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Hedgehog Signaling

Written/Edited by Dr. Stefan Pellenz, PhD

Hedgehog (Hh) signaling is highly conserved across chordates of different taxonomical classification. It is essential for development of the embryo. The Hedehog pathway was first described and characterized in the fruit fly, Drosophila melanogaster. In mammals, Hh signaling regulates cell-fate, tissue polarity, and patterning during early embryogenesis and the morphogenesis of specific organs and tissues. It is subsequently silenced in most adult tissues but can be reactivated following injury to promote repair and regeneration.

Different Hh ligands, including homologs sonic hedgehog (SHH), indian hedgehog (IHH), and desert hedgehog (DHH) are produced as precursors that undergo autocatalytic cleavage, C-terminal cholesterol attachment, and N-terminal palmitoylation prior to secretion. Release and extracellular accumulation of the mature ligands is regulated by the homologs of the Drosophila dispatched (Disp) protein. Binding of secreted Hh ligands to the receptor homolog (PTCH1, PTCH2) triggers the stimulation of the signaling network: the repressive effect of PTCH on the transmembrane receptor SMO is relieved which leads to the activation of glioma-associated oncogene (GLI) transcription factors.

A key specialized structure in this process is the microtubule-based primary cilium. In the absence of the Hh signal unprocessed, non-activating GLI proteins as well as their regulator SUFU are concentrated in the distal tip of the primary cilium. Upon binding of the Hh ligand, PTCH relocates to the cell surface, thus rendering translocation of SMO to the primary cilium and the down-regulation of SUFU possible. Several structurally essential primary cilium proteins have also regulatory effects on the Hh signaling cascade.

Aberrant Hh/GLI regulation leads to major tissular disorders and the development of a wide variety of aggressive cancers. The Hh/GLI cascade has also been linked to the regulation of stemness genes and the survival of cancer stem cells.


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Hh Processing

HHAT (Hedgehog Acyltransferase):

PRKACB (Protein Kinase, CAMP Dependent, Catalytic, beta):

PRKACG (Protein Kinase, CAMP-Dependent, Catalytic, gamma):

PRKAR1A (Protein Kinase, CAMP-Dependent, Regulatory, Type I, alpha (Tissue Specific Extinguisher 1)):

PRKAR1B (Protein Kinase, CAMP-Dependent, Regulatory, Type I, beta):

PRKAR2A (Protein Kinase, CAMP-Dependent, Regulatory, Type II, alpha):

PRKAR2B (Protein Kinase, CAMP-Dependent, Regulatory, Type II, beta):

CSNK1G1 (Casein Kinase 1, gamma 1):

CSNK1G3 (Casein Kinase 1, gamma 3):

GSK3b - GSK3 beta:

SKP1 (S-Phase Kinase-Associated Protein 1):

BTRC (beta-Transducin Repeat Containing):

Hh Receptors

Hh Effectors

GLI2 (GLI Family Zinc Finger 2):

Primary Cilium

EVC (Ellis Van Creveld Syndrome):

KIF7 (Kinesin Family Member 7):

EVC2 (Ellis Van Creveld Syndrome 2):

DYNC2H1 (Dynein, Cytoplasmic 2, Heavy Chain 1):

DYNC2LI1 (Dynein, Cytoplasmic 2, Light Intermediate Chain 1):

KIF3A (Kinesin Family Member 3A):

KIF3B (Kinesin Family Member 3B):

KIF3C (Kinesin Family Member 3C):

KIFAP3 (Kinesin Associated Protein 3):

IFT43 (Intraflagellar Transport 43 Homolog):

WDR35 (WD Repeat Domain 35):

TTC21B (Tetratricopeptide Repeat Domain 21B):

IFT140 (Intraflagellar Transport 140 Homolog):

WDR19 (WD Repeat Domain 19):

PDK4 (Pyruvate Dehydrogenase Kinase, Isozyme 4):

IFT46 (Intraflagellar Transport 46):

TRAF3IP1 (TNF Receptor-Associated Factor 3 Interacting Protein 1):

IFT57 (Intraflagellar Transport 57 Homolog):

TTC30B (Tetratricopeptide Repeat Domain 30B):

IFT74 (Intraflagellar Transport Protein 74 Homolog):

IFT80 (Intraflagellar Transport 80 Homolog):

IFT81 (Intraflagellar Transport 81 Homolog):

IFT88 (Intraflagellar Transport 88 Homolog):

BBS1 (Bardet-Biedl Syndrome 1):

BBS2 (Bardet-Biedl Syndrome 2):

BBS4 (Bardet-Biedl Syndrome 4):

BBS5 (Bardet-Biedl Syndrome 5):

BBS7 (Bardet-Biedl Syndrome 7):

TTC8 (Tetratricopeptide Repeat Domain 8):

BBS9 (Bardet-Biedl Syndrome 9):

Hh Regulators

DISP2 (Dispatched Homolog 2):

SUFUH (Suppressor of Fused Homolog):

HHIP (Hedgehog Interacting Protein):

KCTD11 (Potassium Channel Tetramerisation Domain Containing 11):

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