Regulation of Cell Motility Flashcards
What are the changes that occur in the cells that occur during tumour progression?
Genetic alterations lead to:
- hyperproliferation,
- disassembly of cell-cell contacts,
- loss of polarity,
- increased motility
- cleavage of ECM proteins
What are the different types of tumour cell migration?
Single cell migration:
- ameboid
- Mesenchymal single cells
collective cell migration:
- Mesenchymal chains
- Clusters/cohorts
- Multicellular strands/sheets
What physiological phenomena does tumour migration mimic?
Morphogenesis e.g. angiogenesis
repairing a scratch wound- primary glial cells
What did a comparison of the expression profile of invasive cells vs primary tumours show to be upregulated in invasive cells? (shown by administering EGF)
Cytoskeleton regulation
Motility machinery
What makes normal migrating cells stop moving?
Contact inhibition of locomotion
How are tumour cells different in this aspect?
They lose contact inhibition of locomotion so they can multilayer
What is another term for ECM proteins?
Substratum
What are filopodia?
Finger-like protrusions that are rich in actin filaments
They sense the local environment
What are lamellipodia?
Sheet-like protrusions that are rich in actin filaments
What are the four main stages of cell movement?
Extension
Adhesion
Translocation
De-adhesion
What are the attachments between the cell and the surface that it is moving along called?
Focal adhesions
What are the monomers of actin filaments?
G-actin (F-actin when polymerised)
Describe the polarity of acting filaments.
They have a plus end and a minus end
The monomers preferentially get added on at the plus end
What protein complex is important in initiating polymerisation/ nucleation ?
Arp2/3
This forms a trimer with actin and is good at initiating nucleation (ARP’s bing negative end of actin strand)
What is the limiting step in actin dynamics?
Formation of Arp2/3-actin trimers to initiate polymerisation/nucleation
State two proteins that bind to free G-actin and describe how they affect elongation.
Promote elongation – profilin (these deliver the G-actin to the growing filament)
Sequesters G-actin (inhibits elongation) –thymosin
Name some + end capping proteins.
CapZ
Gelsolin
Fragmin/severin
Name some – end capping proteins.
Tropomodulin
Arp2/3
Name some severing proteins.
Gelsolin
Fragmin/severin
Cofilin/ADF
What are the features of the actin filaments in severed populations?
Actin filaments can grow and shrink more rapidly
unsecured shrink/grow slowly
What can happen to single filaments of actin to improve their structural integrity?
They can be bundled or cross-linked
Name some proteins involved in these processes.
cross linking and bundling
Alpha-actinin Fimbrin Filamin Spectrin Villin Vinculin
Which protein allows branching of the actin filaments?
Arp2/3 (Arp complex)
At what angle do they branch?
70 degree
Summarise the actions of Arp2/3.
They initiate nucleation
They cap filaments
They cause branching
Describe what causes the gel-sol transition.
The actin filaments can be severed to make the cell more fluid
Gel=rigid
sol=more fluid/less rigid
Describe the actin processes that take place during the protusion of lamellipodia.
There is polymerisation/nucleation,
elongation,
disassembly,
branching and capping
There is net filament assembly at the leading edge
Describe the actin processes that take place during the formation of filopodia.
Actin polymerisation elongation Bundling and cross-linking (NO branching) As soon as the finger wants to retract it will collapse at the base
State four signalling mechanisms that regulate the actin cytoskeleton.
Ion flux changes
Phosphoinositide signalling ie phospholipid binding
Kinases/phosphatases
Small GTPases
What are the three most important small GTPases in terms of the actin cytoskeleton and what does activation of each cause?
Cdc42 – filopodia
Rac – lamellipodia
Rho – stress fibres
NOTE: these are all part of the Rho family
Which small GTPases are involved in lamellipodia protrusion?
Rac
Which small GTPases are involved in focal adhesion assembly?
Rac and Rho
Which small GTPases are involved in contraction?
Rho (stress fibres are important for contraction)
what are the stimuli to move a cell
organogenesis
wounding
growth factor/ chemoattractants
de-differentiation