Lecture 11 - TGFβ Signalling

Question 1

Summary of TGFβ Signalling:

Answer 1

TGFβ/BMP (Ligand) BINDS TO

Type II and Type I (Receptors) LIGAND BINDING INDUCES RECEPTOR INTERACTION

Type II phosphorylates Type I, activating Type I.

Activated Type I phosphorylates R-SMAD (1, 2, 3, 5, 8)

Phosphorylated R-SMAD forms an activated complex with SMAD4

Activated complex translocates to the nucleus and binds DNA-binding co-factors

Question 2

How many Type II receptors?

Answer 2

5

Question 3

Diseases Associated With Impaired TGFβ Signalling:

Answer 3

Cancer
Fibrosis
Arthritis
Osteoporosis
Parkinson's

Question 4

SMADs:

Answer 4

R-SMADs = Receptor-Activated SMADs
MH1 = Mad Homology Domain 1
MH2 = Mad Homology Domain 2

“Divergent Linker” allows for signalling diversity in different cellular contexts

SMADs binding to DNA has limited affinity and insufficient selectivity

SMAD: MH1; Divergent Linker; MH2;

Question 5

Physiological Roles of BMP/TGFβ Signalling:

Answer 5

Fundamental roles in embryonic development and homeostasis

Context-dependent cellular roles:

• Cell cycle control
• Differentiation
• Survival
• Motility

Diverse biological processes:

• Haematopoiesis
• Epithelial to mesenchymal transition
• Angiogenesis
• Tissue maintenance, healing, and repair
• Bone formation
• Embryonic cell pluripotency/differentiation

Question 6

Context-Dependent Regulation of TGFβ Signalling:

Answer 6

Accessory ligands and ligand traps

Receptor activity and stability

SMAD activity and stability

Transcriptional co-regulators/epigenetic status

Question 7

Context-Dependent Regulation of TGFβ Signalling:

Answer 7

Accessory ligands and ligand traps

Receptor activity and stability:
-Regulation by reversible phosphorylation and ubiquitination

SMAD activity and stability:
-Regulation by reversible phosphorylation and ubiquitination

Transcriptional co-regulators/epigenetic status:

• Self-Enabling (Positive)
• Switch Enhancer
• Self-Enabling (Negative)
• Derepression