Cell signalling Flashcards
What is signalling transduction?
Conversion of a message from one form into another
What are the main principles of cell signalling?
Target cells have receptors for signalling molecules
Most cells both generate and receive signals
Signals can act over different ranges
What is Endocrine signalling?
Signals mediated by hormones
What is Paracrine signalling?
Signalling to nearby cells
What is neuronal signalling?
Signalling via specialised neurone cells
What is contact dependent signalling?
Signalling between neighbouring cells
What is delta notch signalling?
Idea of a signal peptide being complementary to a receptor protein
What does direct cell-cell contact regulate?
Nerve cell differentiation as a differentiated nerve cell produces inhibitory protein (delta) and neighbouring cell receptors (notch) interact to tell the cells not to differentiate
What determines downstream signalling?
Depends on the cell type - different cell types have different combinations of receptors
Depends on if the appropriate receptors are present
Same signal can induce varying responses in different cell types?
What does cell behaviour depend on?
Depends on the multiple extracellular signals
What happens to a cell If it doesnt receive any signals?
The cell will die
What how cells integrate responses?
Cells respond to multiple signals simultaneously
Different cells must be integrated and one signal may modify the response to another
Different combinations of signals results in different cellular behaviours
What are the different cellular responses and how do they vary?
responses can be fast or slow depending on what the cell is required to do
Is intracellular signalling fast?
Yes
Cell surface receptor pathway is slower
What do extracellular signalling molecules bind to?
bind either to cell surface receptors or to intracellular enzymes or receptors
When will signalling molecules bind to cell surface receptors?
If the signal molecule is hydrophilic
When will signalling molecules bind to intracellular receptors?
If the signal molecules is small and hydrophobic
What is cortisol?
A steroid hormone that binds a nuclear receptor and this new complex moves into the nucleus to activate a targeted gene
How can dissolved gases transmit signals?
nitric oxide (NO) triggers smooth muscle relaxation in blood vessel walls.
What are the features of the signalling pathway?
Extracellular signal molecule binds to receptor protein.
Relay - spread signal through the cell
Amplification - make signal stronger with release of second messenger molecules
Integrate - Receiving more than one signalling input and generating appropriate output
distribute - pass on the signal to more than one pathway
What are protein kinases?
Kinases phosphorylate proteins on serine threonine or tyrosine residues
How do kinases play a role in cell signalling?
Protein phosphorylation alters conformation and activity of proteins.
How does phosphorylation affect cell signalling?
Creates docking sites for signal molecules
Activates signalling molecules
enables recruitment of effector molecules to transduce signals
What are GTPases?
Signalling molecules that act as a molecular switch
How do GTPases act as switches?
Cycle between active GTP bound states and inactive GDP bound forms
Active GTP bound forms can activate downstream effector proteins
What are the varying cell surface receptors?
Ion channel coupled receptors
G-protein coupled receptors
Enzyme coupled receptors
What are Ion channel coupled receptors?
- Opens (or closes) in response to an extracellular signalling molecule
- Results in changes in membrane potential
- Converts chemical signal into an electrical signal
- Found in the nervous system and other electrically excitable cells
What are G-protein coupled receptors (GPCRs)?
- Largest class of cell surface receptors – 700 in humans
- Can be activated by proteins, peptides, amino acid derivatives, fatty acids
- Binding ligand induces a conformational change resulting in activation of a G-protein found on the intracellular side of the plasma membrane
- Activated G-proteins can activate enzymes or ion channels
What is the largest call of enzyme coupled receptors?
Largest class of Enzyme coupled receptors are the Receptor tyrosine kinases (RTKs)
What are GPCRs made of?
Seven pass membrane spanning proteins
consist of an alpha, beta and gamma subunit
What is the alpha subunit of GPCR?
A GTPase
How do GPCRs activate downstream signals?
- Upon binding of the signal molecule, conformational changes in the receptor cause conformational changes in the a subunit resulting in exchange of GDP for GTP and activation
- The asubunit dissociates from the b and g subunits, which stay together
- Activated a subunits and activated bgcomplexes are both able activate downstream signal
How are GPCRs switched off?
When the alpha subunit hydrolyses GTP to GDP
the alpha and bgcomplex re-associate to reform the inactive G-protein
How is cAMP generated?
Activated alpha subunit activates the enzyme adenyl cyclase which is converting ATP to cyclic AMP. (produced as a response to many hormones)
cAMP phosphodiesterase switches the signal off by converting cAMP to AMP allowing basal levels of cAMP to remain low
How does Acetylcholine signal via GPCRs to slow the heart rate
Activated bg complexes directly interact with a K+ channel increasing permeability
How can GPCR signalling can increase the concentration of second messengers
Activation can cause increase in cyclic AMP
Activation of phospholipase C generates diacylglycerol and inositol trisphosphate
Inositol trisphosphate increases intracellular calcium
How does cAMP act through protein kinase A?
Adrenaline binds to GPCR which causes the bgcomplex to activate adenyl cyclase
Adenyl cyclase converts ATP to cAMP
cAMP activates PKA
PKA can phosphorylate a second enzyme which inturn causes glycogen break down
PKA can also activate TFs driving gene expression
How are RTKs activated?
A growth factor binds to the RTK and induces receptor dimerization
The RTK phosphorylate tyrosine’s on the opposite receptors which enables the recruitment of other signalling molecules
How do RTKs cause activation of downstream signalling?
Signal molecule binds and causes receptor dimerization
RTK activated by phosphorylation
The adaptor protein Grb2 binds to phospho-tyrosine
This recruits the Ras activating protein which promotes exchange of GDP for GTP
Conformational changes in Ras cause activation of downstream protein
What is ras?
A molecular switch of a GTPase
Most commonly mutated oncogene in cancer
Why is ras the most commonly mutated oncogene?
Mutations prevent GTP hydrolysis causing it to be permanently switched on
What are MAP kinases?
Mitogen activated protein kinases
What is the MAP signalling cascade?
3 protein signalling cascade activated by RTKs during G1 to drive cells into the cell cycle
How does the MAP signalling cascade work?
- Activated ras (Ras-GTP) causes activation of Raf
- Raf activates MEK by phosphorylation
- MEK activates ERK by phosphorylation
- Activated ERK has a number of targets to phosphorylate including transcription factors and growth factors
- MAP kinase signalling drives entry into the cell cycle
What do inositol phospholipids do?
Play a critical role in intracellular signalling
What is PIP2?
Phosphotidylinositol-4,5-diphosphate (PIP2)
most abundant PI in the plasma membrane
A substrate of phospholipase C
What happens when phospholipase C is activated?
It splits PIPI2 into DAG ( diacylglycerol) and IP3 (inositol triphosphate)
What does IP3 do?
Triggers a rise in intracellular calcium
How does IP3 trigger a rise in intracellular calcium?
Phospholipase C is activated by signalling downstream from GPCRs or RTKs
Products of PIP2 catalysis (DAG) by PLC activates PKC
IP3 causes opening of Ca ion channels releasing Ca into cytosol
Activated PKC has Ca bind to it to trigger many biological processes.
How does calcium trigger biological processes?
Ca acts via interacting with various Ca responsive proteins such as calmodulin
Calmodulin activates its own target proteins (MLCKs)
What is signal integration?
Some signalling proteins act as signal integrators – they can receive signals from multiple signalling pathways
Phosphorylation can result in activation or inhibition
The combination of phosphorylated serines, threonines and/or tyrosines will dictate the response
What happens with permanent activation of growth factor signalling pathways?
Can lead to cancer (mutated ras, RTKs and raf)
