The cell biology of Smo signalling and its relationships with GPCRs

Biochimica et Biophysica Acta - Biomembranes

Volumn 1768, Issue 4, 2007, Pages 901-912

  Ruiz Gómez, Ana ^a   Molnar, Cristina ^a   Holguín, Helena ^a   Mayor Jr , Federico ^a   de Celis, Jose F ^a  

^a UNIVERSIDAD AUTÓNOMA DE MADRID   (Spain)

Author keywords

arrestin; GPCR; GRKs; Hh signalling; Smoothened

Indexed keywords

G PROTEIN COUPLED RECEPTOR; MEMBRANE PROTEIN; PROTEIN SMO; RECEPTOR PROTEIN; UNCLASSIFIED DRUG;

DROSOPHILA; GENE EXPRESSION REGULATION; HUMAN; LIGAND BINDING; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN FAMILY; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN MODIFICATION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

AMINO ACID SEQUENCE; ANIMALS; DROSOPHILA PROTEINS; HUMANS; MOLECULAR SEQUENCE DATA; PHOSPHORYLATION; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 33947383373     PISSN: 00052736     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bbamem.2006.09.020     Document Type: Review

References (134)

1. Mohler J., and Vani K. Molecular organization and embryonic expression of the hedgehog gene involved in cell-cell communication in segmental patterning of Drosophila. Development 115 (1992) 957-971
2. Lee J.J., von Kessler D.P., Parks S., and Beachy P.A. Secretion and localized transcription suggest a role in positional signalling for products of the segmentation gene hedgehog. Cell 71 (1992) 3305-3317
3. Ingham P.W. Signalling by hedgehog family proteins in Drosophila and vertebrate development. Curr. Opin. Genet. Dev. 5 (1995) 492-498
4. Johnston R.L., and Scott M.P. New players and puzzles in the Hedgehog signalling pathway. Curr. Opin. Genet. Dev. 8 (1998) 450-456
5. Kalderon D. Transducing the hedgehog signal. Cell 103 (2000) 371-374
6. Ingham P.W., and McMahon A.P. Hedgehog signalling in animal development: paradigms and principles. Genes Dev. 15 (2001) 3059-3087
7. Hooper J.E., and Scott M.P. Communicating with Hedgehogs. Nat. Rev., Mol. Cell Biol. 6 (2005) 306-317
8. Lum L., Yao S., Mozer B., Rovescalli A., Von Kessler D., Nirenberg M., and Beachy P.A. Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299 (2003) 2039-2045
9. Nybakken K., Vokes S.A., Lin T.Y., McMahon A.P., and Perrimon N. A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signalling pathway. Nat. Genet. 37 (2005) 1323-1332
10. Lum L., and Beachy P.A. The Hedgehog response network: sensors, switches, and routers. Science 304 (2004) 1755-1759
11. Fietz M.J., Concordet J.P., Barbosa R., Johnson R., Krauss S., McMahon A.P., Tabin C., and Ingham P.W. The hedgehog gene family in Drosophila and vertebrate development. Dev. Supple. (1994) 43-51
12. Sasaki H., Nishizaki Y., Hui C., Nakafuku M., and Kondoh H. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signalling. Development 126 (1999) 3915-3924
13. Bai C.B., Stephen D., and Joyner A.L. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev. Cell 6 (2004) 103-115
14. Dai P., Akimaru H., Tanaka Y., Maekawa T., Nakafuku M., and Ishii S. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J. Biol. Chem. 274 (1999) 8143-8152
15. Kalff-Suske M., Wild A., Topp J., Wessling M., Jacobsen E.M., Bornholdt D., Engel H., Heuer H., Aalfs C.M., Ausems M.G., Barone R., Herzog A., Heutink P., Homfray T., Gillessen-Kaesbach G., Konig R., Kunze J., Meinecke P., Muller D., Rizzo R., Strenge S., Superti-Furga A., and Grzeschik K.H. Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. Hum. Mol. Genet. 8 (1999) 1769-1777
16. Vortkamp A., Gessler M., and Grzeschik K.H. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 352 (1991) 539-540
