New players and puzzles in the Hedgehog signaling pathway

Current Opinion in Genetics and Development

Volumn 8, Issue 4, 1998, Pages 450-456

  Johnson, Ronald L ^a,b   Scott, Matthew P ^a  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHOLESTEROL; CYTOPLASM PROTEIN; NUCLEAR PROTEIN; SIGNAL RECOGNITION PARTICLE; SONIC HEDGEHOG PROTEIN;

BRAIN TUMOR; CARCINOGENESIS; CELL PROLIFERATION; CHOLESTEROL METABOLISM; CHROMOSOME MUTATION; CYTOSKELETON; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; REVIEW; SIGNAL TRANSDUCTION; SKIN TUMOR; TRANSCRIPTION REGULATION;

ANIMALIA; ERINACEIDAE;

EID: 0031663608     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(98)80117-2     Document Type: Article

References (77)

1. Hooper JE, Scott MP: The Drosophila patched gene encodes a putative membrane protein required for segmental patterning. Cell 1989, 59:751-765.
2. Nakano Y, Guerrero I, Hidalgo A, Taylor A, Whittle JR, Ingham PW: A protein with several possible membrane-spanning domains encoded by the Drosophila segment polarity gene patched. Nature 1989, 341:508-513.
3. Ingham PW, Taylor AM, Nakano Y: Role of the Drosophila patched gene in positional signalling. Nature 1991, 353:184-187.
4. Marigo V, Davey RA, Zuo Y, Cunningham JM, Tabin CJ: Biochemical evidence that patched is the Hedgehog receptor. Nature 1996, 384:176-179.
5. Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL, Scott MP, Pennica D, Goddard A, Phillips H et al.: The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 1996, 384:129-134.
6. Bejsovec A, Wieschaus E: Segment polarity gene interactions modulate epidermal patterning in Drosophila embryos. Development 1993, 119:501-517.
7. Bokor P, DiNardo S: The roles of hedgehog, wingless and lines in patterning the dorsal epidermis in Drosophila. Development 1996, 122:1083-1092.
8. Alcedo J, Ayzenzon M, Von Ohlen T, Noll M, Hooper JE: The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell 1996, 86:221-232.
9. van den Heuvel M, Ingham PW: smoothened encodes a receptor-like serpentine protein required for hedgehog signalling. Nature 1996, 382:547-551.
10. Orenic TV, Slusarski DC, Kroll KL, Holmgren RA: Cloning and characterization of the segment polarity gene cubitus interruptus dominant of Drosophila. Genes Dev 1990, 4:1053-1067.
11. Alexandre C, Jacinto A, Ingham PW: Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the cubitus interruptus protein, a member of the GLI family of zinc finger DMA-binding proteins. Genes Dev 1996, 10:2003-2013.
12. Sasaki H, Hui C, Nakafuku M, Kondoh H: A binding site for Gli proteins is essential for HNF-3β floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 1997, 124:1313-1322.
13. Von Ohlen T, Hooper JE: Hedgehog signaling regulates transcription through Gli/Ci binding sites in the wingless enhancer. Mech Dev 1997, 68:149-156.
14. Strigini M, Cohen SM: A Hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing. Development 1997, 124:4697-4705. This work examines the range of Hh signaling in vivo in organizing the developing wing.
15. Yang Y, Drossopoulou G, Chuang PT, Duprez D, Marti E, Bumcrot D, Vargesson N, Clarke J, Niswander L, McMahon A, Tickle C: Relationship between dose, distance and time in Sonic Hedgehog-mediated regulation of anteroposterior polarity in the chick limb. Development 1997, 124:4393-4404. A thorough study addressing the mechanism by which Shh patterns the developing chick limb. The authors show that while the effects of Shh are long range, the protein does not diffuse far from its source, suggesting that Shh may be inducing secondary signals to pattern the limb.
16. Struhl G, Barbash DA, Lawrence PA: Hedgehog acts by distinct gradient and signal relay mechanisms to organise cell type and cell polarity in the Drosophila abdomen. Development 1997, 124:2155-2165.
17. Struhl G, Barbash DA, Lawrence PA: Hedgehog organises the pattern and polarity of epidermal cells in the Drosophila abdomen. Development 1997, 124:2143-2154.
18. Hidalgo A, Ingham P: Cell patterning in the Drosophila segment: spatial regulation of the segment polarity gene patched. Development 1990, 110:291-301.
19. Goodrich LV, Johnson RL, Milenkovic L, McMahon JA, Scott MP: Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev 1996, 10:301-312.
