Abstract
Signal strength evoked by ligand stimulation is crucial for cellular responses such as fate decision, cell survival/death, secretion, and migration. For example, morphogens are secreted signaling molecules that form concentration gradients within tissues and induce distinct cell fates in a signal strength-dependent manner. In addition to extracellular ligand abundance, the sensitivity of signal-receiving cells to ligands also influences signal strength. Cell sensitivity to ligands is controlled at various levels: receptor presentation at the cell surface, positive/negative regulation of signal transduction, and target gene activation/repression. While the regulation of signal transduction and gene transcription is well studied, receptor presentation is still not fully understood. Recently, it was reported that cellular sensitivity to the Wingless (Wg)/Wnt morphogen is regulated by balanced ubiquitination and deubiquitination of its receptor Frizzled (Fz). In this review, we review how ubiquitination regulates receptor presentation at the cell surface for the detection of extracellular signal strength.
Similar content being viewed by others
References
Wolpert L (1969) Positional information and the spatial pattern of cellular differentiation. J Theor Biol 25:1–47
Kornberg TB, Guha A (2007) Understanding morphogen gradients: a problem of dispersion and containment. Curr Opin Genet Dev 17:264–271
Sanchez-Camacho C, Bovolenta P (2009) Emerging mechanisms in morphogen-mediated axon guidance. Bioessays 31:1013–1025
Jin T, Xu X, Hereld D (2008) Chemotaxis, chemokine receptors and human disease. Cytokine 44:1–8
Roussos ET, Condeelis JS, Patsialou A (2011) Chemotaxis in cancer. Nat Rev Cancer 11:573–587
Wiley HS, Herbst JJ, Walsh BJ, Lauffenburger DA, Rosenfeld MG, Gill GN (1991) The role of tyrosine kinase activity in endocytosis, compartmentation, and down-regulation of the epidermal growth factor receptor. J Biol Chem 266:11083–11094
Chang CP, Lazar CS, Walsh BJ, Komuro M, Collawn JF, Kuhn LA, Tainer JA, Trowbridge IS, Farquhar MG, Rosenfeld MG et al (1993) Ligand-induced internalization of the epidermal growth factor receptor is mediated by multiple endocytic codes analogous to the tyrosine motif found in constitutively internalized receptors. J Biol Chem 268:19312–19320
Resat H, Ewald JA, Dixon DA, Wiley HS (2003) An integrated model of epidermal growth factor receptor trafficking and signal transduction. Biophys J 85:730–743
Duan L, Miura Y, Dimri M, Majumder B, Dodge IL, Reddi AL, Ghosh A, Fernandes N, Zhou P, Mullane-Robinson K, Rao N, Donoghue S, Rogers RA, Bowtell D, Naramura M, Gu H, Band V, Band H (2003) Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis. J Biol Chem 278:28950–28960
Kerscher O, Felberbaum R, Hochstrasser M (2006) Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol 22:159–180
Mukhopadhyay D, Riezman H (2007) Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315:201–205
Schulman BA, Harper JW (2009) Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol 10:319–331
Ye Y, Rape M (2009) Building ubiquitin chains: E2 enzymes at work. Nat Rev Mol Cell Biol 10:755–764
Deshaies RJ, Joazeiro CA (2009) RING domain E3 ubiquitin ligases. Annu Rev Biochem 78:399–434
Verma R, Oania R, Graumann J, Deshaies RJ (2004) Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system. Cell 118:99–110
Kim I, Mi K, Rao H (2004) Multiple interactions of rad23 suggest a mechanism for ubiquitylated substrate delivery important in proteolysis. Mol Biol Cell 15:3357–3365
Richly H, Rape M, Braun S, Rumpf S, Hoege C, Jentsch S (2005) A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120:73–84
Rape M, Reddy SK, Kirschner MW (2006) The processivity of multiubiquitination by the APC determines the order of substrate degradation. Cell 124:89–103
