MCB Lecture 39 Cell to Cell communication Flashcards
What are the types of ligand?
Protein: growth factors Steroids Amino acids Nucleotides Hormones
Why is cell to cell communication important?
To relay signals from the external environment to the cell so it can modulate its activity
Growth
Development
Physiology
What are the types of receptor?
- Receptor tyrosine kinase
- GPCR
- Integrins
Where are receptors localised?
Membrane bound
Intracellular (nuclear or in the cytosol)
What are the 6 types of signalling?
- Contact dependent
- Paracrine
- Neuronal
- Endocrine
- Autocrine
- Gap junctions
Describe the two short distance types of signalling
- Contact dependent
The cells must be very close
The ligand is membrane bound - Paracrine: ligands are released by cells and act on receptors on cells in close proximity to the cell
Describe the two types of very short distance signalling
- Autocrine
Identical cells in a community all release these ligands which act on receptors on themselves - Gap junctions
Factors move through gap junctions to neighbouring cells
Ca, cAMP
Describe the two types of long distance signalling
- Neuronal
Ligands synthesised in cell body, travels down axon, secreted from synaptic vesicle.
The ligand travels across the synaptic cleft to the receptors on the post-synaptic cell
What are the two types of receptors?
Describe the differences in the associated ligands
Membrane bound: protein ligands (hydrophilic)
Normally growth factors
Intracellular:
Lipid, steroid ligands
Hydrophobic
Describe the generic pathway for cell signalling (7)
- Primary Transduction: Ligand binds to receptor
- Relay: scaffold organises proteins involved in cascade
- Amplification: proteins produce a large number of factors
- Integration: a mediator receives signals from many pathways
- Spread: mediator produces diverging signals
- Effect: signal alters gene transcription
Anchor: cytoskeleton delivers certain elements
What is combinatorial signalling?
What are the generic outcomes of combinatorial signalling?
Many signals acting on a cell produce a concerted response
Survival
Divide
Differentiation
Death
Describe how one ligand may elicit different responses in different cell types
The receptor is different on the different cells
Heart cells: ACh binds to muscarinic receptor
Brings about the slowing of rate of contraction
Muscle cells: nAChR
Brings about muscle contraction
Salivary gland cells: muscarinic receptors
Brings about secretion of saliva
What are the two types of acetyl choline receptors?
Muscarinic
Nicotinic
Describe how steroid hormones signal
They travel in the blood with a chaperone, because this is an aqueous environment
Chaperone releases them very near to the cell membrane, which they pass through easily
Move not nucleus, bind to their receptor.
Receptor has multiple binding domains.
Gene transcription activated
Describe the features of a steroid receptor
What else does it require to be active?
Multiple binding domains
- Ligand binding domain
- DNA binding domain
- Transcription activating domain
Coactivation proteins
What are the two types of enzyme-linked cell surface receptors?
Receptor tyrosine kinases
Receptor Serine Threonine kinases
What types of ligands signal to cell surface receptors?
Protein: Growth Factors
Fibroblast GF, FGF
Epithelial GF, EGF
Are growth factors monomers or dimers?
They can be monomers, dimers, multimers
Describe how glucosaminoglycans can be involved in Growth factor signalling
These bind the growth factors, and present them to receptors
Or, they sequester them from receptors
Describe the general features of Receptor Tyrosine Kinases
- Transmembrane domain
- Highly variable extracellular domains
- Variable intracellular domains
Give an example of how membrane bound ligands act on receptors.
Give a specific example
What sort of processes use this type of signalling?
Ephrin ligand bound to the membrane
Eph receptor bound to membrane of a cell very near.
Important of development and cancer
What is a dimerisation event?
When a ligand binds to a RTK, the two subunits come together and cross phosphorylate
Describe the generic signal - transduction pathway in tyrosine kinase receptors
- Ligand binds
- Dimerisation
- Cross phosphorylation
- Transmission of signal
What is Src?
It is a non receptor tyrosine kinase that has an SH2, SH3 and a tyrosine kinase domain
What are Src Homology domains?
Differentiate between them
These are domains which are highly conserved in proteins that bind to phospho-tyrosines on RTKs
SH2: binds to phospho-tyrosine on RTK
SH3: binds to the GEF
Where are Src Homology domains found?
Src
Grb2
Describe the signalling stage of the Ras-MAPK pathway
- Ligand binds to RTK
- Dimerisation, cross phosphorylation
- Grb2 binds SH2 to RTK
- GEF (eg. Sos) binds to SH3 on Grb2
- GEF activates Ras
In the Ras-MAPK pathway, which protein (with an SH2 domain) binds to a phospho-tyrosine of the RTK?
Grb2
Which protein binds to Grb2 in the Ras-MAPK pathway?
Where does it bind?
A GEF, eg. Sos
What is a GEF?
Give an example of one
Guanyl nucleotide exchange factor
Sos
Describe how Ras is activated and deactivated
What are the other factors required to do this?
GEF removes GDP and puts on GTP
GAP activates hydrolysis of GTP
What is the function of GAP? What does it stand for?
Hydrolysis of GTP
GTPase activating protein
What are the general features of Ras?
Which two factors control its action?
- GTPase activity
- Activated by GEF
- Active for a very short amount of time due to GAP
- On / off switch
- A proto-oncogene
What are the general players in a signal transduction pathway?
Ligand
Receptor
Intracellular proteins
Describe how RTK and Ras are quickly deactivated. What does this mean for the pathway?
RTK: phosphatase a
Ras: GAP
This means that the pathway needs to amplify quickly
How can the same steroid have different effects in different cells?
The coactivator proteins of the transcription factor may be different
What type of receptor is an Eph receptor?
It is a receptor tyrosine kinase
What sort of pathways do Eph receptors and ephrin function in?
Cell migration
Axon guidance
A hyperactive Ras, that was resistant to GAP will lead to…
Cancer
Over proliferation of cells
How is specificity of MAPK activation maintained?
MAPK has tyrosine and threonine residues –> only Mek can phosphorylate both of these
What are the difference between Tyr-Pi and Ser-Pi and Thr-Pi?
Serine and threonine phosphate are longer lived, ie they are acted upon less by phosphatases
Thus the MAPK cascade has a chance to build up