17. Wild A., Kalff-Suske M., Vortkamp A., Bornholdt D., Konig R., and Grzeschik K.H. Point mutations in human GLI3 cause Greig syndrome. Hum. Mol. Genet. 6 (1997) 1979-1984
18. Kang S., Graham Jr. J.M., Olney A.H., and Biesecker L.G. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat. Genet. 15 (1997) 266-268
19. Radhakrishna U., Wild A., Grzeschik K.H., and Antonarakis S.E. Mutation in GLI3 in postaxial polydactyly type A. Nat. Genet. 17 (1997) 269-271
20. Varjosalo M., Li S.P., and Taipale J. Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Dev. Cell 10 (2006) 177-186
21. Kalderon D. The mechanism of hedgehog signal transduction. Biochem. Soc. Trans. 33 (2005) 1509-1512
22. Torroja C., Gorfinkiel N., and Guerrero I. Mechanisms of Hedgehog gradient formation and interpretation. J. Neurobiol. 64 (2005) 334-356
23. Lee J.D., and Treisman J.E. Sightless has homology to transmembrane acyltransferases and is required to generate active Hedgehog protein. Curr. Biol. 11 (2001) 1147-1152
24. Micchelli C.A., The I., Selva E., Mogila V., and Perrimon N. Rasp, a putative transmembrane acyltransferase, is required for Hedgehog signalling. Development 129 (2002) 843-851
25. Callejo A., Torroja C., Quijada L., and Guerrero I. Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix. Development 133 (2006) 471-483
26. Gallet A., Ruel L., Staccini-Lavenant L., and Therond P.P. Cholesterol modification is necessary for controlled planar long-range activity of Hedgehog in Drosophila epithelia. Development 133 (2006) 407-418
27. Burke R., Nellen D., Bellotto M., Hafen E., Senti K.A., Dickson B.J., and Basler K. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signalling cells. Cell 99 (1999) 803-815
28. Dawber R.J., Hebbes S., Herpers B., Docquier F., and van den Heuvel M. Differential range and activity of various forms of the Hedgehog protein. BMC Dev. Biol. 5 (2005) 21
29. Lewis K.E., and Eisen J.S. Hedgehog signalling is required for primary motoneuron induction in zebrafish. Development 128 (2001) 3485-3495
30. Amanai K., and Jiang J. Distinct roles of central missing and dispatched in sending the Hedgehog signal. Development 128 (2001) 5119-5127
31. Nakano Y., Guerrero I., Hidalgo A., Taylor A., Whittle J.R., and Ingham P.W. A protein with several possible membrane-spanning domains encoded by the Drosophila segment polarity gene patched. Nature 341 (1989) 508-513
32. Hooper J.E., and Scott M.P. The Drosophila patched gene encodes a putative membrane protein required for segmental patterning. Cell 59 (1989) 751-765
33. Marigo V., Davey R.A., Zuo Y., Cunningham J.M., and Tabin C.J. Biochemical evidence that patched is the Hedgehog receptor. Nature 384 (1996) 176-179
34. Chen Y., and Struhl G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 87 (1996) 553-563
35. Johnson R.L., and Scott M.P. Control of cell growth and fate by patched genes. Cold Spring Harbor Symp. Quant. Biol. 62 (1997) 205-215
36. Bellaiche Y., The I., and Perrimon N. Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 394 (1998) 85-88
37. The I., Bellaiche Y., and Perrimon N. Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan. Mol. Cell 4 (1999) 633-639
38. Desbordes S.C., and Sanson B. The glypican Dally-like is required for Hedgehog signalling in the embryonic epidermis of Drosophila. Development 130 (2003) 6245-6255
39. Takeo S., Akiyama T., Firkus C., Aigaki T., and Nakato H. Expression of a secreted form of Dally, a Drosophila glypican, induces overgrowth phenotype by affecting action range of Hedgehog. Dev. Biol. 284 (2005) 204-218
40. Gorfinkiel N., Sierra J., Callejo A., Ibanez C., and Guerrero I. The Drosophila ortholog of the human Wnt inhibitor factor shifted controls the diffusion of lipid-modified Hedgehog. Dev. Cell 8 (2005) 241-253
