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SHH-GLI signaling pathway

Monday 15 September 2003

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.




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)
- 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)

- Increased expression of the hedgehog signaling pathway in pediatric solid malignancies. (20152358)

- Hedgehog pathway expression in heterogeneous pancreatic adenocarcinoma: implications for the molecular analysis of clinically available biopsies. (18043287)

See also

- GLI (MIM.165220)


- Increased expression of the hedgehog signaling pathway in pediatric solid malignancies. Oue T, Yoneda A, Uehara S, Yamanaka H, Fukuzawa M. J Pediatr Surg. 2010 Feb;45(2):387-392. PMID: 20152358

- Hedgehog pathway expression in heterogeneous pancreatic adenocarcinoma: implications for the molecular analysis of clinically available biopsies. Steg A, Vickers SM, Eloubeidi M, Wang W, Eltoum IA, Grizzle WE, Saif MW, Lobuglio AF, Frost AR, Johnson MR. Diagn Mol Pathol. 2007 Dec;16(4):229-37. PMID: 18043287


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