The Hedgehog signalling pathway

The Hedgehog signalling pathway regulates cell growth and differentiation to control organ formation during embryonic development. It is critical for normal embryonic development and ensures that tissues reach their correct size and location, and maintain polarity and cellular content.1 In the skin, the Hedgehog pathway regulates hair follicle and sebaceous gland development.2 Hedgehog signalling normally remains inactive in most adult tissues.1

Key components in the Hedgehog signalling pathway

Key components in the Hedgehog signalling pathway

Inactive Hedgehog signalling pathway

When the Hedgehog signalling pathway is inactive, PTCH inhibits SMO activity
When the Hedgehog pathway is inactive, PTCH inhibits SMO activity and there is no target gene expression. 3,4

Normal acitivation of the Hedgehog signalling pathway is initiated by Hh ligand binding PTCH

In normal Hedgehog signalling, the pathway is activitated by Hh ligand binding to PTCH, and the inhibitory effect of PTCH on SMO is removed. SMO becomes localised to the cell surface where it activates a cytoplasmic complex of proteins that ultimately causes the phosphorylation of Gli, a family of transcription factors, which translocate to the nucleus. Phosphorylated Gli proteins are activators of transcription, controlling the expression of Hedgehog target genes that promote cell proliferation and differentiation.3-4

Normal activation of the Hedgehog signalling pathway

Normal activation of the Hedgehog signalling pathway
When the Hh ligand activates the Hedgehog pathway the cell responds by activating expression of target genes.3-6

BCC and abnormal activation of the Hedgehog signalling pathway

The Hedgehog signalling pathway becomes inactive in most adult tissues, with the exception of roles in tissue maintainance and repair.1 However, inappropriate reactivation of Hedgehog signalling may be associated with several human cancers, notably basal cell carcinoma (BCC) and some medulloblastomas.1

Two different mechanisms drive abnormal Hedgehog pathway signalling in different types of cancer.2

  • Ligand-independent signalling driven by alterations in key pathway regulators, such as PTCH or SMO. Results in constitutive activation of the Hedgehog pathway
  • Ligand-dependent signalling driven by overexpression of the Hh ligand by tumour cells

Abnormalities in ligand-independent signalling are associated with BCC and medulloblastoma whilst abnormalities in ligand-independent signalling may be relevant in other cancer types. It is estimated that more than 90% of BCC cases have abnormal activation of Hedgehog signalling,6-8 most commonly resulting from inactivating PTCH mutations.1,4,5,10

Abnormal activation of the Hedgehog signalling pathway

Abnormal activation of the Hedgehog signalling pathway
Inactivating mutations of PTCH result in constitutive pathway activation via removal of PTCH inhibition on SMO.3-6

Futher information on Hedgehog signalling and therapeutic targets that can inhibit abnormal activation of this pathway can be found at www.hedgehogpathway.com

 

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References:

 

  1. Scales SJ, de Sauvage FJ. Trends Pharmacol Sci 2009;30:303–312.
  2. Chiang C et al. Dev Biol 1999;205:1–9.
  3. Rubin LL, de Sauvage FJ. Nat Rev Drug Discov 2006;5:1026–1033.
  4. Caro I, Low JA. Clin Cancer Res 2010;16:3335–3339.
  5. Epstein EH. Nat Rev Cancer 2008;8:743–754.
  6. Teh MT et al. Cancer Res 2005;65:8597–8603.
  7. Kallassy M et al. Cancer Res 1997;57:4731–4735.
  8. Unden AB et al. Cancer Res 1997;57:2336–2340.
  9. Reifenberger J et al. Cancer Res 1998;58:1798–1803.
  10. Rudin CM. Cancer Prev Res 2010;3:1–3.