Williamson A, Wickliffe KE, Mellone BG, Song L, Karpen GH, Rape M (2009) Identification of a physiological E2 module for the human anaphase-promoting complex. Proc Natl Acad Sci USA 106:18213–18218
Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K (2009) Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 11:123–132
Chen ZJ (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7:758–765
Rahighi S, Ikeda F, Kawasaki M, Akutsu M, Suzuki N, Kato R, Kensche T, Uejima T, Bloor S, Komander D, Randow F, Wakatsuki S, Dikic I (2009) Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell 136:1098–1109
Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S (2002) RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419:135–141
Sims JJ, Cohen RE (2009) Linkage-specific avidity defines the lysine 63-linked polyubiquitin-binding preference of rap80. Mol Cell 33:775–783
Spence J, Sadis S, Haas AL, Finley D (1995) A ubiquitin mutant with specific defects in DNA repair and multiubiquitination. Mol Cell Biol 15:1265–1273
Hicke L (1999) Gettin’ down with ubiquitin: turning off cell-surface receptors, transporters and channels. Trends Cell Biol 9:107–112
Polo S, Confalonieri S, Salcini AE, Di Fiore PP (2003) EH and UIM: endocytosis and more. Sci STKE 2003(213):re17
Brooks CL, Li M, Gu W (2004) Monoubiquitination: the signal for p53 nuclear export? Cell Cycle 3:436–438
Haglund K, Sigismund S, Polo S, Szymkiewicz I, Di Fiore PP, Dikic I (2003) Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol 5:461–466
Amerik AY, Hochstrasser M (2004) Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 1695:189–207
Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123:773–786
Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10:550–563
Wilkinson KD, Tashayev VL, O’Connor LB, Larsen CN, Kasperek E, Pickart CM (1995) Metabolism of the polyubiquitin degradation signal: structure, mechanism, and role of isopeptidase T. Biochemistry 34:14535–14546
Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 78:363–397
Acconcia F, Sigismund S, Polo S (2009) Ubiquitin in trafficking: the network at work. Exp Cell Res 315:1610–1618
Komada M (2008) Controlling receptor downregulation by ubiquitination and deubiquitination. Curr Drug Discov Technol 5:78–84
Raiborg C, Stenmark H (2009) The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458:445–452
Hicke L, Riezman H (1996) Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cell 84:277–287
Kolling R, Hollenberg CP (1994) The ABC-transporter Ste6 accumulates in the plasma membrane in a ubiquitinated form in endocytosis mutants. EMBO J 13:3261–3271
Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A (2006) Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell 21:737–748
Huang F, Goh LK, Sorkin A (2007) EGF receptor ubiquitination is not necessary for its internalization. Proc Natl Acad Sci USA 104:16904–16909
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 102:2760–2765
Goh LK, Huang F, Kim W, Gygi S, Sorkin A (2010) Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor. J Cell Biol 189:871–883
Mizuno E, Iura T, Mukai A, Yoshimori T, Kitamura N, Komada M (2005) Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes. Mol Biol Cell 16:5163–5174
Row PE, Prior IA, McCullough J, Clague MJ, Urbe S (2006) The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulation. J Biol Chem 281:12618–12624
Bowers K, Piper SC, Edeling MA, Gray SR, Owen DJ, Lehner PJ, Luzio JP (2006) Degradation of endocytosed epidermal growth factor and virally ubiquitinated major histocompatibility complex class I is independent of mammalian ESCRTII. J Biol Chem 281:5094–5105
Kyuuma M, Kikuchi K, Kojima K, Sugawara Y, Sato M, Mano N, Goto J, Takeshita T, Yamamoto A, Sugamura K, Tanaka N (2007) AMSH, an ESCRT-III associated enzyme, deubiquitinates cargo on MVB/late endosomes. Cell Struct Funct 31:159–172
Jacoby E, Bouhelal R, Gerspacher M, Seuwen K (2006) The 7 TM G-protein-coupled receptor target family. ChemMedChem 1:761–782
