TGF-β signalling Flashcards
Which receptors are bound by TGF-β?
Enzyme coupled receptors with a cytosolic ser/thr kinase domain
What is the likely outcome of TGF-β signalling?
Inhibition of cell growth - tumour suppressors.
Why is TGF-β signalling important in embryo development?
Instructs body plan formation and is inhibited by different signals at different stages of development - e.g. chordin, noggin and follistatin.
How is TGF-β produced?
As an inactive precursor (pro-TGFβ) which is stored in the ECM - via disulfide bonds to a large insoluble ECM similar to fibrillin. Known as the large latent complex.
How are other growth factor precursors stored in the ECM?
Usually via non-covalent binding to heparan sulfate and are released via enzymatic degradation of heparan sulfate.
Describe the signalling downstream of the TGF-β receptor.
- Type II TGFβ receptor ser/thr kinase phosphorylates the Type I TGFβ receptor, when in close spatial proximity – cross phosphorylation.
- SMADs are recruited (like STATs) and are dimerised when phosphorylated by the Type I TGFβ ser/thr kinase.
- SMAD dimer binds SMAD4 and enters the nucleus where it activates transcription of genes with a TGFβ-responsive sequence.
Which Smads are R-Smads and what does this mean?
R-Smads are receptor activated Smads that contain a nuclear localisation sequence (NLS) which allows them to enter the nucleus once dimerised.
- Smad 1, 2, 3, 5 and 8
What is Smad 4?
A co-Smad that can form a complex with any of the 5 R-Smads prior to nucleus entry.
What are the roles of Smad 6 and 7?
Inhibitiory Smads - recruit the ubiquitin ligase Smurf and other phosphatases to the active receptor to shut it down.
Describe Smad activation in early endosomes.
The receptor is internalised by endocytosis in clathrin-coated vesicles. Receptor tails are exposed to the cytoplasm when in the endosome, allowing signalling to continue until the signal is switched off.
