The Hedgehog-Gli (Hh-Gli) signaling pathway controls many aspects of tissue patterning, cell proliferation, differentiation and regeneration and regulates cell number in various organs. In adults, the Hh-Gli pathway remains active in a number of stem cells and regenerating tissues.

Inappropriate and uncontrolled HH-GLI pathway activation has been demonstrated in a variety of human cancers.

Links

KEGG (CGAP)

Function

Transport active Hedgehog from the signaling cell to the responding cell occurs through three mechanisms:

 1). formation of multimeric Hedgehog which makes it soluble;
 2). function of Dispatched in releasing the lipid-anchored protein from the signaling cell;
 3). movement across the plasma membrane of the responding cell by Tout-velu-dependent synthesis of heparan sulfate proteoglycan.

In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling. Patched and Smoothened may shuttle oppositely between the plasma membrane and endocytic vesicles in response to active Hedgehog ligand.

In downstream signaling, Cubitus interruptus (Gli proteins in vertebrates), Costal 2, Fused, and Suppressor of Fused form a tetrameric complex. Cubitus interruptus is a bifunctional transcription regulator.

In the absence of active Hedgehog ligand, a truncated transcriptional repressor is generated that binds target genes and blocks their transcription.

In the presence of active Hedgehog ligand, a full length transcriptional activator binds target genes and upregulates their transcription. Target genes include Wingless (Wnt gene family in vertebrates), Decapentaplegic (Bone Morphogenetic Proteins in vertebrates), and Patched.

The upregulation of Patched expression, resulting in Patched protein at the cell membrane, sequesters Hedgehog and limits its spread beyond the cells in which it is produced. Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other.

Many more factors that are essential for the hedgehog signaling network are also discussed: Megalin, Rab23, Hip, GAS1, PKA, GSK3, CK1, Slimb, SAP18, and CBP.

The hedgehog pathway is a major regulator of embryonic development, and mutations that decrease its activity are known to be associated with severe defects in nervous system development.

Sonic hedgehog (SHH) continues to function in adult tissue, normal as well as diseased, by regulating both cell proliferation and the production of growth and angiogenic factors.

In the adult nervous system, this dual ability is especially important in regulating the behavior of neural stem and progenitor cells. (16776596)

Pathology of hedgehog signaling (Hedgehog-signaling related diseases)

 holoprosencephaly (SHH, PTCH)
 Pallister-Hall syndrome (GLI3)
 Grieg cephalopolysyndactyly (GLI3)
 post-axial polydactyly type 3 (GLI3)
 VACTERL (GLI2 and GLI3)
 Rubinstein-Taybi syndrome
 nevoid basal cell carcinoma syndrome (PTCH)
 sporadic basal cell carcinoma (PTCH)
 sporadic basal cell carcinoma (SMO)
 sporadic medulloblastoma (PTCH)
 Smith-Lemli-Opitz disease (DHCR7)
 glioblastoma (GLI or GLI1)

See also

 GLI (MIM.165220)

References

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 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

 Stecca B, Mas C, Altaba AR. Interference with HH-GLI signaling inhibits prostate cancer. Trends Mol Med. 2005 May;11(5):199-203. PMID: 15882606

 Sanchez P, Clement V, i Altaba AR. Therapeutic targeting of the Hedgehog-GLI pathway in prostate cancer. Cancer Res. 2005 Apr 15;65(8):2990-2. PMID: 15833820

 Roessler E, Muenke M. How a Hedgehog might see holoprosencephaly. Hum Mol Genet. 2003 Apr 2 ;12(Suppl 1) :R15-25. PMID : 12668593

 Mullor JL, Sanchez P, Altaba AR. Pathways and consequences: Hedgehog signaling in human disease. Trends Cell Biol. 2002 Dec;12(12):562-9. PMID: 12495844

 Kalderon D. Similarities between the Hedgehog and Wnt signaling pathways. Trends Cell Biol. 2002 Nov;12(11):523-31. PMID: 12446114

 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

 Bale AE, Yu KP. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet. 2001 Apr;10(7):757-62. PMID: 11257109

 Aza-Blanc P, Kornberg TB. Ci: a complex transducer of the hedgehog signal. Trends Genet. 1999 Nov;15(11):458-62. PMID: 10529809

 Ruiz i Altaba A. Gli proteins and Hedgehog signaling: development and cancer. Trends Genet. 1999 Oct;15(10):418-25. PMID: 10498938