Signalling Flashcards
Why is cell signalling important?
- to coordinate development:
- e.g. morphogens
- Cyclopes = a failure of SHH (sonic hedgehog) signalling during developing
- to maintain homeostasis:
- e.g. control of blood glucose levels
- abnormal signalling causes disease:
- e.g. diabetes = lack of sufficient insulin production/reduced responsiveness to insulin in target cells
- e.g. cancer - mutated K-Ras is too active and causes cells to grow/divide/survive in the absence of growth signals
- many drugs work by targeting signalling proteins:
- e.g. Herceptin (used in breast cancer) - targets overexpression of growth factor HER2
- e.g. Salbutamol (asthma reliever) - targets cell surface receptor beta 2
- e.g. Gleevec (chronic myeloid leukaemia) - targets intracellular protein tyrosine kinase (bar-abl)
- Avastin (various cancers) - targets and inhibit activity of VEGF
What are the different types of signals that cells can respond to?
- physical e.g. temperature
- electrical e.g. never impulses
- (bio) chemical e.g. hormones, growth factors and neurotransmitters
How can biochemical signals be classified?
- By their chemical structure
2. Range of action (distance)
Chemical classifications of signalling molecules
Hormones:
- amino acid derivatives: - modified amino acids e.g. adrenaline - peptide hormones e.g. oxytocin - protein hormones e.g, insulin, growth hormone - steroid hormones: - derived from cholesterol e.g. testosterone, cortisol - eicosanoids: - derived from lipids e.g. prostaglandins
Range of action classification of signalling molecules
- long distance e.g. endocrine via blood
- nearby cells by diffusion e.g. paracrine
- neighbouring cell via cell:cell contact e.g. juxtacrine
- same cell (auto rinse)
What are the three stages of cell signalling?
- Detect
- Transduce
- Respond
Discuss intracellular receptors
- for signalling molecules that are hydrophobic so can diffuse through plasma membrane of target cell without need for cell surface receptor or transporter e.g. steroid hormones, nitric oxide
- e.g. steroid hormones
- bind directly to intracellular receptor proteins
- hormone-receptor complex acts as a transcription factor
- complex binds to DNA and alters gene expression
Discuss cell surface receptors
- these are for water-soluble/hydrophilic signalling molecules (hydrophilic)
- binds to receptor protein
- cell surface receptor becomes activated when ligand binds to it
- changes conformational shape and shape change changes activity to activate/trigger a response within the cell e.g. insulin/adrenaline signalling
What are the 3 main types of cell surface receptor?
- Ion-channel-linked
- G-protein-linked (GPCR)
- Enzyme linked
Describe an ion channel linked receptor
E.g. glutamate neurotransmitter
- signal molecule binds to receptor, channel opens
- ions can flow into or out of cell along concentration gradient - common in nerve impulses transmission
- the ion flow into the cell changes the electrical properties of the cell
Describe a G protein coupled receptor (GPCR)
E.g. adrenaline, serotonin
- activated G protein activates enzyme that passes on signal into cell
-
Discuss enzyme linked receptors
- where receptor either is or is directly linked to an enzyme
- a key subtype is receptor tyrosine kinases (RTK) e.g. many growth factors
What is a kinase?
An enzyme that catalyses the addition of a phosphate group from an ATP on to a target protein. This can alter the function e.g. activation or inhibition
- dephosphorylation reverses the process - common way to turn signal ‘off’
What is a tyrosine kinase?
E.g. EGF
- ligand binding
- receptor dimerisation and activation
- autophosphorylation
- docking sites
- relay proteins recruited and transmit signal further into cell
What happens when a signal is amplified?
- one receptor molecules activates many relay molecules:
- enzyme cascades
- second messengers
Discuss enzyme cascades in reference to the MAPK cascade
MAPK = Mitogen activated protein kinase
- growth factor binds to receptor
- autophosphorylation and binding of relay proteins
- relay proteins activate Ras (proto-oncogene)
- Ras activates a MAP Kinase cascade (enzyme cascade: signal amplified)
- many growth factors use MAPK cascades e.g. EGF
Discuss the second messenger system
A second messenger is a small molecule that is produced in large amounts inside the cell after receptor activation e.g. cAMP, calcium ions, IP3
- second messenger coordinates cell response
- e.g. adrenaline signalling GPCR > cAMP cAMP > PKA activation > effector proteins phosphorylated
What are some molecular level responses to signal transduction?
- gene expression
- protein activity eg. Phosphorylation alters metabolic enzyme activity
- protein binding e.g. to inhibitor/activator proteins or to DNA
- protein localisation e.g. transcription factor ‘activated’ by moving from cytosol to nucleus
What are some cellular level responses to signal transduction?
- die
- grow
- divide
- differentiate
- migrate
- change shape
- increase or decrease cell activity
- produce new proteins
- transcribe new genes
- release hormones
How many responses can one receptor activate?
Many!
E.g. EGF receptor can activate responses to evade apoptosis, proliferate and invade
Can a single effector protein only be targeted by one signalling pathway?
No - it can be targeted by multiple signalling pathways
E.g. p53 is targeted by different pathways depending on the level of DNA damage in the cell:
- low damage levels > p53 phosphorylated on serine 15 > activates gene expression that causes cell cycle arrest so DNA can be repaired
- high damage levels > p53 phosphorylated on serine 15 AND serine 46 > activates gene expression to cause apoptosis as damage is too severe to repair
Name some drugs that target receptor tyrosine kinases in cancer
- Herceptin is a monoclonal antibody used in breast cancer treatment to target the HER2 receptor
- Avastin is a monoclonal antibody used in the treatment of colorectal cancer to target VEGF (angiogenesis
- Iressa is a small molecule inhibitor used in the treatment of lung cancer to target EPGF
