TGFb and FGF signalling (L10) Flashcards
What are the common features in signal transduction pathways?
- Reception -the ligand binds to a receptor and activates it
- Transduction - REceptor activation induces transduction of the signal via a cascade of secondary messengers
- Response- A transcription factor is activated or inhibited and alters the transcription of specific target genes.
What are the properties of the TGFb protein superfamily?
TGF = transforming growth factor.
The super family is made up fo the BMP like family, GDNF family and TGFb like family. BMP = bone morphogenic protein - it was first discovered in bones but has many other roles.
They all share the same signal transduction mechanism except that receptor components and SMADs change.
What is the signal transduction pathway for TGFb family receptors?
- Ligand binds to type II receptor and causes polymerisation with Type I receptor to make a dimer.
- This causes Type II to phosphorylate the type I (it has a kinase). This is essential to trigger the overall activation of the receptor
- SMADs are recruited (2 and 3 for TGFb and 1 and 5 for BMP) and phosphorylated then activated by SMAD4. This makes the active transcription complex.
- The complex moves into the nucleus to target TGFb genes and induce cell responses.
How is BMP signalling controlled?
Through inhibition by many antagonists like chordin and noggin. This allows for tight regulation so only certain cells respond and in a specific time and place.
What are the properties of RTKs?
Receptor tyrosine kinases.
20 families each with many individual receptors (with their ligand partners). In humans, 58 RTKs have been identified
Some ligands are specific for one receptor and vice versa.
RTKs include EGF, FGF, insulin and NGF. They’re mostly monomers (except insulin). Their extracellular domains vary greatly - many have immunoglobulin-like domains. The intracellular domains have a kinase. They have 1 transmembrane spanning domain.
How are RTKs activated?
The ligand itself dimerises and then binds to one of the RTKs. This, in turn, causes the RTK to dimerise with another. Once positioned correctly, the kinase domains phosphorylate each other which increases the stability of the kinase and the receptor (so it remains in an active state). It also causes the kinase to phosphorylate other tyrosines which creates docking sites for signal transduction.
What is the signal transduction of RTKs once they have been activated?
The docking sites enables proteins to bind that trigger certain pathways - like PI3-kinase/PLC-gamma (inositol lipid pathway), GTPase-activating proteins (Ras/MapK pathway). The SH2 domain in Src recognises the phosphopeptides.
Explain the Ras pathway of transduction
Ras exists in 2 flavours - inactive (bound to GDP) and active (bound to GTP). Ras can continuously move between states through the activity of GEF (swaps GDP for GTP) and GAP (catalyses GTP to GDP)
Binding of GRB2 and Sos are GEFs that couple active RTKs to inactive Ras. Sos promotes the dissociation of GDP from Ras. GTP binds Ras and then it dissociates from Sos - this activates Ras. Because Ras is unstable, you translate its transient activation into something stable via RTKs e.g. Raf, Mek and MapK) (activates through dual phosphorylation of serine and threonine)
Raf = MapKKK (activated by Ras). MapKKK phosphorylates MapKK (Mek) which phosphorylates MapK. Activated (phosphorylated) MapK then goes on to alter transcription and function of proteins.
What are the properties of the FGF family?
Family of FGF ligands contains 22 members. They can be endocrine, paracrine and intracrine. They have very important roles in embryonic development. e.g. FGF8 - which is expressed in many places discretely (somites, midbrain-hindbrain junction, nodule, limb buds, eyes)
The FGF receptor family contains 3 repeated Ig-like domains (ligands bind to the 2nd and 3rd ones) and a kinase domain. Its kinase receptor is split into 2. there are 4 FGF receptors that trigger pathways for all FGF ligands. This means that 1 FGF receptor will have the ability to bind multiple ligands
How is the specificity defined for the signalling pathways that give discrete boundaries?
One mechanism thought to be responsible for dictating the specificity of the receptor is that FGF and its receptor form a complex with HSPGs (FGFs are unable to act on their own). FGF first forms oligomers on HSPGs. The HSPGs have very distinct patterns of distributions within cells.
What are the properties of HSPGs and how do they contribute to FGF signalling?
Made of a protein core which comes in 3 flavours (completely extracellular (secreted), transmembrane and tethered to the membrane). the protein core is associated with a very large sugar chain and each sugar chain can be modified in different ways, especially by sulphatation (addition of an NSO3- group). This modification could result in a code that creates binding sites for specific proteins e.g. FGF2. Its the sequence, not the 3D structure that may carry information. It may trigger different processes through distinct pathways e.g. proliferation, cell survival or motility.
What are mutations in FGF receptors associated with?
Many human diseases like achondroplasia (mutations in bone formation)