41. Glise B., Miller C.A., Crozatier M., Halbisen M.A., Wise S., Olson D.J., Vincent A., and Blair S.S. Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog. Dev. Cell 8 (2005) 255-266
42. Fisher C.E., and Howie S.E. The role of megalin (LRP-2/Gp330) during development. Dev. Biol. 296 (2006) 279-297
43. Yao S., Lum L., and Beachy P. The Ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 125 (2006) 343-357
44. Tenzen T., Allen B.L., Cole F., Kang J.S., Krauss R.S., and McMahon A.P. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signalling pathway and feedback network in mice. Dev. Cell 10 (2006) 647-656
45. Zhang W., Kang J.S., Cole F., Yi M.J., and Krauss R.S. Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev. Cell 10 (2006) 657-665
46. Denef N., Neubuser D., Perez L., and Cohen S.M. Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell 102 (2000) 521-531
47. Torroja C., Gorfinkiel N., and Guerrero I. Patched controls the Hedgehog gradient by endocytosis in a dynamin-dependent manner, but this internalization does not play a major role in signal transduction. Development 131 (2004) 2395-2408
48. Martin V., Carrillo G., Torroja C., and Guerrero I. The sterol-sensing domain of Patched protein seems to control Smoothened activity through Patched vesicular trafficking. Curr. Biol. 11 (2001) 601-607
49. Strutt H., Thomas C., Nakano Y., Stark D., Neave B., Taylor A.M., and Ingham P.W. Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation. Curr. Biol. 11 (2001) 608-613
50. Nakano Y., Nystedt S., Shivdasani A.A., Strutt H., Thomas C., and Ingham P.W. Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila. Mech. Dev. 121 (2004) 507-518
51. Incardona J.P., Gruenberg J., and Roelink H. Sonic hedgehog induces the segregation of patched and smoothened in endosomes. Curr. Biol. 12 (2002) 983-995
52. Smelkinson M.G., and Kalderon D. Processing of the Drosophila hedgehog signalling effector Ci-155 to the repressor Ci-75 is mediated by direct binding to the SCF component Slimb. Curr. Biol. 16 (2006) 110-116
53. Dai P., Akimaru H., and Ishii S. A hedgehog-responsive region in the Drosophila wing disc is defined by debra-mediated ubiquitination and lysosomal degradation of Ci. Dev. Cell 4 (2003) 817-828
54. Nybakken K., Turck C.W., Robbins D.J., and Bishop J.M. Hedgehog stimulated phosphorylation of the kinesin-related protein Cos2 is mediated by the serine/threonine kinase fused. J. Biol. Chem. 277 (2002) 24638-24647
55. Jia J., Tong C., and Jiang J. Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail. Genes. Dev. 17 (2003) 2709-2720
56. Ruel L., Rodriguez R., Gallet A., Lavenant-Staccini L., and Therond P.P. Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nat. Cell Biol. 5 (2003) 907-913
57. Stegman M.A., Goetz J.A., Ascano Jr. M., Ogden S.K., Nybakken K.E., and Robbins D.J. The Kinesin-related protein Costal2 associates with membranes in a Hedgehog-sensitive, Smoothened-independent manner. J. Biol. Chem. 279 (2004) 7064-7071
58. Ogden S.K., Ascano Jr. M., Stegman M.A., Suber L.M., Hooper J.E., and Robbins D.J. Identification of a functional interaction between the transmembrane protein Smoothened and the kinesin-related protein Costal2. Curr. Biol. 13 (2003) 1998-2003
59. Zhu A.J., Zheng L., Suyama K., and Scott M.P. Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction. Genes Dev. 17 (2003) 1240-1252
60. Lum L., Zhang C., Oh S., Mann R.K., von Kessler D.P., Taipale J., Weis-Garcia F., Gong R., Wang B., and Beachy P.A. Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol. Cell 12 (2003) 1261-1274
61. Stegman M.A., Vallance J.E., Elangovan G., Sosinski J., Cheng Y., and Robbins D.J. Identification of a tetrameric hedgehog signalling complex. J. Biol. Chem. 275 (2000) 21809-21812
