P (1999) Contact-dependent inhibition of cortical neurite growth mediated by Notch signaling. Science 286:741–746PubMedGoogle Scholar
  136. 136.
    Jorissen E, De Strooper B (2010) Gamma-secretase and the intramembrane proteolysis of Notch. Curr Top Dev Biol 92:201–230PubMedGoogle Scholar
  137. 137.
    Kaether C, Schmitt S, Willem M, Haass C (2006) Amyloid precursor protein and Notch intracellular domains are generated after transport of their precursors to the cell surface. Traffic 7:408–415PubMedGoogle Scholar
  138. 138.
    Sorensen EB, Conner SD (2010) Gamma-secretase-dependent cleavage initiates Notch signaling from the plasma membrane. Traffic 11:1234–1245PubMedGoogle Scholar
  139. 139.
    Tarassishin L, Yin YI, Bassit B, Li YM (2004) Processing of Notch and amyloid precursor protein by gamma-secretase is spatially distinct. Proc Natl Acad Sci USA 101:17050–17055PubMedGoogle Scholar
  140. 140.
    Vaccari T, Lu H, Kanwar R, Fortini ME, Bilder D (2008) Endosomal entry regulates Notch receptor activation in Drosophila melanogaster. J Cell Biol 180:755–762PubMedGoogle Scholar
  141. 141.
    Tagami S, Okochi M, Yanagida K, Ikuta A, Fukumori A, Matsumoto N, Ishizuka-Katsura Y, Nakayama T, Itoh N, Jiang J et al (2008) Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1. Mol Cell Biol 28:165–176PubMedGoogle Scholar
  142. 142.
    Kapoor A, Hsu WM, Wang BJ, Wu GH, Lin TY, Lee SJ, Yen CT, Liang SM, Liao YF (2010) Caveolin-1 regulates gamma-secretase-mediated AbetaPP processing by modulating spatial distribution of gamma-secretase in membrane. J Alzheimers Dis 22:423–442PubMedGoogle Scholar
  143. 143.
    Osenkowski P, Ye W, Wang R, Wolfe MS, Selkoe DJ (2008) Direct and potent regulation of gamma-secretase by its lipid microenvironment. J Biol Chem 283:22529–22540PubMedGoogle Scholar
  144. 144.
    Ezratty EJ, Stokes N, Chai S, Shah AS, Williams SE, Fuchs E (2011) A role for the primary cilium in Notch signaling and epidermal differentiation during skin development. Cell 145:1129–1141PubMedGoogle Scholar
  145. 145.
    Ahmed KA, Xiang J (2011) Mechanisms of cellular communication through intercellular protein transfer. J Cell Mol Med 15:1458–1473PubMedGoogle Scholar
  146. 146.
    Pitulescu ME, Adams RH (2010) Eph/ephrin molecules–a hub for signaling and endocytosis. Genes Dev 24:2480–2492PubMedGoogle Scholar
  147. 147.
    Cagan RL, Kramer H, Hart AC, Zipursky SL (1992) The bride of sevenless and sevenless interaction: internalization of a transmembrane ligand. Cell 69:393–399PubMedGoogle Scholar
  148. 148.
    Kusakari S, Ohnishi H, Jin FJ, Kaneko Y, Murata T, Murata Y, Okazawa H, Matozaki T (2008) Trans-endocytosis of CD47 and SHPS-1 and its role in regulation of the CD47-SHPS-1 system. J Cell Sci 121:1213–1223PubMedGoogle Scholar
  149. 149.
    Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133:38–52PubMedGoogle Scholar
  150. 150.
    Thakar S, Chenaux G, Henkemeyer M (2011) Critical roles for EphB and ephrin-B bidirectional signalling in retinocollicular mapping. Nat Commun 2:431PubMedGoogle Scholar
  151. 151.
    del Alamo D, Rouault H, Schweisguth F (2011) Mechanism and significance of cis-inhibition in Notch signalling. Curr Biol 21:R40–R47PubMedGoogle Scholar
  152. 152.
