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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 113

Module 2: Table Hedgehog signalling toolkit
The Hedgehog signalling toolkit.
Component Comment
Hedgehog (Hh) ligands
Shh Sonic Hedgehog
Ihh Indian Hedgehog
Dhh Desert Hedgehog
Hedgehog-binding proteins
HIP Hh-interacting protein
Megalin A member of the low-density lipoprotein (LDL)-receptor-related family
Hedgehog receptors
PTC1 Patched 1
PTC2 Patched 2
Transducer
SMO Smoothened; a seven-membrane-spanning protein
Cytoplasmic regulators
KIF7 Functions to repress Sh responses
FU The fused serine/threonine protein kinase
SUFU Suppressor of fused; a negative regulator of GLI transcription factors
MIM Missing in metastasis; an actin-binding protein that potentiates transcription
Iguana A zinc-finger protein that promotes localization of GLI1
IFT88 Ciliary protein that regulates GLI function
IFT172 Ciliary protein that regulates GLI function
FKBP8 Antagonizes Shh action
SIL Cytoplasmic protein that acts downstream of PTC
Rab23 This regulator of vesicular traffic is a negative regulator of Hh signalling
Transcription factors
The multifunctional GLI transcription factors function to
either activate or repress transcription
GLI1 A zinc-finger transcriptional activator
GLI2 A zinc-finger transcriptional activator/repressor
GLI3 A zinc-finger transcriptional repressor
The function of some of these toolkit components are illustrated in Module 2: Figure Hedgehog signalling pathway.

Module 2: Figure Hedgehog signalling pathway

Hh
Hh
HIP
PTC SMO SMO Hh
PTC
X
SU
KIF7
SU
KIF7 GLI1
SUFU SU GLI1
KIF7
GLI1 SUFU
GLI1
miR-324-5p
Positive Negative
Iguana + + MIM feedback feedback

GLI1, MIM
PTC, HIP
GLI1 Wnt, BMP

Activation of gene transcription by the Hedgehog signalling pathway.
Under resting conditions, the patched (PTC) receptor for Hedgehog (Hh) inhibits the activity of the seven-membrane-spanning receptor smoothened
(SMO). In this inhibited state, SMO is not able to act on the complex of cytoplasmic factors that collectively regulate the transcription factor GLI1.
When Hh is present, it binds to PTC, and this removes the inhibitory effect of the latter on SMO, which is now capable of activating transcription
by releasing GLI from its associated cytoplasmic factors. GLI1 then translocates into the nucleus, where it activates a variety of genes that fall into
three main groups. One group consists of components of the signalling pathway, such as GLI1 and missing in metastasis (MIM), which set up a
positive-feedback loop. The second group consists of genes coding for PTC and Hh-interacting protein (HIP), which thus set up a negative-feedback
loop. The HIP protein acts on the outside to bind Hh and thus reduce its activity. The last group of genes code for proteins not involved in Hedgehog
signalling, but some do function in other signalling pathways such as Wnt (Module 2: Figure Wnt canonical pathway) and the bone morphogenetic
proteins (BMPs) (Module 2: Figure Smad signalling).

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