Intracellular transduction of the BMP signal

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Table of contents

Résumé
Summary
CHAPTER 1 INTRODUCTION
1.1 The Transforming Growth Factor-beta signaling pathway
1.1.1 Overview of the TGF-beta pathway
1.1.2 TGF-beta Ligands and Receptors
1.2 The Smad transcription factors
1.2.1 The Smad family of transcription factors
1.2.2 Structure of the Smad proteins
1.2.3 Activation of R-Smads
1.2.4 Dephosphorylation of Smad C-terminal motifs by phosphatases
1.2.5 Proteasomal degradation of Smad proteins
1.2.4 R-Smads oligomerization with Smad
1.2.5 Smad nucleocytoplasmic shuttling
1.2.6 DNA recognition by Smad proteins
1.2.7 Negative regulation of R-Smads through linker phosphorylation
1.3 The canonical Wnt signaling pathway
1.3.1 Overview of the Wnt signaling pathway
1.3.2 The Wnt pathway regulates proteins stability
1.4 The FGF/EGF pathway
1.5 Conclusions
CHAPTER 2 Smad1/5/8 Linker Phosphorylations Integrate the BMP and Wnt Signaling Pathways
2.1 Introduction: embryonic axis formation and the double gradient model
2.2 Dorsal–ventral patterning: a morphogenetic gradient of BMP ligands
2.3 Intracellular transduction of the BMP signal
2.4 Anterior–posterior patterning and Wnt signaling
2.5 Regulation of Smad1 via linker phosphorylations downstream of BMP
2.5.1 Inhibitory Smad1 linker phosphorylations by MAPK
2.5.2 GSK3/Wnt regulates BMP/Smad1 signal termination
2.6 Asymmetric inheritance of Smad1
2.7 Smad1 signal duration: phenotypic similarities between BMP and Wnt antagonists in the developing embryo
2.8 Linker regulation of Drosophila Mad
2.8.1 Mad linker phosphorylations: BMP dependent or independent?
2.8.2 Phospho-resistant Mad mutants display Wg-like phenotypes
2.8.3 Mad and Smad1 are required for segment formation
2.8.4 The ancestry of segmentation
2.9 Conclusions
CHAPTER 3 Phosphorylation of Mad Controls Competition Between Wingless and BMP Signaling
3.1 Introduction
3.2 Results
3.2.1 GSK3 phosphorylation of Mad inhibits both BMP and Wg signaling
3.2.2 Mad activates Wg target genes independently of phosphorylation of its C terminus
3.2.3 Mad and Medea are required for Wg signal transduction
3.2.4 Mad binds to Pangolin in the absence of phosphorylation of its C terminus
3.2.5 The Pangolin-Mad-Armadillo complex binds to Tcf DNA binding sites
3.3 Discussion
3.4 Experimental Procedures
CHAPTER 4 The Tumor Suppressor Smad4/DPC4 is Regulated by Phosphorylations that Integrate FGF, Wnt and TGF-beta Signaling
4.1 Summary
4.2 Introduction
4.3 Results
4.3.1 Wnt and FGF regulate phosphorylation of Smad4 linker region
4.3.2 Wnt/GSK3 regulates the polyubiquitination and degradation of Smad4
4.3.3 Wnt/GSK3 regulates a Smad4 beta-TrCP phosphodegron
4.3.4 Wnt and TGF-beta signaling cross-talk via Smad4
4.3.5 The Smad4 linker contains a growth-factor regulated transcriptional activation domain
4.3.6 Phosphorylation by MAPK/Erk promotes Smad4 peak activity
4.3.7 Smad4 regulation by GSK3 determines germ layer specification
4.4 Discussion
4.4.1 Smad4 activity is regulated by growth factors
4.4.2 beta-TrCP binds to the Smad4 phosphodegron
4.4.3 Signalling insulation and crosstalk
4.4.4 Smad4 linker phosphorylation and tumor suppression
4.5 Experimental Procedures
CHAPTER 5 CONCLUSIONS AND PERSPECTIVES
5.1 One transcription factor, two signaling pathways: Mad as a transducer of Dpp and Wg
5.2 One structure, two functions: Smad4 activity and stability are co-regulated
5.3 Is Smad4 phosphorylated by GSK3 after TGF-beta stimulation?
5.4 Is Smad4 degraded in the Wnt destruction complex?
5.5 Smad4 and cancer: the loss-of-Smad4 and the progression of cancer
5.6 Smad4 degradation by beta-TrCP in pancreatic carcinoma
5.7 Concluding remarks
References