Cell Signalling Flashcards
What is cell signalling for
Controlling a cells behaviour.
It induces a response in a cell
Eg gene expression, structual change, enzyme activity
Give examples of where cell signalling is important
The nervous system (electrical signals)
Immune system - WBCs / antigens
Cell cycle
Metabolism- controlling blood glucose (via adrenaline/insulin)
what are the 5 steps of cell signalling and the proteins involved / molecules
Signal - messenger/ligand
Reception - detection by receptors
Transduction - transducer proteins
Amplification - secondary messengers/ cascades
Response - effectors eg enzymes/ transcription factors
What is transduction
Conversion of a signal to another type of signal by transducer proteins
To pass info down pathway
Name 2 ways protein activity in signalling pathways are altered (switching)
1- conformational change can switch on and off
2- covalent modification
What is covalent modification/ example of how it alters proteins in signalling pathways
Proteins can be switched on and off by adding of molecules
Eg phosphorylation
Kinase will phosphorylate a protein
And to switch it off phosphatase switches it off by removing phosphate
Name some signals / Ligands cells respond to
Physical signals - light, heat
Chemical - hormones, NTs, antigen, nitrous oxides gases
Name the 4 local signalling methods (short distance)
1- gap junctions
2- contact dependant
3- para crine
4- autocrine
How does gap junction signalling work ?
Small signalling molecules such as ions and metabolites (ATP,camp, iP3)
Pass cell to cell through connexon hemi channels
What are the channels called in gap junctions between cells
Connexon hemichannels
How does contact dependant signalling work
When cells nearby each other can form surface receptor/signalling molecule complexes
Eg in immunity these are antigens and receptors
How does paracrine and autocrine signalling work
Paracrine - signalling cells will release local mediator signal molecules/ ligands and then nearby cells will bind to them via receptor = response induced
Autocrine- where cells will release local mediator signal molecules themselves and then bind to the molecules via receptors they released
Give example of local mediator signals in paracrine signalling
Cytokines and growth factors (for proliferation)
Name the 2 major distant cell signalling methods
Synaptic signalling (neurone to neurone via Nts)
Endocrine signalling - via hormones in the blood stream
Cell receptors can be intracellular. Name 2 examples
Nuclear hormone receptors (ligand induced transcription factors)
Nitric oxide receptors (guanylyl)
How does nuclear hormone receptors work - how are they transcription factors (regulating transcription)
When a hormone binds to the receptor on the ligand binding domain this causes a conformational change
This allows the ligand- receptor complex to enter nucleus and bind to dna (via dna binding domain) and initiate gene expression
How are nitric oxide receptors (guanylyl) an intracellular receptor allowing cell response?
When nitrous oxides diffuse across and bind to GUANYLYL RECEPTORS
This causes a conformational change
This causes GTP to be converted into cyclic GMP
Cyclic gmp secondary messenger causes muscle dilation/ relaxation
What would happen if cells didn’t have receptors for the signals?
No response would be induced by the cell
How is androgen insensitivity syndrome an example of receptor importance
They have no androgen binding receptors that bind to steroids like testosterone
If males don’t have them they develop as a female male due to testosterone having no effect
What are the 3 types of cell surface receptors
Ion channel coupled receptors / ligand gated
G protein coupled receptors
Enzyme coupled receptors
Give an example of ion channel coupled receptors
Nicotinic AcH receptors on synapse which change in confirmation to allow Na to flow through
Why are G protein coupled receptors called 7 pass transmembrane receptors
They’re made of 7 alpha helixes which pass the membrane 7 times (embedded in membrane)
What are the 2 types or transducing G proteins
Trimeric - transduce signals from G protein receptors
Monomeric - transduce signals from enzyme linked receptors
Name the 3 parts of a trimeric G protein
3 subunits
Alpha subunit (Ras) is where GDP or GTP bind
Beta and gamma subunits dissociate from alpha when the protein is activated
Explain what happens when a signal molecule binds to a trimeric g coupled protein receptor
The signal causes a conformational change causing alpha subunit to release its GDP molecule
This allows for GTP to bind
When GTP is bound the alpha subunit dissociates as it is activated
The alpha subunit then moves to activate target proteins
What does alpha subunit do when activated
The subunit binds to a target protein and transduces a signal to the protein
The protein then detaches away from subunit when GTP is hydrolysed back into GDP and P
The subunit is then inactivated and reassembles to B and gamma subunit
What are Ligands
Molecules that bind to intracellular receptors such as testosterone and cortisol
Why are the 2 main proteins targeted by the trimeric G protein and what secondary messengers do they produce when activated
Adenylate Cyclase - cyclic amp
Phospholipids C - ip3
Explain the whole cascade of events when adrenaline binds to muscle or liver trimeric G protein coupled receptors
This activates conversion of glycogen into glucose for flight or fight response
When it binds the conformational change in the G protein occurs
The alpha subunit then targets the adenylate cyclase and activates it (transduces the signal)
The adenylate cyclase then converts ATP into cAMP
cAMP activates protein kinase A
Protein kinase A then causes causes phosphorylation by activating phosphorylase kinase
This leads to phosphorylation of enzyme phosphorylase A
Leads to breakdown of glycogen into glucose
Why is cascades for amplification important for cell signalling
It causes a faster response by the cell
What does cAMP dependant protein kinase do when camp activates it
Undergoes a conformational change where the catalytic subunits are released to allow phosphorylation of phosphorylase kinase
Which 2 secondary messengers are produced by phospholipase C (activated by trimeric G proteins)
IP3 and DAG
What happens to phospholipids when phospholipase C is activated?