Fredholm BB, Hokfelt T, Milligan G (2007) G-protein-coupled receptors: an update. Acta Physiol (Oxf) 190:3–7
Chen L, Davis NG (2002) Ubiquitin-independent entry into the yeast recycling pathway. Traffic 3:110–123
Obin MS, Jahngen-Hodge J, Nowell T, Taylor A (1996) Ubiquitinylation and ubiquitin-dependent proteolysis in vertebrate photoreceptors (rod outer segments). Evidence for ubiquitinylation of Gt and rhodopsin. J Biol Chem 271:14473–14484
Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ (2001) Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294:1307–1313
Marchese A, Benovic JL (2001) Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting. J Biol Chem 276:45509–45512
Martin NP, Lefkowitz RJ, Shenoy SK (2003) Regulation of V2 vasopressin receptor degradation by agonist-promoted ubiquitination. J Biol Chem 278:45954–45959
Jacob C, Cottrell GS, Gehringer D, Schmidlin F, Grady EF, Bunnett NW (2005) c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2. J Biol Chem 280:16076–16087
Cottrell GS, Padilla B, Pikios S, Roosterman D, Steinhoff M, Gehringer D, Grady EF, Bunnett NW (2006) Ubiquitin-dependent down-regulation of the neurokinin-1 receptor. J Biol Chem 281:27773–27783
Li JG, Haines DS, Liu-Chen LY (2008) Agonist-promoted Lys63-linked polyubiquitination of the human kappa-opioid receptor is involved in receptor down-regulation. Mol Pharmacol 73:1319–1330
Wolfe BL, Marchese A, Trejo J (2007) Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1. J Cell Biol 177:905–916
Tanowitz M, Von Zastrow M (2002) Ubiquitination-independent trafficking of G protein-coupled receptors to lysosomes. J Biol Chem 277:50219–50222
Henry AG, White IJ, Marsh M, von Zastrow M, Hislop JN (2011) The role of ubiquitination in lysosomal trafficking of delta-opioid receptors. Traffic 12:170–184
Shenoy SK, Xiao K, Venkataramanan V, Snyder PM, Freedman NJ, Weissman AM (2008) Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor. J Biol Chem 283:22166–22176
Nabhan JF, Pan H, Lu Q (2010) Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the beta2-adrenergic receptor. EMBO Rep 11:605–611
Marchese A, Raiborg C, Santini F, Keen JH, Stenmark H, Benovic JL (2003) The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Dev Cell 5:709–722
Bhandari D, Robia SL, Marchese A (2009) The E3 ubiquitin ligase atrophin interacting protein 4 binds directly to the chemokine receptor CXCR4 via a novel WW domain-mediated interaction. Mol Biol Cell 20:1324–1339
Bhandari D, Trejo J, Benovic JL, Marchese A (2007) Arrestin-2 interacts with the ubiquitin-protein isopeptide ligase atrophin-interacting protein 4 and mediates endosomal sorting of the chemokine receptor CXCR4. J Biol Chem 282:36971–36979
Hislop JN, Henry AG, Marchese A, von Zastrow M (2009) Ubiquitination regulates proteolytic processing of G protein-coupled receptors after their sorting to lysosomes. J Biol Chem 284:19361–19370
Dupre DJ, Chen Z, Le Gouill C, Theriault C, Parent JL, Rola-Pleszczynski M, Stankova J (2003) Trafficking, ubiquitination, and down-regulation of the human platelet-activating factor receptor. J Biol Chem 278:48228–48235
Berthouze M, Venkataramanan V, Li Y, Shenoy SK (2009) The deubiquitinases USP33 and USP20 coordinate beta2 adrenergic receptor recycling and resensitization. EMBO J 28:1684–1696
Mines MA, Goodwin JS, Limbird LE, Cui FF, Fan GH (2009) Deubiquitination of CXCR4 by USP14 is critical for both CXCL12-induced CXCR4 degradation and chemotaxis but not ERK ativation. J Biol Chem 284:5742–5752
Hasdemir B, Murphy JE, Cottrell GS, Bunnett NW (2009) Endosomal deubiquitinating enzymes control ubiquitination and down-regulation of protease-activated receptor 2. J Biol Chem 284:28453–28466
Berlin I, Higginbotham KM, Dise RS, Sierra MI, Nash PD (2010) The deubiquitinating enzyme USP8 promotes trafficking and degradation of the chemokine receptor 4 at the sorting endosome. J Biol Chem 285:37895–37908
Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233
Weinmaster G, Fischer JA (2011) Notch ligand ubiquitylation: what is it good for? Dev Cell 21:134–144
Le Bras S, Loyer N, Le Borgne R (2011) The multiple facets of ubiquitination in the regulation of notch signaling pathway. Traffic 12:149–161
Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X, Pan DJ, Ray WJ, Kopan R (2000) A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 5:197–206
Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A (2000) A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 5:207–216
Schroeter EH, Kisslinger JA, Kopan R (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393:382–386
Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T, Kudo T, Takeda M, Haass C (2002) Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J 21:5408–5416
Seugnet L, Simpson P, Haenlin M (1997) Requirement for dynamin during Notch signaling in Drosophila neurogenesis. Dev Biol 192:585–598
Vaccari T, Lu H, Kanwar R, Fortini ME, Bilder D (2008) Endosomal entry regulates Notch receptor activation in Drosophila melanogaster. J Cell Biol 180:755–762
Lu H, Bilder D (2005) Endocytic control of epithelial polarity and proliferation in Drosophila. Nat Cell Biol 7:1232–1239
Vaccari T, Duchi S, Cortese K, Tacchetti C, Bilder D (2010) The vacuolar ATPase is required for physiological as well as pathological activation of the Notch receptor. Development 137:1825–1832
Yan Y, Denef N, Schupbach T (2009) The vacuolar proton pump, V-ATPase, is required for notch signaling and endosomal trafficking in Drosophila. Dev Cell 17:387–402
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 166:73–83
Tagami S, Okochi M, Yanagida K, Ikuta A, Fukumori A, Matsumoto N, Ishizuka-Katsura Y, Nakayama T, Itoh N, Jiang J, Nishitomi K, Kamino K, Morihara T, Hashimoto R, Tanaka T, Kudo T, Chiba S, Takeda M (2008) Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1. Mol Cell Biol 28:165–176
Moberg KH, Schelble S, Burdick SK, Hariharan IK (2005) Mutations in erupted, the Drosophila ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth. Dev Cell 9:699–710
Thompson BJ, Mathieu J, Sung HH, Loeser E, Rorth P, Cohen SM (2005) Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila. Dev Cell 9:711–720
Vaccari T, Bilder D (2005) The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating notch trafficking. Dev Cell 9:687–698
Herz HM, Chen Z, Scherr H, Lackey M, Bolduc C, Bergmann A (2006) vps25 mosaics display non-autonomous cell survival and overgrowth, and autonomous apoptosis. Development 133:1871–1880
Childress JL, Acar M, Tao C, Halder G (2006) Lethal giant discs, a novel C2-domain protein, restricts notch activation during endocytosis. Curr Biol 16:2228–2233
Gallagher CM, Knoblich JA (2006) The conserved c2 domain protein lethal (2) giant discs regulates protein trafficking in Drosophila. Dev Cell 11:641–653
Jaekel R, Klein T (2006) The Drosophila Notch inhibitor and tumor suppressor gene lethal (2) giant discs encodes a conserved regulator of endosomal trafficking. Dev Cell 11:655–669
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 131:5527–5537
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 275:251–263
Jehn BM, Dittert I, Beyer S, von der Mark K, Bielke W (2002) c-Cbl binding and ubiquitin-dependent lysosomal degradation of membrane-associated Notch1. J Biol Chem 277:8033–8040
Wang Y, Chen Z, Bergmann A (2010) Regulation of EGFR and Notch signaling by distinct isoforms of D-cbl during Drosophila development. Dev Biol 342:1–10
Fostier M, Evans DA, Artavanis-Tsakonas S, Baron M (1998) Genetic characterization of the Drosophila melanogaster Suppressor of deltex gene: a regulator of notch signaling. Genetics 150:1477–1485
Chastagner P, Israel A, Brou C (2008) AIP4/Itch regulates Notch receptor degradation in the absence of ligand. PLoS One 3:e2735
