Hedgehog Flashcards
What happens to the hedghog pathway in the absence of Shh, Ihh or Dhh?
Full length Gli phosphorylated by PKA, GSK3 and; CKI.
Hyperphoshorylated form bound by adaptor protein B-TrCP
Complex ubiquitinated by Cul1-based E3 ligase and targeted for proteasomal processing forming TRUNCATED REPRESSOR.
Which Gli’s are activator and which are the repressor forms?
Gli1 activatory
Gli2 and 3 proteolytically cleaved into repressor forms in absence of HH as contain repressor domains.
How are developmental outcomes controlled by the ligands?
Concentration and duration dependent manner.
What is Sufu?
A negative pathway regulator. Interacts with and sequesters full length Gli in cytoplasm preventing nuclear translocation and promoting phosphorylation and processing into a truncated repressor.
Sequestration stabilises full length Gli2 and Gli3.
What are the different categories of cancer that Hh signalling plays a role in?
CI: signalling important for tumour initiation and maintenance e.g. BCC
CII: Hh signalling important for maintenance but not tumour initiation e.g. Colon cancer.
CIII: Hh signalling implicated in tumourigenesis but role not determined. e.g. Lymphoma.
What causes Gorlin syndrome?
Loss of one functional copy of PTCH –> activates Hh pathway.
How has NOCTH signalling been linked to T cell leukaemia?
~50% T-ALL patients have activating mutations in Notch receptor.
- Translocation drives ectopic expression of NICD = t(7;9)(q34;q34.4) –> fusion of 3’ region of NOTCH1 into TCRB locus - overexpression of active form of Notch1.
What mutations are often found in lymphomas?
HD domain - ligand independent activation
PEST mutations - increased stability (and half life) of NICD.
Ikaros - a repressor and absence –> Notch signalling.
FWB7 - responsible for degrading active Notch receptor.
What are the pleiotropic effects of Hedgehog signalling?
Proliferation Survival Immune escape EMT (snail) Angiogenesis
