Controlling cells Flashcards
What is cellular signalling important for?
- Communication between cells
- Critical for normal development and function
What is the general mechanism of cellular signalling?
1) Reception of a signal
2) Transduction of signal
3) Cellular response
What 5 crucial functions do signaling cascades perform?
1) Transduce
- Signal into molecular form that can stimulate a response
2) Relay
- Signal from point of reception to point of action in the cell
3) Ampliy
- The received signal
4) Distribute
- The signal to influence several responses in parallel
5) Modulation
- By other signals
- Can happen at any step
Examples of direct communication between cells?
1) Gap junction s
2) Interaction of cell surface molecules
Examples of local communication between cells?
1) Paracrine signalling
2) Synaptic signalling
3) Hormonal signalling
How do hydrophobic molecules act as signalling molecules?
Give an example
- Pass through the membrane
- Directly acitvate intracellular receptos in the cytoplasm or nucleus of the target cell
eg. steroid hormones
How do hydrophillic molecules act as signalling molecules?
Give an example
- Can’t cross the membrane
- Rely on membrane receptors
eg. NO, chemically unstable, uncharged gas
What are the 3 categories of enzyme-linked receptors?
1) Receptor tyrosine kinase
2) Cytokine receptors
3) TGT- beta type receptors
What are the ligands of receptor tyrosine kinases?
Soluble or membrane-bound peptide or protein hormones
What do mutant forms of RTK do?
Send proliferative signals to cells in the absence of a signal
What do RTKs do?
1) Autophosphorylate themselves
2) Phosphorylate tyrosine residues on target proteins and themselves
3) Stimulates assembly of a signalling complex where other proteins can ‘dock’
How are the RTK complexes disassembled?
By protein tyrosine phosphatases
What do RTKs activate?
1) Activate Ras (G protein)
2) Activate the PI-3 kinase-Akt pathway
What happens when Ras is activated?
Ras activates a the MAP-kinase cascade
- MAP-kkk
- MAP-kk
- MAP-k
What happens when the PI-3 kinase-Akt pathway is activated?
Akt serves as a suvival signal for the cell and stimulates cell growth
What are cytokines?
Small, secreted proteins which control growth and differentiation of many types of tissues
What happens when a cytokine receptor is activated?
it signals to the nucleus in a direct pathway
What do TGF beta receptors do?
Exert anti-proliferative signals to cells
What happens if there is a mutation in the TGF beta pathway?
- Contribute to malignancy
- Often associates with pancreatic cancers
- But also implicated in colon, liver and gastric tumours
What is the OFF state of WNT signalling?
1) Beta-catenin is associated with E-cadherin
2) Targeted phosphorylation of B-catenin by CDK1 and GSK3beta leads to ubiquitination
3) Ubiquitination leads to breakdown of B-catenin
What is the ON state in WNT signalling?
1) WNT ligand binds frizzled receptors
2) LRP5/6 brought to WNT/frizzled complex
3) This complex activates dishevelled (Dvl)
4) Dvl displaces GSK3beta, preventing Beta-catenin destruction
5) Beta-catenin is free to be translocated to nucleus, turns on genes by displacing co-repressors from TCF/LEF1 (on DNA)
5 ways to inactivate receptor signalling?
1) Receptos sequestation
2) Receptor downregulation
3) Receptor inactivation
4) Inactivatio of signalling protein
5) Production of inhibitory protein
What ligands can bind to TGF-beta receptors?
NODAL
ActivinA
TGFb
Which SMADs do the TGF-b receptors phosphorylate?
2 or 3
What ligands can bind to BMP receptors?
GDF3
NOGGIN
Which SMADs do BMP receptors phosphorylate?
1, 5 or 8
Which co-SMAD are all SMADs competing for and what does this mean?
SMAD4
There must be a balance of TGF-beta and BMP signalling
What type of signalling is WNT and BMP?
Long range
What type of signalling is NOTCH?
Short range - works between adjacent cells