62. Sisson J.C., Ho K.S., Suyama K., and Scott M.P. Costal2, a novel kinesin-related protein in the Hedgehog signalling pathway. Cell 90 (1997) 235-245
63. Robbins D.J., Nybakken K.E., Kobayashi R., Sisson J.C., Bishop J.M., and Therond P.P. Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Cell 90 (1997) 225-234
64. Chen C.H., von Kessler D.P., Park W., Wang B., Ma Y., and Beachy P.A. Nuclear trafficking of cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression. Cell 98 (1999) 305-316
65. Wang Q.T., and Holmgren R.A. The subcellular localization and activity of Drosophila cubitus interruptus are regulated at multiple levels. Development 126 (1999) 5097-5106
66. Wang G., Amanai K., Wang B., and Jiang J. Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus. Genes Dev. 14 (2000) 2893-2905
67. Muller G. Towards 3D structures of G protein-coupled receptors: a multidisciplinary approach. Curr. Med. Chem. 7 (2000) 861-888
68. Lander E.S., Linton L.M., Birren B., Nusbaum C., Zody M.C., Baldwin J., Devon K., Dewar K., Doyle M., FitzHugh W., Funke R., Gage D., Harris K., Heaford A., Howland J., Kann L., Lehoczky J., LeVine R., McEwan P., McKernan K., Meldrim J., Mesirov J.P., Miranda C., Morris W., Naylor J., Raymond C., Rosetti M., Santos R., Sheridan A., Sougnez C., Stange-Thomann N., Stojanovic N., Subramanian A., Wyman D., Rogers J., Sulston J., Ainscough R., Beck S., Bentley D., Burton J., Clee C., Carter N., Coulson A., Deadman R., Deloukas P., Dunham A., Dunham I., Durbin R., French L., Grafham D., Gregory S., Hubbard T., Humphray S., Hunt A., Jones M., Lloyd C., McMurray A., Matthews L., Mercer S., Milne S., Mullikin J.C., Mungall A., Plumb R., Ross M., Shownkeen R., Sims S., Waterston R.H., Wilson R.K., Hillier L.W., McPherson J.D., Marra M.A., Mardis E.R., Fulton L.A., Chinwalla A.T., Pepin K.H., Gish W.R., Chissoe S.L., Wendl M.C., Delehaunty K.D., Miner T.L., Delehaunty A., Kramer J.B., Cook L.L., Fulton R.S., Johnson D.L., Minx P.J., Clifton S.W., Hawkins T., Branscomb E., Predki P., Richardson P., Wenning S., Slezak T., Doggett N., Cheng J.F., Olsen A., Lucas S., Elkin C., Uberbacher E., Frazier M., et al. Initial sequencing and analysis of the human genome. Nature 409 (2001) 860-921
69. Venter J.C., Adams M.D., Myers E.W., Li P.W., Mural R.J., Sutton G.G., Smith H.O., Yandell M., Evans C.A., Holt R.A., Gocayne J.D., Amanatides P., Ballew R.M., Huson D.H., Wortman J.R., Zhang Q., Kodira C.D., Zheng X.H., Chen L., Skupski M., Subramanian G., Thomas P.D., Zhang J., Gabor Miklos G.L., Nelson C., Broder S., Clark A.G., Nadeau J., McKusick V.A., Zinder N., Levine A.J., Roberts R.J., Simon M., Slayman C., Hunkapiller M., Bolanos R., Delcher A., Dew I., Fasulo D., Flanigan M., Florea L., Halpern A., Hannenhalli S., Kravitz S., Levy S., Mobarry C., Reinert K., Remington K., Abu-Threideh J., Beasley E., Biddick K., Bonazzi V., Brandon R., Cargill M., Chandramouliswaran I., Charlab R., Chaturvedi K., Deng Z., Di Francesco V., Dunn P., Eilbeck K., Evangelista C., Gabrielian A.E., Gan W., Ge W., Gong F., Gu Z., Guan P., Heiman T.J., Higgins M.E., Ji R.R., Ke Z., Ketchum K.A., Lai Z., Lei Y., Li Z., Li J., Liang Y., Lin X., Lu F., Merkulov G.V., Milshina N., Moore H.M., Naik A.K., Narayan V.A., Neelam B., Nusskern D., Rusch D.B., Salzberg S., Shao W., Shue B., Sun J., Wang Z., Wang A., Wang X., Wang J., Wei M., Wides R., Xiao C., Yan C., et al. The sequence of the human genome. Science 291 (2001) 1304-1351
70. Pierce K.L., Premont R.T., and Lefkowitz R.J. Seven-transmembrane receptors. Nat. Rev., Mol. Cell. Biol. 3 (2002) 639-650
71. Gether U., Asmar F., Meinild A.K., and Rasmussen S.G. Structural basis for activation of G-protein-coupled receptors. Pharmacol. Toxicol. 91 (2002) 304-312
