Cell Signalling Flashcards
Signals and responses examples
- oxygen supply, temperature, pathogens, hormones, growth factors
- response: differentiation, apoptosis, secretion, transcribe different genes
Drugs
Herceptin (breast cancer)- target cell surface growth factors receptors (HER2)
Salbutamol (asthma reliever)- target cell surface receptor (beta 2 receptor)
Gleevec (imatinib, leukaemia)- target intracellular protein tyrosine kinase
Avastin (bevacizumab, various cancers)- targets VEGF: signal for angiogenesis
Types of signals
-physical: pressure, temperature
- electrical
-biochemical: hormones, growth factors
Hormones
- amino acid derivatives
- modified amino acid: adrenaline, peptide hormone: oxytocin, protein hormone: insulin
- steroid hormone
- derived from cholesterol, eg testosterone, cortisol
- eicosanoids
- derived from lipids eg prostaglandins
Range of action of chemical signals
- long distance (endocrine via blood)
- nearby cells, by diffusion ( paracrine)
- neighbouring cell, via cell:cell contact (juxtacrine)
- same cell (autocrine)
Stages of all signals
Individual cells need to:
- DETECT signal/stimuli
- TRANSDUCER the signal from site of detection to part of cell that will respond
- RESPOND- must be coordinated with responses to other signals; and with responses of other cells (tissue/organ/body)
Receptors: intracellular
- hydrophobic signal molecules can diffuse through plasma membrane into cell
- eg steroid hormones, nitric oxide
- steroid hormones bind directly to intracellular receptor proteins
• hormone receptor complex acts as a transcription factor
• complex binds to DNA and alters gene expression
Receptors: cell surface
- water soluble/ hydrophilic signalling molecules must use a cell surface receptor protein, insulin,
- 3 types: ion channel linked, g- protein linked (adrenaline) and enzyme linked (RTK, growth factors)
Ion- channel-linked
- eg. Glutamate neurotransmitter
- ions flow into cell changes electrical properties of cell
- eg. Nerve impulse transmission between nerve cells
G- protein- linked/coupled (GPCR)
- eg. Adrenaline, serotonin
- activated G protein activated enzyme that passes on signal into cell
- N.B large heterotrimeric G protein ( alpha/beta subunits)
Enzyme linked receptor
- key subtypes: receptor tryrosine kinase (RTK)
Eg. Many growth factors, insulin
Reversible protein phosphorylation
- adding phosphate can layer protein function eg. Activate a target enzyme
- dephosphorylation reverses the processes- protein phosphates often then “OFF” signalling pathways
Transduction and amplification
- when signal is transducer it is also amplified
-one receptor molecule activated many relay molecules - different receptors use different transducers/amplifiers
- two main methods: enzyme cascade, second messengers
Enzyme cascade: MAPK cascades
- often activated in response to growth factor RTK activation eg. EGF
- relay proteins Grb/Sos activated Ras
- RAS: proto oncogene, commonly mutated in cancer
- Ras activated a MAP kinase cascade
- enzyme cascade: signal amplified
Second messengers
- small molecules produced in large amounts inside cell after receptor activation
- second messengers coordinates cell response
-eg. Adrenaline GPCR- cAMP - PJA activation - effector protein phosphorylated
Different repsonses that are possible
- gene expression
- protein activity: phosphorylation alters metabolic enzyme activity
- protein binding eg, to inhibitor/activator protein, or to DNA
- protection localisation eg. Transcription factors “activated@ by moving from cytosol to nucleus
Receptor tyrosine kinases in cancer
- GF/RTK pathways often overactive in cancer
• activating mutation or overexpression, of RTK or other pathway proteins - treatment: activating antibodies or small molecule kinase inhibitors
GPCR activation
- ligand bind to receptor causes conformational change in cytoplasmic domain
- conformational change allows G- proteins to bind/ be activated by receptors
- activated G-proteins activated intracellular enzymes
How G-proteins in GPCR work
- GTP- bound: active
GDP- bound: inactive - activated (GTP-bound) G-protein activated downstream effector proteins
- GAP/ RGS proteins- off switch
Effect of GPCR activation
- lots of different targets of activated alpha (and free beta y) subunits
- can activate or inhibit targets, directly or indirectly
- common: causes production of second messengers molecules
Multiple signalling pathway and responses
- one receptor can activate multiple signalling pathways
- one signalling pathway can activate multiple different responses
Specificity in signaling
- a cells response to a given signal depends on the types and levels of receptors, transducers and effectors are expressed in that cell type
- genes same: expression differs
- this means that same hormones can have different effects in different tissues
- in vivo, specific GPCR use only a specific subset G- protein types, which couple to only a specific subset of target proteins
