Hedgehog signalling pathway
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The Hedgehog Signaling Pathway is an essential cellular pathway required during embryogenesis. It involves the Hedgehog protein (Hh) which is an autoproteolytic secreted morphogen. Mutations cause severe developmental defects and many maligancies result from mis-activation of the pathway. In man there are three genes that encode for Hh proteins:
- Desert hedgehog (dhh)
- Indian hedgehog (ihh)
- Sonic hedgehog (shh)
In order for Hh to be active as a secreted signaling molecule it is processed by:
- Auto-cleavage generating an N-terminal fragment (HhNp)
- The covalent bonding of cholesterol to the C-terminus of HhNp
- The addition of palmitic acid to the N-terminus of HhNp.
The release of Hh from cells requires a multiple-pass, transmembrane transport-like protein, Dispatched (Disp). In the absence of Disp, the cholesterol-Hh complex is not secreted from cells.
Hh triggers key cytoplasmic effectors
- Costal-2 (cos2) a kinesin-related microtubule binding protein
- Fused (Fu), a putative serine/threonine kinase
- A transcription factor Cubitus interruptus (Ci).
Hh signaling hyper phosphorylates Fu, leading to inhibition of Ci proteolysis with conversion of Ci from a transcriptional repressor to an activator leading to target gene activation in cells receiving Hh.
- Extracellular matrix proteins outside the cell also are involved in Hh signalling. These are heparan sulphate proteoglycans such as the mammalian EXT tumor suppressor gene family.
Diseases associated with this pathway
Several other conditions are suspected to be associated with defects and a fuller list is at The Hedgehog Pathway Database. Please note that other gene defects may also cause some of these conditions.
- Acrocapitofemoral dysplasia (ACFD)[1]
- Brachydactyly,Type A1 (BDA1)[2]
- Breast cancer[3]
- Coloboma[4]
- Desmosterolosis[5]
- Enchondromatosis[6][7]
- Gastric cancer[8]
- Glioblastoma
- Gonadal dysgenesis[9]
- Holoprocencephaly (HPE)[10]
- Holoprocencephaly 3
- Holoprocencephaly 4
- Holoprocencephaly 7
- Pituitary Anomalies with Holoprocencephaly-Like Features
- Medulloblastoma[11]
- Multiple exostoses
- Nevoid basal cell carcinoma syndrome (NBCCS)
- Basal cell carcinoma (BCC)[12]
- Gorlin syndrome
- Oesophageal cancer[13]
- Pallister-Hall syndrome
- Grieg cephalopolysydactyly (GCPS)
- Pancreatic cancer[14]
- Prostate cancer
- Rhabdomyosarcoma
- Small cell cancer of lung
- Smith-Lemli-Opitz syndrome (SLO)
- Solitary median maxillary central incisor syndrome (SMMCI)
- VATER (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial dysplasia.) may be caused due to mouse model of SHH blockage[15]
References
- ↑ Hellemans J, Coucke P J, Giedion A, De Paepe A, Kramer P, Beemer F, Mortier G R. Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Am. J. Hum. Genet. 72: 1040-1046, 2003
- ↑ Gao B, Guo J, She C, Shu A, Yang M, Tan Z, Yang X, Guo S, Feng G, He L. Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1. Nature Genet. 28: 386-388, 2001
- ↑ Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S, Katano M. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res. 2004;64(17):6071-4.
- ↑ Schimmenti LA, de la Cruz J, Lewis RA, Karkera JD, Manligas GS, Roessler E, Muenke M.Novel mutation in sonic hedgehog in non-syndromic colobomatous microphthalmia.Am J Med Genet A. 2003 Jan 30;116(3):215-21.
- ↑ Waterham H R, Koster J, Romeijn G J, Hennekam R C M, Vreken P, Andersson H C, FitzPatrick D R, Kelley R I, Wanders R J A. Mutations in the 3-beta-hydroxysterol delta-24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. Am. J. Hum. Genet. 69: 685-694, 2001
- ↑ Vortkamp, A, Lee K, Lanske B, Segre G V, Kronenberg H M, Tabin C J. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273: 613-622, 1996.
- ↑ Kobayashi T, Soegiarto D W, Yang Y, Lanske B, Schipani E, McMahon A P, Kronenberg H M. Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP. J. Clin. Invest. 115: 1734-1742, 2005
- ↑ Berman D M, Karhadkar S S, Maitra A, Montes de Oca R, Gerstenblith M R, Briggs K, Parker A R, Shimada Y, Eshleman J R, Watkins D N, Beachy P A. Widespread requirement for hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425: 46-851, 2003.
- ↑ Umehara F, Tate G, Itoh K, Yamaguchi N, Douchi T, Mitsuya T, Osame M. A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied by minifascicular neuropathy. Am. J. Hum. Genet. 67: 1302-1305, 2000.
- ↑ Belloni E, Muenke M, Roessler E, Traverso G, Siegel-Bartelt J, Frumkin A, Mitchell H F, Donis-Keller H, Helms C, Hing A V, Heng H H Q, Koop B, Martindale D, Rommens J M, Tsui L C, Scherer S W. Identification of Sonic Hedgehog as a candidate gene responsible for holoprosencephaly. Nature Genet. 14: 353-356, 1996.
- ↑ Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM, Beachy PA. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science. 2002;297(5586):1559-61.
- ↑ Bale, A. E.; Yu, K.-P. The hedgehog pathway and basal cell carcinomas. Hum. Molec. Genet. 10: 757-762, 2001
- ↑ Berman D M, Karhadkar S S, Maitra A, Montes de Oca R, Gerstenblith M R, Briggs K, Parker A R, Shimada Y, Eshleman J R, Watkins D N, Beachy P A. Widespread requirement for hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425: 46-851, 2003.
- ↑ Berman D M, Karhadkar S S, Maitra A, Montes de Oca R, Gerstenblith M R, Briggs K, Parker A R, Shimada Y, Eshleman J R, Watkins D N, Beachy P A. Widespread requirement for hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425: 46-851, 2003.
- ↑ Kim J H, Kim P C W, Hui C. The VACTERL association: lessons from the Sonic hedgehog pathway. Clin. Genet. 59: 306-315, 2001.
