Hedgehog and Notch Signalling

Sonic Hedgehog
- Sonic hedgehog is a member of hedgehog family
- There are 3 family but s.hedgehog is the most important in development and it’s the
one that’s most characterized in terms of cancer
- S.H regulates growth through regulation of cell proliferation and survival, patterning
- Growth of thumb is different from finger and this is based on the concentration of
sonic hedgehog your thumb received during development
- Concentration of SH also determines which types of neurons are formed
- There are syndromes related to deregulation of sonic – BCC etc
- Mutation of transcriptional component of hedgehog signaling Gli3 causes Greig
Cephalopolysyndactly (too many digits and fusion of digits)
- Mutation in SH pathway are associated to BCC

The Hedgehog Pathway

- You have the membrane protein call PTC (patch),
- in the absence of hedgehog signaling, it inhibits Smoothen (SMO), which results in
complex of proteins basically processing the GliR (Gli transcription factors)
- Gli has 1,2,3, Gli 1 only expressed when hedgehog signaling is active
- In the absence of Hedgehog signaling, these gli transcription factors are cleaved, and
this represses the expression of hedgehog targets
- Hedghog is modulated by cholesterol, deregulation of cholesterol can affect
hedgehog signaling
1. Hedgehog binds to P TC together with coreceptors (Cdo/Boc) this inhibits the
binding of PTC to SMO, liberates SMO, the complex breaks down
2. Proteins are not cleaved, and are translocated into the nucleus where they
activate gene transcription
3. Hedgehog targets = Bcl2, cyclinD1, Snail (transcription factor), Gli1

Activation of SH pathway in primary cilia

- HH signaling requires presence of a cilia
- Components of HH signaling moves up and down in the cilia by anterograde and
retrograde transport
- HH pathway on: SMO enters the cillia, transcription factor is modulated and pathway
is activated
- If you have mutations in the proteins that affect the cilia, alter cilia formation or alter
anterograde and retrograde transport, this will affect HH pathway

Cilia
- Primary cilia is different, almost all cells in the body has one, and its where HH
signaling pathway takes place, its different from motile cilia in trachea that move
mucus!
GLI transcription factors
- GLI2 and GLI3 has repression domain, in absence of hedgehog signaling they
proteolytically cleaved at the beginning of green activation domain, the repression
domain and dna binding domain enters the nucleus to repress transcription
- In HH signaling the entire GLI enters nucleus and activates gene transcription
- GLI1 is a target of HH signaling and its only expressed when HH signaling is present

Balance of GLI1
- In high levels of HH signaling you have GLI1 expressed and GL1 2 and GLI 3
altogether act as activators
- Without HH signaling, GLI2 and 3 are just repressors

Hedgehog signaling and cancer

Red: mutation in the component of HH pathway is the initiator of cancer progression Yellow:
HH dysregulation causes tumor maintenance
Green: HH signaling present but tumor is present, uncertain

Category 1 = RED
 - Lost of function mutation in PTC so it can’t inhibit SMO causes inactivation of
pathway
- Lost of function in SUFU

Notch Signaling
- T cell ALL due to mutation of notch receptor
- Paracrine signaling, growth factor release by one cell, and enters a cell
- Juxtracrine signaling= notch signaling pathway. The ligand and receptor are cell
membrane protein. The activation occurs in cell next door, ligand binds to receptor
on adjacent cell

Notch Pathway
- Extracellular domain contain EGF-like repeats
- Intracellular d has nuclear localization signal, transcriptional activation domain and
PEST sequence which is involve in regulating stability of this intracellular domain
- Ligand is also membrane bound with many EGF like repeats they are delta genes and
JAG1 and 2
- Mammals have 4 notch receptors, intracellular domain is linked to extracellular
domain
1. Ligand binding to notch receptor and cleavage by TACE and y-secretase
2. This liberates intracellular domain which contain nucleus localization sequence
and TAD and this domain then go straight into nucleus where it modulates
transcription