Invasion – 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 and cleavage of ECM proteins
What are the different types of tumour cell migration?
Single cell migration (ameboid) Mesenchymal single cells Mesenchymal chains Clusters/cohorts Multicellular strands/sheets
What physiological phenomena does tumour migration mimic?
Morphogenesis e.g. angiogenesis
What did a comparison of the expression profile of invasive cells vs primary tumours show to be upregulated in invasive cells?
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
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?
Arp2/3
This forms a trimer with actin and is good at initiating polymerisation
What is the limiting step in actin dynamics?
Formation of Arp2/3-actin trimers to initiate polymerisation
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 beta–4 thymosin ADF, cofilin
Name some + end capping proteins.
CapZ
Gelsolin
Fragmin/severin
Name some – end capping proteins.
Tropomodulin
Arp2/3
Name some severing proteins.
Gelsolin ADF
Framin/severin
Cofilin
What are the features of the actin filaments in severed populations?
Actin filaments can grow and shrink more rapidly
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.
Alpha-actinin Fimbrin Filamin Spectrin Villin Vinculin
Which protein allows branching of the actin filaments?
Arp2/3
At what angle do they branch?
70 degrees
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
Describe the actin processes that take place during the protusion of lamellipodia.
There is polymerisation, 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
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
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
Explain how Rac causes actin polymerisation/organisation.
Rac binds to and activates WAVE
WAVE then activates Arp2/3, which is important in actin organisation
Explain how Cdc42 causes actin polymerisation/organisation.
Cdc42 binds to WASP
WASP also activates Arp2/3
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)