20. Taylor AM, Nakano Y, Mohler J, Ingham PW: Contrasting distributions of patched and hedgehog proteins in the Drosophila embryo. Mech Dev 1993, 42:89-96.
21. Chen Y, Struhl G: Dual roles for patched in sequestering and transducing Hedgehog. Cell 1996, 87:553-563.
22. Goodrich LV, Milenkovic L, Higgins KM, Scott MP: Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 1997, 277:1109-1113. Mice lacking the function of ptc were constructed and used to analyze the effects on the development of the central nervous system. The neural tube was found to be ventralized in the mutants. This paper demonstrates that Sonic hedgehog target genes are derepressed in the absence of ptc as they are in flies, and confirms the role of ptc in brain cancer.
23. Takabatake T, Ogawa M, Takahashi TC, Mizuno M, Okamoto M, Takeshima K: Hedgehog and patched gene expression in adult ocular tissues. FEBS Lett 1997, 410:485-489.
24. Motoyama J, Takabatake T, Takeshima K, Hui C: Ptch2, a second mouse Patched gene is co-expressed with Sonic hedgehog. Nat Genet 1998, 18:104-106. Ptc2 is shown to be highly related to Ptc1 except in putative cytosolic regions. In the developing epidermis, Ptc2 appears to be upregulated not in Shh-responding cells but in the Shh-producing cells.
25. Hepker J, Wang QT, Motzny CK, Holmgren R, Orenic TV: Drosophila cubitus interruptus forms a negative feedback loop with patched and regulates expression of Hedgehog target genes. Development 1997, 124:549-558.
26. Von Ohlen T, Lessing D, Nusse R, Hooper JE: Hedgehog signaling regulates transcription through cubitus interruptus, a sequence-specific DNA binding protein. Proc Natl Acad Sci USA 1997, 94:2404-2409.
27. Yoon JW, Liu CZ, Yang JT, Swart R, Iannaccone P, Walterhouse D: GLI activates transcription through a herpes simplex viral protein 16- like activation domain. J Biol Chem 1998, 273:3496-3501.
28. Motzny CK, Holmgren R: The Drosophila cubitus interruptus protein and its role in the wingless and hedgehog signal transduction pathways. Mech Dev 1995, 52:137-150.
29. Aza-Blanc P, Ramirez-Weber FA, Läget MP, Schwartz C, Kornberg TB: Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 1997, 89:1043-1053. A seminal paper that reveals a key mechanism in Hh regulation of Ci activity. Hh is found to inhibit the proteolysis of Ci into a 75 kDa form which acts as a repressor of target gene expression. This paper reconciles why Hh causes an apparent increase in Ci protein levels in the cystol and identifies a nuclear form of Ci.
30. Jiang J, Struhl G: Regulation of the Hedgehog and Wingless signalling pathways by the F- box/WD40-repeat protein Slimb. Nature 1998, 391:493-496. The identification of slimb implicates the ubiquitination/proteosome pathway in the regulation of Hh signaling. This gene appears to regulate the degradation of both Ci and Armadillo, a wingless pathway component, to control patterning in Drosophila.
31. Marigo V, Johnson RL, Vortkamp A, Tabin CJ: Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development. Dev Biol 1996, 180:273-283.
32. Mo R, Freer AM, Zinyk DL, Crackower MA, Michaud J, Heng HH, Chik KW, Shi XM, Tsui LC, Cheng SH et al.: Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development 1997, 124:113-1 23.
33. Robbins DJ, Nybakken KE, Kobayashi R, Sisson JC, Bishop JM, Therond PP: Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Cell 1997, 90:225-234. This work breaks new ground in our understanding of how Hh signaling is transmitted from the cytosol to the nucleus. Fu, Cos2, and Ci are shown to associate with each other and form part of a high molecular weight complex that binds microtubules.
34. Sisson JC, Ho KS, Suyama K, Scott MP: Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell 1997, 90:235-245. This paper implicates the cytoskeleton in the regulation of Hh signaling. Cos2, an antagonist of Hh signaling, is shown to encode a kinesin-related protein that binds microtubules and Ci.
35. Forbes AJ, Nakano Y, Taylor AM, Ingham PW: Genetic analysis of hedgehog signalling in the Drosophila embryo. Development 1993, Suppl.:115-124.
36. Therond PP, Knight JD, Kornberg TB, Bishop JM: Phosphorylation of the fused protein kinase in response to signaling from hedgehog. Proc Natl Acad Sci USA 1996, 93:4224-4228.
