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
Inactive Hedgehog signalling pathway
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
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
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