Lecture 18 Intercellular Signal Trafficking Flashcards
Signal transport mechanisms
- Diffusion
- Transcytosis
- Exovesicle
- Cytoneme
Passive diffusion
Diffusion gradients
Reaches equilibrium
Physical flow of material
Challenges of signalling through diffusion
Secretion from source cell Interaction with matrix Interaction with receptors and uptake in target cells Degradation of ligand Release of ligand from target cell
Characteristics of diffusion based transport
Long life time of ligand in extracellular space
Short intracellular life time of ligand
Limited control of conc of ligand in cell
No control of direction
What influences diffusion
The extracellular matrix
The extracellular matrix influences diffusion by
Hindering diffusion
Complexing
Cell interactions
Proteoglycans can regulate
the Fgf signalling pathway
Fgf
Fibroblast Growth Factors
family of cell signalling proteins involved in development and regeneration
Fgf’s are released locally upon
Injury
HSPGs
Heparin sulfate proteoglycans
components of the ECM
HSPGs mediate
Fgf signal transduction by acting as receptors or co receptors
regulate Fgf receptor trafficking
control secretion of Fgf ligands
regulate the structure of the ECM and establishment of Fgf signalling gradients (through hindered diffusion)
RCM
Restrictive clearance molecule
describes the transport of a ligand through a tissue
In the RCM extracellular ligand concentration is reduced which leads to
continuous degradation to maintain a concentration gradient
In RCM the rate of uptake determines the
Gradient:
Decreased uptake = long term spreading
Increased uptake = short range spreading
Fgf8 example of DIFFUSION
Rate of Fgf8 endocytosis and degradation determines the signalling gradient
Fgf8 is taken up by Rab5 (GTPase) increased activity of Rab5=shorter range for Fgf8
Planar Transcytosis
Transport of a ligand THROUGH cells
continuous uptake, degradation and recycling with secretion
The rate of endocytosis regulates the
Spreading
Dpp example of TRANSCYTOSIS
Dpp = decapentaplegic signalling factor
regulates cell fate
Taken up by Rab5
Dpp is taken up by Rab5 increased activity of Rab5=shorter range for Dpp
Exovesicles
Exosomes
Lipid bilayer contains lipids, nucleic acids, signalling and cellular proteins
Exosome secretion pathway
Multi vesicular bodies are released as exosomes into the extracellular space
ESCRT complex important for exosome formation
ESCRT is a protein complex that is
Highly conserved in eukaryotes
ESCRT
Intracellular sorting machinery
Complex of 4 proteins
ESCRT complex
ESCRT 0 - sequesters TM proteins in endosome
ESCRT 1,2 - causes membrane deformation into buds
ESCRT 3/Vsp4 - vesicle scission
All form a star like shape that bubbles the exosome
Filopodia
Cytoplasmic fingers of actin
functions: movement, sensing, cell-cell signalling
Signalling filopodia are called
Cytonemes
Cytonemes are like
Arms that transport components of signalling machinery
Filopodia formation
Initiation phase
Protrusion phase
Retraction phase
Filopodia intiation phase
Nucleation complex
cdc42+IRSP53+Bar proteins bend the membrane
Filopodia protrusion phase
cdc42 causes Actin filaments stabilise protrusions
Growth by actin incorporation at the tip (mysoin10 transports actin to tip)
Fascin connects actin filaments into bundles
Wnt cytonemes
have an initiation, protrusion and retraction phase
Causes signalling in the recipient cell
The Shh gradient (sonic hedgehog)
Limb bud development
Low to high conc = thumb to little finger!
Shh is transported on
Cytonemes
Long signalling range as filopodia are very long
DIFFUSION summary
- Target cells control gradient by uptake
- RCM
- Signal interacts with ECM
- Undirected, slow transport
- E.g. Fgf, Egf, Nodal
PLANAR TRANSCYTOSIS summary
- Repetitive process of secretion and uptake
- Target cell controls gradient by degradation and release of signalling proteins
- Fast, directed transport
- E.g. Dpp
EXOVESICLE summary
- Complex, includes MVBs and ESCRT machinery
- Undirected transport
- Difficult to get through epithelium
- Found in bodyfluids, biomarker
- E.g. Wnt, Shh
CYTONEMES summary
- Complex, requires filopodia
- Source cell controls gradient (direction and length of cytonemes)
- Fast and directed transport
- Signal specificity (specific cytonemes for specific molecules
- E.g. Wnt, Shh, Fgf
Biomarker
A naturally occurring molecule, gene, or characteristic by which a particular pathological or physiological process, disease, etc. can be identified