37. Krishnan V, Pereira FA, Qiu Y, Chen CH, Beachy PA, Tsai SY, Tsai MJ: Mediation of Sonic hedgehog-induced expression of COUP-TFII by a protein phosphatase. Science 1997, 278:1947-1950. This study provides evidence for a non-Gli transcription factor which is activated by Shh. The importance of serine/threonine phosphatases in the regulation of Shh signaling is also indicated.
38. Chen Y, Gallaher N, Goodman RH, Smolik SM: Protein kinase A directly regulates the activity and proteolysis of cubitus interruptus. Proc Natl Acad Sci USA 1998, 95:2349-2354.
39. Ohlmeyer JT, Kalderon D: Dual pathways for induction of wingless expression by protein kinase A and Hedgehog in Drosophila embryos. Genes Dev 1997, 11:2250-2258. PKA regulation of Hh signaling is shown to be more complex than originally thought. In addition to its antagonizing role in Hh signaling, PKA is shown to induce Hh target genes.
40. Akimaru H, Chen Y, Dai P, Hou DX, Nonaka M, Smolik SM, Armstrong S, Goodman RH, Ishii S. Drosophila CBP is a co-activator of cubitus interruptus in hedgehog signalling. Nature 1997, 386:735-738. This paper identifies CBP as a necessary component for Hh signaling. Using genetic and biochemical approaches, CBP is shown to interact with the carboxy-terminal region of Ci to activate transcription of Hh-regulated genes.
41. Porter JA, Young KE, Beachy PA: Cholesterol modification of hedgehog signaling proteins in animal development. Science 1996, 274:255-259.
42. Porter JA, von Kessler DP, Ekker SC, Young KE, Lee JJ, Moses K, Beachy PA: The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature 1995, 374:363-366.
43. Hall TM, Porter JA, Young KE, Koonin EV, Beachy PA, Leahy DJ: Crystal structure of a Hedgehog autoprocessing domain: homology between Hedgehog and self-splicing proteins. Cell 1997, 91:85-97. Using crystallography, the structure of the C-terminal half of Hh was elucidated. This half mediates the autocatalytic cleavage of Hh and the addition of cholesterol to the N-terminal half. The structure reveals a similarity to self-splicing proteins called inteins and provides insights into the mechanism of Hh autoprocessing.
44. Belloni E, Muenke M, Roessler E, Traverso G, Siegel-Bartelt J, Frumkin A, Mitchell HF, Donis-Keller H, Helms C, Hing AV et al.: Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet 1996, 14:353-356.
45. Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M: Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 1996, 14:357-360.
46. Roessler E, Belloni E, Gaudenz K, Vargas F, Scherer SW, Tsui LC, Muenke M: Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. Hum Mol Genet 1997, 6:1847-1853.
47. Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA: Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 1996, 383:407-413.
48. •] report that NPC1 shares homology to Ptc and sterol-sensing proteins. The NPC1/Ptc similarity suggests that the reception of Hh signaling may involve sterol detection and vesicle trafficking.
49. •].
50. Vanier MT, Suzuki K: Recent advances in elucidating Niemann-Pick C disease. Brain Pathol 1998, 8:163-174.
51. Liscum L, Faust JR: Low density lipoprotein (LDL)-mediated suppression of cholesterol synthesis and LDL uptake is defective in Niemann-Pick type C fibroblasts. J Biol Chem 1987, 262:17002-17008.
52. Pentchev PG, Comly ME, Kruth HS, Tokoro T, Butler J, Sokol J, Filling-Katz M, Quirk JM, Marshall DC, Patel S et al.: Group C Niemann-Pick disease: faulty regulation of low-density lipoprotein uptake and cholesterol storage in cultured fibroblasts. FASEB J 1987, 1:40-45.
53. Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, Toftgard R: The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 1996, 14:78-81.
54. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S et al.: Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996, 85:841-851.
55. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein E Jr, Scott MP: Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996, 272:1668-1671.
56. Gorlin RJ: Nevoid basal cell carcinoma syndrome. Dermatol Clin 1995, 13:113-125.
57. Chidambaram A, Goldstein AM, Gailani MR, Gerrard B, Bale SJ, DiGiovanna JJ, Bale AE, Dean M: Mutations in the human homologue of the Drosophila patched gene in Caucasian and African-American nevoid basal cell carcinoma syndrome patients. Cancer Res 1996, 56:4599-4601.