Qiu L, Joazeiro C, Fang N, Wang HY, Elly C, Altman Y, Fang D, Hunter T, Liu YC (2000) Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase. J Biol Chem 275:35734–35737
Sakata T, Sakaguchi H, Tsuda L, Higashitani A, Aigaki T, Matsuno K, Hayashi S (2004) Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation. Curr Biol 14:2228–2236
Wilkin MB, Carbery AM, Fostier M, Aslam H, Mazaleyrat SL, Higgs J, Myat A, Evans DA, Cornell M, Baron M (2004) Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins. Curr Biol 14:2237–2244
Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810
Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480
Couso JP, Bishop SA, Martinez Arias A (1994) The wingless signalling pathway and the patterning of the wing margin in Drosophila. Development 120:621–636
Zecca M, Basler K, Struhl G (1996) Direct and long-range action of a wingless morphogen gradient. Cell 87:833–844
Neumann CJ, Cohen SM (1997) Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. Development 124:871–880
Schulte G, Bryja V (2007) The Frizzled family of unconventional G-protein-coupled receptors. Trends Pharmacol Sci 28:518–525
Muller P, Schier AF (2011) Extracellular movement of signaling molecules. Dev Cell 21:145–158
Cadigan KM, Fish MP, Rulifson EJ, Nusse R (1998) Wingless repression of Drosophila frizzled 2 expression shapes the Wingless morphogen gradient in the wing. Cell 93:767–777
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 301:1391–1394
Yamamoto H, Komekado H, Kikuchi A (2006) Caveolin is necessary for Wnt-3a-dependent internalization of LRP6 and accumulation of beta-catenin. Dev Cell 11:213–223
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 12:129–141
Purvanov V, Koval A, Katanaev VL (2010) A direct and functional interaction between Go and Rab5 during G protein-coupled receptor signaling. Sci Signal 3:ra65
Mukai A, Yamamoto-Hino M, Awano W, Watanabe W, Komada M, Goto S (2010) Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt. EMBO J 29:2114–2125
Berndt JD, Aoyagi A, Yang P, Anastas JN, Tang L, Moon RT (2011) Mindbomb 1, an E3 ubiquitin ligase, forms a complex with RYK to activate Wnt/beta-catenin signaling. J Cell Biol 194:737–750
Lyu J, Yamamoto V, Lu W (2008) Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis. Dev Cell 15:773–780
Kowalski JR, Dahlberg CL, Juo P (2011) The deubiquitinating enzyme USP-46 negatively regulates the degradation of glutamate receptors to control their abundance in the ventral nerve cord of Caenorhabditis elegans. J Neurosci 31:1341–1354
Lin A, Hou Q, Jarzylo L, Amato S, Gilbert J, Shang F, Man HY (2011) Nedd4-mediated AMPA receptor ubiquitination regulates receptor turnover and trafficking. J Neurochem 119:27–39
Nakamura M, Tanaka N, Kitamura N, Komada M (2006) Clathrin anchors deubiquitinating enzymes, AMSH and AMSH-like protein, on early endosomes. Genes Cells 11:593–606
Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, Kipps TJ, Corr M, Carson DA (2004) Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 101:3118–3123
Cai J, Crotty TM, Reichert E, Carraway KL 3rd, Stafforini DM, Topham MK (2010) Diacylglycerol kinase delta and protein kinase C(alpha) modulate epidermal growth factor receptor abundance and degradation through ubiquitin-specific protease 8. J Biol Chem 285:6952–6959
Acknowledgments
This work was supported by Grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan to SG.
Author information
Authors and Affiliations
Corresponding author
Additional information
A. Mukai and M. Yamamoto-Hino contributed equally to this work.
Rights and permissions
About this article
Cite this article
Mukai, A., Yamamoto-Hino, M., Komada, M. et al. Balanced ubiquitination determines cellular responsiveness to extracellular stimuli. Cell. Mol. Life Sci. 69, 4007–4016 (2012). https://doi.org/10.1007/s00018-012-1084-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-012-1084-4