    Carvalho RF, Beutler M, Marler KJ, Knoll B, Becker-Barroso E, Heintzmann R, Ng T, Drescher U (2006) Silencing of EphA3 through a cis interaction with ephrinA5. Nat Neurosci 9:322–330PubMedGoogle Scholar
  153. 153.
    Yin Y, Yamashita Y, Noda H, Okafuji T, Go MJ, Tanaka H (2004) EphA receptor tyrosine kinases interact with co-expressed ephrin-A ligands in cis. Neurosci Res 48:285–296PubMedGoogle Scholar
  154. 154.
    Parker M, Roberts R, Enriquez M, Zhao X, Takahashi T, Pat Cerretti D, Daniel T, Chen J (2004) Reverse endocytosis of transmembrane ephrin-B ligands via a clathrin-mediated pathway. Biochem Biophys Res Commun 323:17–23PubMedGoogle Scholar
  155. 155.
    Bruckner K, Pablo Labrador J, Scheiffele P, Herb A, Seeburg PH, Klein R (1999) EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains. Neuron 22:511–524PubMedGoogle Scholar
  156. 156.
    Vihanto MM, Vindis C, Djonov V, Cerretti DP, Huynh-Do U (2006) Caveolin-1 is required for signaling and membrane targeting of EphB1 receptor tyrosine kinase. J Cell Sci 119:2299–2309PubMedGoogle Scholar
  157. 157.
    Yoo S, Shin J, Park S (2010) EphA8-ephrinA5 signaling and clathrin-mediated endocytosis is regulated by Tiam-1, a Rac-specific guanine nucleotide exchange factor. Mol Cells 29:603–609PubMedGoogle Scholar
  158. 158.
    Irie F, Okuno M, Pasquale EB, Yamaguchi Y (2005) EphrinB-EphB signalling regulates clathrin-mediated endocytosis through tyrosine phosphorylation of synaptojanin 1. Nat Cell Biol 7:501–509PubMedGoogle Scholar
  159. 159.
    Bouvier D, Tremblay ME, Riad M, Corera AT, Gingras D, Horn KE, Fotouhi M, Girard M, Murai KK, Kennedy TE et al (2010) EphA4 is localized in clathrin-coated and synaptic vesicles in adult mouse brain. J Neurochem 113:153–165PubMedGoogle Scholar
  160. 160.
    Carpentier JL, Sawano F, Geiger D, Gorden P, Perrelet A, Orci L (1989) Potassium depletion and hypertonic medium reduce “non-coated” and clathrin-coated pit formation, as well as endocytosis through these two gates. J Cell Physiol 138:519–526PubMedGoogle Scholar
  161. 161.
    Vercauteren D, Vandenbroucke RE, Jones AT, Rejman J, Demeester J, De Smedt SC, Sanders NN, Braeckmans K (2010) The use of inhibitors to study endocytic pathways of gene carriers: optimization and pitfalls. Mol Ther 18:561–569PubMedGoogle Scholar
  162. 162.
    Ellis S, Mellor H (2000) Regulation of endocytic traffic by rho family GTPases. Trends Cell Biol 10:85–88PubMedGoogle Scholar
  163. 163.
    Marston DJ, Dickinson S, Nobes CD (2003) Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion. Nat Cell Biol 5:879–888PubMedGoogle Scholar
  164. 164.
    Cowan CW, Shao YR, Sahin M, Shamah SM, Lin MZ, Greer PL, Gao S, Griffith EC, Brugge JS, Greenberg ME (2005) Vav family GEFs link activated Ephs to endocytosis and axon guidance. Neuron 46:205–217PubMedGoogle Scholar
  165. 165.
    Hunter SG, Zhuang G, Brantley-Sieders D, Swat W, Cowan CW, Chen J (2006) Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis. Mol Cell Biol 26:4830–4842PubMedGoogle Scholar
  166. 166.
    Deininger K, Eder M, Kramer ER, Zieglgansberger W, Dodt HU, Dornmair K, Colicelli J, Klein R (2008) The Rab5 guanylate exchange factor Rin1 regulates endocytosis of the EphA4 receptor in mature excitatory neurons. Proc Natl Acad Sci USA 105:12539–12544PubMedGoogle Scholar
  167. 167.
