Lecture 10 TGFbeta and FGF
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How do morphogens act
They act combinatorially to gradually define cell fates in the embryo
2 examples of morphogens
Shh Nodal
How do some secreted signals that aren’t morphogens act
They exert only a local effect, without concentration-dependence
Give an example of a non-morphogen, secreted signal and how it acts
FGF - acts to enhance proliferation and survival in the NT - for growth
What does a signal refer to
The secreted protein/ligand itself
What does signalling refer to
The signal transduction pathway operating in a receptive cell that responds to signal
Give 2 examples of signal transduction pathways
• e.g. Shh initiates a signalling pathway which brings about Gli transcription in the nucleus (altering a balance between Gli activators and Gli repressors) • e.g. Wnt signalling initiates a signalling pathway which brings about β-catenin transcription in the nucleus of Wnt responding cells
3 common features of signalling pathways
Reception Transduction Response
TGFbeta stands for
Transforming growth factor beta
What sort of family is TGFbeta in
A superfamily
Name the 3 TGFbeta families
• Activin family (which includes Nodal) • TGFβ family • BMP family
What is meant by a superfamily
At the amino acid sequence level, and so genetic levels, these proteins are all quite similar
How are members of the TGFbeta superfamily produced
all produced as a pro-protein, from which the pro- domain is cleaved during trafficking through the secretory pathway to leave the mature protein
What does the pro-domain mediate
mediates the formation of homodimers and heterodimers i.e. these are formed before the proteins are exported from the cells
What do different heterodimers and homodimers have?
Different biological activity
What do the dimers interact to form
Activin receptors TGFbeta receptors BMP receptors
What are the receptors also known as
ALK receptors
What occurs when the receptors are stimulated by a ligand
The receptor kinases are activated to phosphorylate SMAD
Which SMAD is phosphorylated by BMP
SMAD 1,5,8
Which SMAD is phosphorylated by TGFbeta
SMAD 2,3
What must occur for the SMAD to be activated
They must be phosphorylated
Is phosphorylation alone sufficient for SMAD 1,5,8/2,3 to enter the nucleus
NO
What else must occur for SMAD 1,5,8/2,3 to enter the nucleus?
They must be attached to SMAD4 which they do after phosphorylation
What occurs after SMAD enters the nucleus with SMAD4?
They must bind to promotors and regulate transcription in the responsive cell