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Receptor Modifications in Hedgehog Regulation

  • Qing Shi
  • Jin JiangEmail author
Chapter
  • 555 Downloads
Part of the Topics in Medicinal Chemistry book series (TMC, volume 16)

Abstract

The Hedgehog (Hh) signaling pathway is one of the highly conserved signaling cascades that control cell growth, cell fate, and pattern formation in species ranging from Drosophila to human. Smoothened (Smo), a G-protein-coupled-receptor (GPCR) family protein, serves as a core component to tranduce Hh signal across the cell membrane. Studying how the activity of Smo is regulated is a key to understand how Hh morphegen gradiant differentially induces target gene expression during normal animal development as well as how abnormal Hh signaling activity contributes to various human diseases. In this chapter, we focus on the regulation of Smo by its posttranslational modifications. By reviewing our current knowledge on how Hh ligands dynamically induce phosphorylation and ubiquitination of Smo and how these modifications coordinatedly modulate Smo function and downstream signaling events, we hope to inspire future exploration of comprehensive mechanisms underlying the regulation of Smo.

Keywords

Hedgehog Phospohrylation Posttranslational modification Smo Smo binding proteins Ubiquitination 

Abbreviations

A

Anterior

BCC

Basal cell carcinoma

CFP

Cyan fluorescent protein

CiA

Ci activator

CiR

Ci repressor

CK1

Casein kinase 1

CK2

Casein kinase 2

Cos2

Costal2

C-tail

Carboxyl-terminal cytoplasmic tail

dSmo

Drosophila Smo

DUBs

Deubiquitinating enzymes

E1

An Ub-activation enzyme

E2

An Ub-conjugating enzyme

E3

An Ub ligase

FRET

Fluorescence resonance energy transfer

Fu

Fused

GPCR

G-protein-coupled-receptor

Gprk2/GRK2

G-protein-coupled-receptor kinase 2

GSK3

Glycogen synthase kinase 3

Hh

Hedgehog

Krz

Kurtz

L3

The third intracellular loop

mSmo

Mammalian Smo

P

Posterior

PKA

Protein kinase A

PP1

Protein phosphatase 1

PP2A

Protein phosphatase 2A

Ptc

Patched

PTM

Posttranslational modification

RA

Arg to Ala

SAID

Smo auto-inhibitory domain

Ub

Ubiquitin

YFP

Yellow fluorescent protein

Notes

Acknowledgments

J.J. is supported by grants from National Institute of Health (GM061269 and GM067045), Cancer Prevention Research Institute of Texas (RP100561), and Welch Foundation (I-1603).

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© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Developmental BiologyUniversity of Texas Southwestern Medical Center at DallasDallasUSA
  2. 2.Department of pharmacologyUniversity of Texas Southwestern Medical Center at DallasDallasUSA

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