72. Schoneberg T., Schulz A., and Gudermann T. The structural basis of G-protein-coupled receptor function and dysfunction in human diseases. Rev. Physiol., Biochem. Pharmacol. 144 (2002) 143-227
73. Attwood T.K., and Findlay J.B. Fingerprinting G-protein-coupled receptors. Protein Eng. 7 (1994) 195-203
74. Kolakowski Jr. L.F. GCRDb: a G-protein-coupled receptor database. Recept. Channels 2 (1994) 1-7
75. Kristiansen K. Molecular mechanisms of ligand binding, signalling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function. Pharmacol. Ther. 103 (2004) 21-80
76. Schioth H.B., and Fredriksson R. The GRAFS classification system of G-protein coupled receptors in comparative perspective. Gen. Comp. Endocrinol. 142 (2005) 94-101
77. Barnes M.R., Duckworth D.M., and Beeley L.J. Frizzled proteins constitute a novel family of G protein-coupled receptors, most closely related to the secretin family. Trends Pharmacol. Sci. 19 (1998) 399-400
78. Foord S.M. Receptor classification: post genome. Curr. Opin. Pharmacol. 2 (2002) 561-566
79. Dann C.E., Hsieh J.C., Rattner A., Sharma D., Nathans J., and Leahy D.J. Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 412 (2001) 86-90
80. Nusse R. Wnts and Hedgehogs: lipid-modified proteins and similarities in signalling mechanisms at the cell surface. Development 130 (2003) 5297-5305
81. Stone D.M., Hynes M., Armanini M., Swanson T.A., Gu Q., Johnson R.L., Scott M.P., Pennica D., Goddard A., Phillips H., Noll M., Hooper J.E., de Sauvage F., and Rosenthal A. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384 (1996) 129-134
82. Johnson R.L., Milenkovic L., and Scott M.P. In vivo functions of the patched protein: requirement of the C terminus for target gene inactivation but not Hedgehog sequestration. Mol. Cell 6 (2000) 467-478
83. Taipale J., Cooper M.K., Maiti T., and Beachy P.A. Patched acts catalytically to suppress the activity of Smoothened. Nature 418 (2002) 892-897
84. Bulenger S., Marullo S., and Bouvier M. Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation. Trends Pharmacol. Sci. 26 (2005) 131-137
85. Durroux T. Principles: a model for the allosteric interactions between ligand binding sites within a dimeric GPCR. Trends Pharmacol. Sci. 26 (2005) 376-384
86. Maggio R., Novi F., Scarselli M., and Corsini G.U. The impact of G-protein-coupled receptor hetero-oligomerization on function and pharmacology. FEBS J. 272 (2005) 2939-2946
87. Angers S., Salahpour A., and Bouvier M. Dimerization: an emerging concept for G protein-coupled receptor ontogeny and function. Annu. Rev. Pharmacol. Toxicol. 42 (2002) 409-435
88. Hooper J.E. Smoothened translates Hedgehog levels into distinct responses. Development 130 (2003) 3951-3963
89. Kalderon D. Hedgehog signalling: Costal-2 bridges the transduction gap. Curr. Biol. 14 (2004) R67-R69
90. Murone M., Rosenthal A., and de Sauvage F.J. Sonic hedgehog signalling by the patched-smoothened receptor complex. Curr. Biol. 9 (1999) 76-84
91. DeCamp D.L., Thompson T.M., de Sauvage F.J., and Lerner M.R. Smoothened activates Galphai-mediated signalling in frog melanophores. J. Biol. Chem. 275 (2000) 26322-26327
92. Norris W., Neyt C., Ingham P.W., and Currie P.D. Slow muscle induction by Hedgehog signalling in vitro. J. Cell Sci. 113 Pt. 15 (2000) 2695-2703
93. Riobo N.A., Saucy B., Dilizio C., and Manning D.R. Activation of heterotrimeric G proteins by Smoothened. Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 12607-12612
94. Hammerschmidt M., and McMahon A.P. The effect of pertussis toxin on zebrafish development: a possible role for inhibitory G-proteins in hedgehog signalling. Dev. Biol. 194 (1998) 166-171
