TGFβ Signalling Flashcards
TGFβ Function
induce proliferation and growth (paracrine or autocrine)
development and homeostasis
TGFβ Signalling
- TGFβ binds to TGFβ receptor II
- TGFβ receptor II binds, phosphorylates TGFβ receptor I
- SARA recruits R-SMADs (1/5) (2/3)
- SMAD4 interact with R-SMADs –> translocate nucleus
- interact with TFs, co-activators, co-repressors
- I-SMAD (6/7) = inhibit R-SMADs
Canonical vs Non-Canonical
Canonical = SMAD translocation
Non-Canonical = trigger other mediators (no SMAD)
Bone Morphogenetic Protein vs TGFβ Signalling
TGFβ Signalling
- TGFβ synthesized as inactive
- activate TGFβ1 = proteolytic cleavage
- SMADs 2/3
Bone Morphogenetic Protein
- BMP secreted as active
- BMP bound to antagonist = no bind to receptor
- SMADs 1/5/8
TGFβ Signalling Regulation
Level of Ligand
- inhibitors (noggin/follistatin) AND no proteases
Level of Receptor
- FKBP12 = T1 receptor inactive AND degrade receptor
Level of SMADs
- I-SMADs (6/7)
Level of Transcriptional Complexes
- Sno/Ski repress SMAD complex
TGFβ Mutations/Knockouts
no TGFβ1 = embryonic lethal (lungs)
no TGFβ2 = embryonic lethal (heart, less ossification)
no noggin (inhibitor) = large growth plates, no limb distinction
TGFβ Signalling Syndromes
Marfan Syndrome
- fibrillin-1 gene stabilize TGFβ signalling = inactive
- mutation –> high levels of active TGFβ
Loeys-Dietz Syndrome
- aortic aneurysm/rupture, skeletal abnormality
- mutations in TGFβR2 and TGFβR1 = more signalling
Mutations to SMAD4
Juvenile polyposis
- SMAD protein complex not activated = colon cancer
Hereditary Hemorrhagic Telangiectasia Syndrome
- mutations in TGFβ receptors = vascular bleeding
Myhre Syndrome
- SMAD4 protein remains active = intellectual disability
TGFβ Signalling in Cancer
loss of SMAD4 = block some things/promote others
TGFβ – tumour promoting and suppressing effects
