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Canonical and Non-Canonical Hedgehog Signaling Pathways: Role of G Proteins

  • Natalia A. RioboEmail author
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 16)

Abstract

The Hedgehog (Hh) signaling pathway has received a great deal of attention in the past decade due to its involvement in cancer, angiogenesis, and fibrosis. Several inhibitors of the pathway were developed which target the 7-transmembrane protein Smoothened (Smo), core component of the canonical pathway that controls Gli-dependent transcriptional activity. However, recent studies revealed that the Hh pathway has other transcription-independent functions, collectively known as “non-canonical signaling.” This review describes the role and function of each Hh pathway component in canonical and non-canonical signaling, with emphasis on the role of Smo as a GPCR that selectively activates heterotrimeric Gi proteins.

Keywords

Gli Hedgehog Heterotrimeric G proteins Non-canonical Smoothened 

Abbreviations

12TM

12 transmembrane

20(S)OHC

20(S)-Hydroxycholesterol

25OHC

25-hydroxycholesterol

5HT

5-hydroxytriptamine

7TM

7 transmembrane

AMP

Adenosine monophosphate

cAMP

3′-5′-cyclic adenosine monophosphate

CCK

Cholecystokinin

ChIP

Chromatin immunoprecipitation

CoA

Coenzyme A

cyclopamine

(2′R,3S,3′R,3′aS,6′S,6aS,6bS,7′aR,11aS,11bR)-1,2,3,3′a,4,4′,5′,6,6′,6a,6b,7,7′,7′a,8,11,11a,11b-Octadecahydro-3′,6′,10,11b-tetramethylspiro[9H-benzo[a]fluorene-9,2′(3′H)-furo[3,2-b]pyridin]-3-ol

GDC-0449

(2-chloro-N-[4-chloro-3-pyridin-2-yl-phenyl]-4-methane-sulfonyl benzamide)

GSA-10

4-[[(1-Hexyl-1,2-dihydro-2-oxo-3-quinolinyl)carbonyl]amino]benzoic acid propyl ester

GTP

Guanosine-5′-triphosphate

GTPγ[S]

Guanosine 5′-O-[γ-thio]triphosphate

H89

N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide

LDE-225

N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4′-(trifluoromethoxy)biphenyl-3-carboxamide

M25

N-[[1-(2-Methoxyphenyl)-1H-indazol-5-yl]methyl]-2-propylpentanamide

NES

Nuclear export signal

PI4P

Phosphatidylinositol 4-phosphate

SAG

N-Methyl-N′-(3-pyridinylbenzyl)-N′-(3-chlorobenzo[b]thiophene-2-carbonyl)-1,4-diaminocyclohexane

SANT-1

(4-Benzyl-piperazin-1-yl)-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethylene)-amine

siRNA

Small interference RNA

XL-139

N-(2-methyl-5-((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular Biology and Kimmel Cancer Center, Sidney Kimmel Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA

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