58. Wicking C, Shanley S, Smyth I, Gillies S, Negus K, Graham S, Suthers G, Haites N, Edwards M, Wainwright B, Chenevix-Trench G: Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident. Am J Hum Genet 1997, 60:21-26. A comprehensive study examining 28 ptc1 mutations in BCNS patients indicates an absence of mutation hotspots in the gene and the lack of distinct mutations correlating with particular clinical features.
59. Dahmane N, Lee J, Robins P Heller P, RuiziAltaba A: Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 1997, 389:876-881. Gli1 is found to be transcriptionally induced in most BCCs and may be an important mediator of the formation of these tumors. This and other studies have shown that Gli1 transcription is induced by Hedgehog and repressed by Patched. The current view is that Gli1 is a mediator of Hedgehog signaling, active both when Hedgehog is present (to functionally oppose Ptc protein) and when ptc is inactivated as it is known to be in many tumors. Thus Hedgehog induces higher level production of its own mediator.
60. Kallassy M, Toftgard R, Ueda M, Nakazawa K, Vorechovsky I, Yamasaki H, Nakazawa H: Patched (ptch)-associated preferential expression of smoothened (smoh) in human basal cell carcinoma of the skin. Cancer Res 1997, 57:4731-4735.
61. Unden AB, Zaphiropoulos PG, Bruce K, Toftgard R, Stahle-Backdahl M: Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res 1997, 57:2336-2340.
62. •] to human cells.
63. Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein E Jr, Scott MP: Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 1997, 276:817-821. Overexpression of Shh in the skin of transgenic mice is shown to cause developmental defects including spina bifida and polydactyly, and a BCC-like condition. This study demonstrates the role of the Hedgehog pathway in BCC formation, and demonstrates the similarity between flies and mammalian skin in that too much Hedgehog has the same effect as too little Patched in both cases.
64. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A et al.: Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 1998, 391:90-92. An oncogenic role for smo is revealed. Two point mutations in smo are identified in BCC's and are shown to cause the disease pathology when overexpressed in the skin of transgenic mice.
65. Evans DG, Farndon PA, Burnell LD, Gattamaneni HR, Birch JM: The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer 1991, 64:959-961.
66. Pietsch T, Waha A, Koch A, Kraus J, Albrecht S, Tonn J, Sorensen N, Berthold F, Henk B, Schmandt N et al. : Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 1997, 57:2085-2088.
67. Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD: Sporadic medulloblastomas contain PTCH mutations. Cancer Res 1997, 57:842-845.
68. Vorechovsky I, Tingby O, Hartman M, Stromberg B, Nister M, Collins VP, Toftgard R: Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. Oncogene 1997, 15:361-366.
69. Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G: Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 1997, 57:2581-2585.
70. Xie J, Johnson RL, Zhang X, Bare JW, Waldman FM, Cogen PH, Menon AG, Warren RS, Chen LC, Scott MP, Epstein E Jr: Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res 1997, 57:2369-2372.
71. Rorke LB, Trojanowski JQ, Lee VM, Zimmerman RA, Sutton LN, Biegel JA, Goldwein JW, Packer RJ: Primitive neuroectodermal tumors of the central nervous system. Brain Pathol 1997, 7:765-784.
72. Vorechovsky I, Under AB, Sandstedt B, Toftgard R, Stahle-Backdahl M: Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis. Cancer Res 1997, 57:4677-4681.
73. Pham A, Therond P, Alves G, Tournier FB, Busson D, Lamour-Isnard C, Bouchon BL, Preat T, Tricoire H: The Suppressor of fused gene encodes a novel PEST protein involved in Drosophila segment polarity establishment. Genetics 1995, 140:587-598.
74. Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O'Brien SJ, Wong AJ, Vogelstein B: Identification of an amplified, highly expressed gene in a human glioma. Science 1987, 236:70-73.
75. Vortkamp A, Gessler M, Grzeschik KH: GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 1991, 352:539-540.
76. Wild A, Kalff-Suske M, Vortkamp A, Bornholdt D, Konig R, Grzeschik KH: Point mutations in human GLI3 cause Greig syndrome. Hum Mol Genet 1997, 6:1979-1984.
77. Kang S, Graham J Jr, Olney AH, Biesecker LG: GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 1997, 15:266-268.