Cell communication Flashcards
why is cell communication important?
- important for development and homeostasis
- can break down in old age -> has pathology
what is the range of cell communication?
- short range
- medium range
- long range
what is the conceptual basis of communication characterised by?
- speed of signal
- duration of signal
- receptor mechanism of action
what can short-range signals be?
- contact-dependent
- synpatic
what is contact-dependent signalling?
short-range signalling:
- cell has membrane-bound signalling molecule interacting with a receptor on a neighbouring cell
- 1-to-1 communication
example: notch pathway signalling that spaces R8 photoreceptors in Drosophila eye disc
what is synaptic signalling?
short-range signalling:
- neuronal
- neurons may have a very small number of targets
what can medium-range signals be?
paracrine signalling
- signalling cell releases an endogenous molecule which acts on neighbouring cells
- autocrine: when the signal acts on cells of the same type as the signalling cells
example: Hedgehog expression stimulates Dpp ligand expression which is secreted by a strip of cells in the middle of the Drosophila wing
- Hh and Dpp are large proteins with post-translational modifications and interact with ECM components before diffusing to act downstream in local cells
what can long-range signalling be?
endocrine signalling:
- cell releases endogenous molecule into bloodstream
- slow acting but body-wide/systematic changes
example: adrenaline is produced by the adrenal glands and act via adrenergic receptor to produce a wide range of physiological responses including fight or flight
how to cells receive signals?
- extracellular signal molecule binds to a receptor on cell surface
- this triggers intracellular signalling molecules which alter the activity of effector proteins
how do cells respond to signalling?
the activity of effector proteins is altered:
- altered metabolism -> a metabolic enzyme is affected
- e.g. changes in yeast metabolism triggered by different sugars provided as energy source - altered gene expression -> gene regulatory protein is affected
- e.g. expression of Iroquois family genes in E12 mouse embryo - altered shape or movement -> cytoskeletal protein is affected
- e.g. human neutrophil chasing signal given off by a pathogen
Is signalling binary (on/off)?
no:
- there is a quantitative response to a signal
- cells can react in different ways based on the strength of signal received
- there is a qualitatively different response to a signal
- a morphogen gradient may form where responses occur at different thresholds
what is the French Flag Model?
- Bicoid mRNA is deposited by the mother in the anterior of the egg and forms a gradient of protein which acts as a morphogen
- This gradient defines the anterior parts of the resulting embryo
- Gene expression downstream of bicoid has sharp boundaries
- Thresholds of signal trigger sharp on/off gene expression
how does the speed of a cellular response change?
- by changing the structure of an existing protein e.g. an ion channel response occurs very quick
- by changing post-translational modifications e.g. phosphorylation is quite fast
- by changing proteins via gene expression -> this is a slow process
why is signal regulation important?
if it isn’t regulated, it can lead to disease:
1. myeloproliferative neoplasms
- JAK2 V617F is a mutation in the negative regulatory pseudokinase domain of JAK2
- mutation is associated with >95% of polycythaemia vera (blood cancer) patients
- Chronic myeloid leukaemia (CML)
- BCR-Abl fusion protein causes sustained ABL tyrosine kinase expression by the BCR promoter region, leading to CML
- ABL kinase can be inhibited by imatinib
at which stages can signalling pathways be regulated?
- extracellularly via ligand or receptor
- intracellularly via transduction of the signal
- via effectors that can feed back into their own pathways
what is a positive feedback effector?
- effector is stimulated which causes the induction of the same response at a greater amplitude
- short stimulus causes very fast response that is SUSTAINED
e.g. notch pathway lateral inhibition
what is a negative feedback effector?
It the component in a feedback system that causes a change to reverse the situation and return the value to the normal range
e.g. JAK/STAT pathway downregulation by SOCS negative regulator
what do fast cellular responses require?
the rapid turnover of an effector - effector must be readily available
why is the rapid turnover of an effector a wasteful process? how can it be fixed?
- making and then immediately destroying proteins to achieve rapid turnover is wasteful
- to fix this, the activity of the protein must be altered
- add a post-translational modification to an existing protein that can act as a molecular switch that activates/inactivates protein function
what are molecular switches?
monomeric/small GTPases which have enzymatic activity to hydrolyse GTP to GDP
- GTP activates the effector
- GDP inactivates the effector
how are GTPase molecular switches regulated?
- GAP (GTPase Activating Protein) - hydrolyses GTP to GDP
- GEF (GDP to GTP Exchange Factor) - converts GDP to GTP
modulating GAP and GEF levels can rapidly change the activity of the GTPase molecular switch
what are the 2 major groups of protein kinase in eukaryotes?
- serine/threonine kinase (S/T)
- Tyrosine kinase (Y)
give an example of a receptor tyrosine kinase:
EGF receptor (EGFR) is a receptor tyrosine kinase which recognises the epidermal growth factor (EGF)
- it is possible to generate antibodies that specifically recognise phosphotyrosine (pY)
give examples of some kinase inhibitors:
ruxolitinib and imatinib
what do kinase inhibitors do?
- normally, ATP is bound within the ATP-binding pocket of S/T or Y kinases
kinase inhibitors block the ATP-binding pocket
what are the 4 types of kinase inhibitors?
- Type I inhibitors bind to the active conformation of the kinase with the aspartate residue (white backbone) of the DFG motif pointing into the ATP-binding pocket
- Type II inhibitors bind and stabilise the inactive conformation of the kinase with the flipped aspartate residue facing outward of the binding pocket
- Type III inhibitors occupy an allosteric pocket that is adjacent to the ATP-binding pocket but does not overlap with it
- Type IV inhibitors bind to an allosteric pocket remote from the ATP-binding pocket.
what are phosphatases?
- they are key regulators of signalling
phosphatase can downregulate JAK/STAT signalling in flies:
- Overexpression of ptp61c in vivo is able to reduce the tumour phenotype associated with the fly equivalent of the JAK2 V617F mutation