95. Kasai K., Takahashi M., Osumi N., Sinnarajah S., Takeo T., Ikeda H., Kehrl J.H., Itoh G., and Arnheiter H. The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling. Genes Cells 9 (2004) 49-58
96. Molnar C., and de Celis J.F. Independent roles of Drosophila Moesin in imaginal disc morphogenesis and hedgehog signalling. Mech. Dev. 123 (2006) 337-351
97. Xie J., Murone M., Luoh S.M., Ryan A., Gu Q., Zhang C., Bonifas J.M., Lam C.W., Hynes M., Goddard A., Rosenthal A., Epstein Jr. E.H., and de Sauvage F.J. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391 (1998) 90-92
98. Apionishev S., Katanayeva N.M., Marks S.A., Kalderon D., and Tomlinson A. Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nat. Cell Biol. 7 (2005) 86-92
99. Zhang C., Williams E.H., Guo Y., Lum L., and Beachy P.A. Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 17900-17907
100. Jia J., Tong C., Wang B., Luo L., and Jiang J. Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432 (2004) 1045-1050
101. Chen W., Ren X.R., Nelson C.D., Barak L.S., Chen J.K., Beachy P.A., de Sauvage F., and Lefkowitz R.J. Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2. Science 306 (2004) 2257-2260
102. Pronin A.N., Morris A.J., Surguchov A., and Benovic J.L. Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J. Biol. Chem. 275 (2000) 26515-26522
103. Seibold A., Williams B., Huang Z.F., Friedman J., Moore R.H., Knoll B.J., and Clark R.B. Localization of the sites mediating desensitization of the beta(2)-adrenergic receptor by the GRK pathway. Mol. Pharmacol. 58 (2000) 1162-1173
104. Yoshida N., Haga K., and Haga T. Identification of sites of phosphorylation by G-protein-coupled receptor kinase 2 in beta-tubulin. Eur. J. Biochem. 270 (2003) 1154-1163
105. Chen W., Kirkbride K.C., How T., Nelson C.D., Mo J., Frederick J.P., Wang X.F., Lefkowitz R.J., and Blobe G.C. Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signalling. Science 301 (2003) 1394-1397
106. Cant S.H., and Pitcher J.A. G protein-coupled receptor kinase 2-mediated phosphorylation of ezrin is required for G protein-coupled receptor-dependent reorganization of the actin cytoskeleton. Mol. Biol. Cell 16 (2005) 3088-3099
107. Wilbanks A.M., Fralish G.B., Kirby M.L., Barak L.S., Li Y.X., and Caron M.G. Beta-arrestin 2 regulates zebrafish development through the hedgehog signalling pathway. Science 306 (2004) 2264-2267
108. Pitcher J.A., Freedman N.J., and Lefkowitz R.J. G protein-coupled receptor kinases. Annu. Rev. Biochem. 67 (1998) 653-692
109. Penela P., Ribas C., and Mayor Jr. F. Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. Cell Signal 15 (2003) 973-981
110. Shenoy S.K., and Lefkowitz R.J. Multifaceted roles of beta-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling. Biochem. J. 375 (2003) 503-515
111. Ferguson S.S. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signalling. Pharmacol. Rev. 53 (2001) 1-24
112. McDonald P.H., Chow C.W., Miller W.E., Laporte S.A., Field M.E., Lin F.T., Davis R.J., and Lefkowitz R.J. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290 (2000) 1574-1577
113. Luttrell L.M., Ferguson S.S., Daaka Y., Miller W.E., Maudsley S., Della Rocca G.J., Lin F., Kawakatsu H., Owada K., Luttrell D.K., Caron M.G., and Lefkowitz R.J. Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science 283 (1999) 655-661
114. Luttrell L.M., Roudabush F.L., Choy E.W., Miller W.E., Field M.E., Pierce K.L., and Lefkowitz R.J. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 2449-2454
115. DeFea K.A., Zalevsky J., Thoma M.S., Dery O., Mullins R.D., and Bunnett N.W. beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J. Cell Biol. 148 (2000) 1267-1281