PIP2 phospholipids are cleaved (cut)
Produces DAG and IP3
What is IP3s role in cell response
IP3 binds to calcium channels on the ER of a cell
Calcium is used then to activate proteins
How does calcium and calmodulin protein cause activating of kinase C?
The calmodulin protein binds to 4 ca2+ and this causes a conformational change
This calcium- calmodulin complex wraps on target proteins eg PKC
= activated
What is DAGs role in PKC - cell response
DAG is membrane bound and allows PKC to stick there.
This allows for the phosphorylation of proteins = cell response
What 2 things do enzyme coupled receptors need for activation
Dimerisation and phosphorylation (eg in RTKs)
Dimerisation just means bringing subunits together of the receptors
What 2 things do receptors called enzyme coupled need to be enzyme coupled
1- intrinsic enzyme activity
2- associated with an enzyme to catalyse a reaction
Receptor tyrosine kinases (RTKs) are a group of enzyme coupled receptors. What molecules do they usually bind with?
Growth factors (which control cell proliferation- RTKs are v important)
What does binding of the growth factor of RTKs cause
Leads to autophosphosphorylation and dimerisation of the receptor (2 subunits are brought closer together)
Why doesn’t dimerisation occur with insulin receptors (also RTKs)
Because insulin is already a tetramer of polypeptides
They just auto phosphorylate instead
How does auto phosphorylation of RTKs like Ras allow for activation of cell signalling pathway proteins?
The proteins associated with it (monomeric G proteins) are activated by the phosphorylation
What is Ras
A monomeric G protein which is activated by the RTKs (when growth factors bind)
What do monomeric G proteins do?
Transduce signals from the enzyme coupled receptors
Eg Ras from the RTKs
What 2 proteins do monomeric G proteins need for the activation and the deactivation of the G protein (trimeric don’t need these)
GEF- guanine exchange factor
GAP- GTPase activation protein
What is GEF needed for by monomeric G proteins
Guanine exchange factor
Needed to activate release of GDP(so it can be activated)
What is GAP needed for by monomeric G proteins like Ras - needed to deactivate the protein
GAP
Needed for the aid of GTP hydrolysis back into GDP aswell as GTPase (too weak on its own)
Explain the steps of the activation of the Ras monomeric G protein when growth factors bind to RTK
RTK when phosphorylated and dimerised
The adaptor protein GRB2 binds to it
This then allows GEF to stimulate GDP release from Ras monomeric protein
GTP instead is added to Ras G protein
This then is activated
What is the phosphorylation cascade that Ras activates called and what are the 3 components
MAP kinase cascade
MapKKK - RAF
MAPKK - MEK
MAPK - ERK
Proteins in nucleus (MAPs)
Explain the steps from Ras activation to the phosphorylation of proteins in the nucleus
Ras protein when activated
Activated RAF mapKKK
RAF KKK phoshphorylates MEK
MEK phosphorylase ERK
ERK translocates into nucleus
ERK phosphorylates proteins in nucleus
Proteins that activate gene transcription of for example cyclin production = allow cell division/proliferation
What is Ras in terms of cancer?
It’s a protooncogene (because it controls cell proliferation)
What happens when Ras has mutations (cancer)
GTP hydrolysis is inhibited
Ras stays active
Signalling switched on constantly
Cell proliferation
What do inhibitors targeting the Ras and map K cascade do?
Stop cell proliferation
What does single pass transmembrane proteins mean?
Their helixes only passes membrane once
Apart from acH, what other ligand hormone acts differently on diff cells
Adrenaline at muscle cells causes glycogenolysis
At heart cells they cause increased heart rate
Why does epinephrine cause heart contraction in contrast to acetylcholine
Epinephrine causes presence of camp from activation of adenylate cyclase when epinephrine hormone binds to heart muscle
