Cell signals and responses Flashcards
Types of cell communication
Remote signalling by secreted molecules
Contact signalling by membrane bound molecules (cell surface receptors on one cell bond to cell surface receptors of another cell)
Contact signalling via gap junctions
Endocrine signalling
Secreted
Hormone produced, enters bloodstream and is carried to target cell
Paracrine signalling
Secreted
Local chemical mediator released, acts on cells in immediate environment (e.g. cytokine)
Autocrine signalling
Secreted
On itself
Synaptic signalling
Secreted
Neurotransmitters released at synapses, diffuse to post-synaptic target cell
Order of cell signalling
Signal –> reception –> transduction –> response
Signal (outside)
Growth factors Hormones ECM Chemicals Proteins Sugars Synaptic
Cell responses to signals
Growth, cell division Differentiation Metabolism (faster or slower) Apoptosis (tells cell to die) Gene transcription Secretion Contract/ relax Membrane charge (can generate a.p) Migration (often towards signal e.g. chemokine)
How is transduction caused?
Signal –> cell surface receptor –> transduction
Examples of transduction
Amplification, phosphorylation cascades, secondary messengers
Intracellular receptors
Hydrophobic: can pass through plasma membrane
Transported into nucleus
Response: influence gene transcription
e.g. steroids, NO
Types of membrane receptors
G-protein linked
Tyrosine kinases
Enzyme linked
Ion channels
Monomeric (small) G-proteins
Ras
Family: H-Ras, K-Ras, N-Ras
Function controlled by GDP/ GTP cycle
Stimulates cascade of kinases (effectors)
Proliferation, differentiation, cell death
What does mutation do to Ras
Makes Ras insensitiveto GTPase activation proteins (active for longer i.e. on all the time)
Where are Ras mutations found
in ~30% of all tumours
G-protein coupled receptors
Integral trans-membrane proteins
Receptor occupation promotes interaction with G-protein
Promotes exchange of bound GDP for GTP
Activates G protein (α subunit) which leaves receptor
Initiates signalling through secondary messengers
-another way of switching on/ off protein
Why is cell signalling important?
For adaptation (e.g. to changes in environment), co-ordination and regulation
What are endocrine hormones produced by?
Endocrine glands
Do cytokines last long?
Have very short half-life, works for short time
Two potential routes of signal to cell
Signal –> internal cell receptor
Signal –> cell surface receptor –> signal transduction
Testosterone: hydrophilic or hydrophobic?
Describe pathway
Hydrophobic - can pass through cell membrane
Intracellular receptor
Binds to hormone-receptor coplex in cytoplasm, transported into nucleus, gene transcription altered, mRNA produced, new protein
Example of post-translational modification. What does this do to protein
Phosphorylation (by kinase enzyme)
Phophorylation is like an on/off switch - big charge change
E.g. serine / threonine/ tyrosine
How many times do G-protein coupled receptors cross membrane
7 times
Are G-protein coupled receptors specific?
Yes, very. Won’t recognise other molecules
LOOK AT WORD DOC
LOOK AT WORD DOC
How many types of G-proteins
2
- one that associates with receptors
- one that doesn’t interact with receptors and floats around in cytoplasm (monomeric)
Receptor tyrosine kinases
Dimerise upon ligand binding
Have intrinsic enzymatic activity
Puts phosphate from ATP on tyrosine (autophosphorylation)
Bind src homology-2 (SH-2) proteins
Initiates series of phosphrylation reactions
What can complicated signal cascades do
Amplify signal
Lots of different levels to regulate process (fine tuning)
Example of a transduction cascade
Mitogen activated protein (MAP) kinase system
Enzyme linked receptors
Cytokine receptors
- no intrinsic activity but associates with enzymes involved in phosphorylation - JAKs
- rapid signal by shortcut system to nucleus by STATs
Ion channels
Receptor is ion channel
Ligand (e.g. neurotransmitter) binds to and opens channel (some voltage gated)
Response: influx of Na+, change in membrane potential, a.p.
Secondary messengers
Small molecules
Bind and activates other molecules
Examples of secondary messengers
Cyclic adenosine monophosphate (cAMP)
Inositol triphosphate (IP3)
Ca2+
Diacylglycerol
Control of signalling
Pathway leads to single response
Pathway branches leading to 2 responses
Cross-talk occurs between 2 patways (e.g. growth factor signalling)
Different receptor leads to diff response
Example of control of signalling
Inhibition by protein phosphatases
Example of specificity of signal
Fibroblast growth factor receptor (FGFR) stimulation: -in fibroblasts - proliferation -in neuronal cells - differentiation Cellular compartmental isation e.g. STAT Scaffold proteins
Scaffold proteins
Acts like enzyme in cytoplasm - makes reaction much more likely to happen
Difficulty with therapeutic targets for cancer
If you target cells that are growing, will also target normal cells as well
Therapeutic targets
Cell signalling transmits mitogenic and survival signals
Over-expression in cancer - MAPK, PI3K
Constitutive expression - transformation
Activating mutations of G subunits and receptors
Specific inhibitors - PD184352 (MEK) reduce tumour growth by up to 80%
PTEN a tumour suppressor is a IP3 phosphatase
What is the most important signalling molecules to target for tumours?
Epithelial growth factor receptors (most tumours are epithelial)
Monomeric G-proteins and GDP/ GTP cycle
Inactive when bound to GDP
Phosphorylated (using ATP) to become bound to GTP –> active
