SHH
MIM.600725 7q36
Function
Sonic Hedgehog (Shh) is a secreted protein identified genetically as an important developmental factor. Shh provides a morphogenic signal in the developing CNS, organizing the spatial patterning of cells in the midbrain and inducing proliferation of neuronal precursor cells in the developing cerebellum, neural tube and retina.
Sonic hedgehog signaling may proceed by more than one mechanism. One signaling pathway is activated by Shh binding to Patched (Ptc-1) which releases inhibition of the GPCR Smoothened, activating the Shh signaling pathway and allowing progression through the G1 phase of the cell cycle.
Shh can also affect progression through the G2/M transition. Patched binds to phosphorylated Cyclin B1, one component of the M-phase promoting factor (MPF), along with the kinase Cdc2. The interaction of Cyclin B1 with Patched blocks MPF activity, blocking progression through the G2/M transition.
Shh binding leads to degradation of Ptc-1, release of Cyclin B1, and entry of the cyclin B1 into the nucleus.
Patched acts as a tumor suppressor by blocking MPF activity. Blockade of the Hedgehog pathway by cyclopamine demonstrated the therapeutic potential of Hedgehog inhibition in the treatment of some cancers.
(From Biocarta)
Hedgehog proteins as lipid-linked morphogens
Wnt and Hedgehog family proteins are secreted morphogens that act on surrounding cells to pattern many different tissues in both vertebrates and invertebrates.
The discovery that these proteins are covalently linked to lipids has raised the puzzling problem of how they come to be released from cells and move through tissue.
A synergistic combination of biochemical, cell biological and genetic approaches over the past several years is beginning to illuminate both the forms in which lipid-linked morphogens are released from cells and the variety of molecular and cell biological mechanisms that control their dispersal. (16364628)
Pathology
germline mutations in
- holoprosencephaly 3 (MIM.142945)
- ocular coloboma (MIM.120200)
- solitary median maxillary central incisor (SMMCI)(MIM.147250)
Proliferative signaling by Shh is involved in the development of cancer, including specific brain and skin cancers such as basal cell carcinomas.
Features
SHH-GLI signaling pathway
References
Lavine KJ, Ornitz DM.Fibroblast growth factors and Hedgehogs: at the heart of the epicardial signaling center.Trends Genet. 2008 Jan;24(1):33-40. PMID: 18054407
Ingham PW, Placzek M. Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet. 2006 Nov;7(11):841-50. PMID: 17047684
Eaton S. Release and trafficking of lipid-linked morphogens. Curr Opin Genet Dev. 2006 Feb;16(1):17-22. PMID: 16364628
Dellovade T, Romer JT, Curran T, Rubin LL. The hedgehog pathway and neurological disorders. Annu Rev Neurosci. 2006;29:539-63. PMID: 16776596
Ferretti E, Smaele ED, Marcotullio LD, Screpanti I, Gulino A. Hedgehog checkpoints in medulloblastoma: the chromosome 17p deletion paradigm. Trends Mol Med. 2005 Dec;11(12):537-45. PMID: 16290230
Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance.Nat Rev Cancer. 2003 Dec;3(12):903-11. PMID: 14737121
Roessler E, Muenke M. How a Hedgehog might see holoprosencephaly. Hum Mol Genet. 2003 Apr 2;12(Suppl 1):R15-25. PMID: 12668593
Ruiz I Altaba A, Palma V, Dahmane N. Hedgehog-Gli signalling and the growth of the brain. Nat Rev Neurosci. 2002 Jan;3(1):24-33. PMID: 11823802
Hammerschmidt M, Brook A, McMahon AP. The world according to hedgehog. Trends Genet. 1997 Jan;13(1):14-21. PMID: 9009843