    Shamah SM, Lin MZ, Goldberg JL, Estrach S, Sahin M, Hu L, Bazalakova M, Neve RL, Corfas G, Debant A et al (2001) EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin. Cell 105:233–244PubMedGoogle Scholar
  168. 168.
    Hiramoto-Yamaki N, Takeuchi S, Ueda S, Harada K, Fujimoto S, Negishi M, Katoh H (2010) Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J Cell Biol 190:461–477PubMedGoogle Scholar
  169. 169.
    Sahin M, Greer PL, Lin MZ, Poucher H, Eberhart J, Schmidt S, Wright TM, Shamah SM, O’Connell S, Cowan CW et al (2005) Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron 46:191–204PubMedGoogle Scholar
  170. 170.
    Lamaze C, Chuang TH, Terlecky LJ, Bokoch GM, Schmid SL (1996) Regulation of receptor-mediated endocytosis by Rho and Rac. Nature 382:177–179PubMedGoogle Scholar
  171. 171.
    Lamaze C, Fujimoto LM, Yin HL, Schmid SL (1997) The actin cytoskeleton is required for receptor-mediated endocytosis in mammalian cells. J Biol Chem 272:20332–20335PubMedGoogle Scholar
  172. 172.
    Zimmer M, Palmer A, Kohler J, Klein R (2003) EphB-ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion. Nat Cell Biol 5:869–878PubMedGoogle Scholar
  173. 173.
    Georgakopoulos A, Litterst C, Ghersi E, Baki L, Xu C, Serban G, Robakis NK (2006) Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J 25:1242–1252PubMedGoogle Scholar
  174. 174.
    Inoue E, Deguchi-Tawarada M, Togawa A, Matsui C, Arita K, Katahira-Tayama S, Sato T, Yamauchi E, Oda Y, Takai Y (2009) Synaptic activity prompts gamma-secretase-mediated cleavage of EphA4 and dendritic spine formation. J Cell Biol 185:551–564PubMedGoogle Scholar
  175. 175.
    Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, Nikolov DB (2005) Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell 123:291–304PubMedGoogle Scholar
  176. 176.
    Janes PW, Wimmer-Kleikamp SH, Frangakis AS, Treble K, Griesshaber B, Sabet O, Grabenbauer M, Ting AY, Saftig P, Bastiaens PI et al (2009) Cytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10. PLoS Biol 7:e1000215PubMedGoogle Scholar
  177. 177.
    Litterst C, Georgakopoulos A, Shioi J, Ghersi E, Wisniewski T, Wang R, Ludwig A, Robakis NK (2007) Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. J Biol Chem 282:16155–16163PubMedGoogle Scholar
  178. 178.
    Tomita T, Tanaka S, Morohashi Y, Iwatsubo T (2006) Presenilin-dependent intramembrane cleavage of ephrin-B1. Mol Neurodegener 1:2PubMedGoogle Scholar
  179. 179.
    Song JK, Giniger E (2011) Noncanonical Notch function in motor axon guidance is mediated by Rac GTPase and the GEF1 domain of Trio. Dev Dyn 240:324–332PubMedGoogle Scholar
  180. 180.
    Schlessinger K, Hall A, Tolwinski N (2009) Wnt signaling pathways meet Rho GTPases. Genes Dev 23:265–277PubMedGoogle Scholar
  181. 181.
    Steiner H, Fluhrer R, Haass C (2008) Intramembrane proteolysis by gamma-secretase. J Biol Chem 283:29627–29631PubMedGoogle Scholar
  182. 182.
    Zolkiewska A (2008) ADAM proteases: ligand processing and modulation of the Notch pathway. Cell Mol Life Sci 65:2056–2068PubMedGoogle Scholar
  183. 183.
    LaVoie MJ, Selkoe DJ (2003) The Notch ligands, jagged and delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem 278:34427–34437PubMedGoogle Scholar

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© Springer Basel AG 2011

Authors and Affiliations

  1. 1.Department of Cell and Molecular BiologyKarolinska InstituteStockholmSweden

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