116. Girnita L., Shenoy S.K., Sehat B., Vasilcanu R., Girnita A., Lefkowitz R.J., and Larsson O. {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J. Biol. Chem. 280 (2005) 24412-24419
117. Mukherjee A., Veraksa A., Bauer A., Rosse C., Camonis J., and Artavanis-Tsakonas S. Regulation of Notch signalling by non-visual beta-arrestin. Nat. Cell Biol. 7 (2005) 1191-1201
118. Carman C.V., Som T., Kim C.M., and Benovic J.L. Binding and phosphorylation of tubulin by G protein-coupled receptor kinases. J. Biol. Chem. 273 (1998) 20308-20316
119. Ruiz-Gomez A., Humrich J., Murga C., Quitterer U., Lohse M.J., and Mayor Jr. F. Phosphorylation of phosducin and phosducin-like protein by G protein-coupled receptor kinase 2. J. Biol. Chem. 275 (2000) 29724-29730
120. Freeman J.L., Gonzalo P., Pitcher J.A., Claing A., Lavergne J.P., Reboud J.P., and Lefkowitz R.J. Beta 2-adrenergic receptor stimulated, G protein-coupled receptor kinase 2 mediated, phosphorylation of ribosomal protein P2. Biochemistry 41 (2002) 12850-12857
121. Dinudom A., Fotia A.B., Lefkowitz R.J., Young J.A., Kumar S., and Cook D.I. The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels. Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 11886-11890
122. Carman C.V., Lisanti M.P., and Benovic J.L. Regulation of G protein-coupled receptor kinases by caveolin. J. Biol. Chem. 274 (1999) 8858-8864
123. Koch W.J., Inglese J., Stone W.C., and Lefkowitz R.J. The binding site for the beta gamma subunits of heterotrimeric G proteins on the beta-adrenergic receptor kinase. J. Biol. Chem. 268 (1993) 8256-8260
124. Premont R.T., Claing A., Vitale N., Freeman J.L., Pitcher J.A., Patton W.A., Moss J., Vaughan M., and Lefkowitz R.J. beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein. Proc. Natl. Acad. Sci. U. S. A. 95 (1998) 14082-14087
125. Hildreth K.L., Wu J.H., Barak L.S., Exum S.T., Kim L.K., Peppel K., and Freedman N.J. Phosphorylation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-2 reduces receptor signalling and interaction with the Na(+)/H(+) exchanger regulatory factor. J. Biol. Chem. 279 (2004) 41775-41782
126. Gao J., Li J., Chen Y., and Ma L. Activation of tyrosine kinase of EGFR induces Gbetagamma-dependent GRK-EGFR complex formation. FEBS. Lett. 579 (2005) 122-126
127. Shetzline M.A., Premont R.T., Walker J.K., Vigna S.R., and Caron M.G. A role for receptor kinases in the regulation of class II G protein-coupled receptors. Phosphorylation and desensitization of the secretin receptor. J. Biol. Chem. 273 (1998) 6756-6762
128. A.R. Meloni, G.B. Fralish, P. Kelly, A. Salahpour, J.K. Chen, R.J. Wechsler-Reya, R.J. Lefkowitz and M.G. Caron, Smoothened Signal Transduction is Promoted by G-Protein Coupled Receptor Kinase 2, Mol Cell Biol (in press).
129. Lee S.J., Xu H., and Montell C. Rhodopsin kinase activity modulates the amplitude of the visual response in Drosophila. Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 11874-11879
130. Schneider L.E., and Spradling A.C. The Drosophila G-protein-coupled receptor kinase homologue Gprk2 is required for egg morphogenesis. Development 124 (1997) 2591-2602
131. Lannutti B.J., and Schneider L.E. Gprk2 controls cAMP levels in Drosophila development. Dev. Biol. 233 (2001) 174-185
132. C. Molnar, H. Holguin, F.J. Mayor, A. Ruiz-Gomez and J.F. de Celis, unpublished data.
133. Kohout T.A., Lin F.S., Perry S.J., Conner D.A., and Lefkowitz R.J. beta-Arrestin 1 and 2 differentially regulate heptahelical receptor signalling and trafficking. PNAS 98 (2001) 1601-1606
134. Jaber M., Koch W.J., Rockman H., Smith B., Bond R.A., Sulik K.K., Ross Jr. J., Lefkowitz R.J., Caron M.G., and Giros B. Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function. PNAS 93 (1996) 12974-12979