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Y2 - CANCER > Invasion – Regulation of Cell Motility > Flashcards

Invasion – Regulation of Cell Motility Flashcards

1
Q

What are the changes that occur in the cells that occur during tumour progression?

A
  • Genetic alterations lead to…
  • Hyperproliferation
  • Disassembly of cell-cell contacts
  • Loss of polarity
  • Increased motility
  • Cleavage of ECM proteins
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2
Q

What are the different types of tumour cell migration?

A
  • Single cell migration (ameboid)
  • Mesenchymal single cells
  • Mesenchymal chains
  • Clusters/cohorts
  • Multicellular strands/sheets
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3
Q

What does collective migration require?

A
  • Modulation of cell-cell contacts
  • Communication between cells e.g gap junctions
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4
Q

What physiological phenomena does tumour migration mimic?

A
  • Morphogenesis e.g. angiogenesis when forming breast tissue in breast-feeding mothers
  • This is where there must be collective migration of cells for example in vascular sprouting
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5
Q

What did a comparison of the expression profile of invasive cells vs primary tumours show to be upregulated in invasive cells?

A
  • Cytoskeleton regulation
  • Motility machinery
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6
Q

1) What makes normal migrating cells stop moving?
2) How are tumour cells different in this aspect?

A

1) Contact inhibition of locomotion
2) They lose contact inhibition of locomotion so they can multilayer

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7
Q

What are the 2 types of cell motility - in terms of what they are motile in response to?

A
  1. Hapoptatic - random movement
  2. Chemotactic - movement along a chemical gradient
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8
Q

What is another term for ECM proteins?

A
  • Substratum
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9
Q

In cell motility, what structures allow attachment to the substratum, briefly describe these structures (much detail not needed) and what happens?

A
  • Focal adhesions
  • These are integrins which extend extracellularly, have a transcellular domain and an intracellular domain
  • The intracellular domain binds actin cytoskeleton filaments at the ends of the cell
  • They hook onto the ECM matrix and provide points of attachment
  • Traction forces are generated about this attachment
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10
Q

1) What is the name of the monomers of actin filaments?
2) What is the name of the actin filaments?

A

1)

  • G-actin

2)

  • F-actin
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11
Q

What are filopodia?

A
  • Finger-like protrusions that are rich in actin filaments
  • They sense the local environment
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12
Q

What are lamellipodia?

A
  • Sheet-like protrusions that are rich in actin filaments
  • In order for the cell to migrate in a direction, the sheets of membrane project to the front of the cell
  • The sheets then ruffle back, so the cell can move
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13
Q

What are the four main stages of cell movement and briefly describe what is happening?

A
  • Extension - the focal adhesions act like feet, hooking onto substratum, cell protrusions (lamellipod) protrude and extend
  • Adhesion - the focal adhesion sticks onto the substratum (picture suction cups-like thing going on)
  • Translocation - the back of the cell must contract in order to propel the rest of the cell forward, there are various cytoskeletal changes and so forth
  • De-adhesion - the focal adhesions at the back are left behind (picture a suction cup coming off)
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14
Q

What are the attachments between the cell and the surface that it is moving along called?

A
  • Focal adhesions
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15
Q

What are the monomers of actin filaments?

A
  • G-actin
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16
Q

Describe the polarity of actin filaments

A
  • They have a plus end and a minus end
  • The monomers preferentially get added on at the plus end
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17
Q

6 processes in actin filament formation and arrangement?

A
  1. Nucleation
  2. Elongation
  3. Capping
  4. Severing
  5. Cross-linking / bundling
  6. Branching
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18
Q

Describe what happens in nucleation - in regards actin

A
  • Arp-2,3 binds the minus end of the actin filament to form the initial trimer, and extend the filament
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19
Q

Describe what happens in the elongation step in regards actin

A
  • After Arp-2,3 binds to the actin filament and forms a trimer in nucleation, elongation occurs
  • Profilin binds G-actin and drags it over actin filament
  • Thymosin also competes with profilin to inhibit the polymerisation process
20
Q

What do Beta-4 thymosin and ADF / cofilin do?

A
  • It competes with profilin in order to prevent it from elongating the actin filament
  • They sequester the G-actin to prevent it being used in elongation
21
Q

Describe what happens in the capping process in regards actin filaments

A
  • After nucleation and elongation, capping of the actin filament ends occurs
  • This is in order to prevent more monomers from being added on
  • CapZ, Gelsolin and Fragmin / severin cap off the +ve end and tropomodulin and the Arp complex cap off the -ve end
22
Q

Describe what happens in the severing process in regards the actin filament and why this is useful

A
  • The actin filaments once formed can be severed into smaller branches which themselves can be polymerised, therefore it is a method to speed up the actin polymerisation process, severed ends may then be re-annealed or just form separate fibres
  • The filaments are severed by the following proteins:
  1. Gelsolin
  2. ADF / cofilin
  3. Fragmin / severin
23
Q

Describe what happens in the branching process in regards actin filaments and the importance of this

A
  • Arp-2 causes branching appearance of actin filaments, arranging them at 70 degrees (because Arp-2 complex can initiate polymerisation forming new filaments at angles on already existing filaments to form branches)
  • This facilitates nucleation and elongation
  • It facilitates lamellar (lamellipod) protrusion also
24
Q

What protein complex is important in initiating polymerisation?

A
  • Arp2/3
  • This forms a trimer with actin and is good at initiating polymerisation
25
Q

Describe what happens in cross-linking and bundling of actin filaments, mentioning some proteins involved and the roles they play

A
  • Fascin - bind filaments
  • Fimbrin - bind filaments at a long distance
  • Alpha-actinin - dimer that brings together filaments
  • Spectrin, filamin and dystrophin all cross-link actin filaments
26
Q

Why is it important that actin filaments are certain distances apart?

A
  • For motor proteins to be able to slot in
  • E.g. Myosin
27
Q

What is the limiting step in actin dynamics?

A
  • Formation of Arp2/3-actin trimers to initiate polymerisation
28
Q

State two proteins that bind to free G-actin (excluding Arp-2,3) and describe how they affect elongation

A
  • Promote elongation – profilin (these deliver the G-actin to the growing filament)
  • Sequesters G-actin - beta–4 thymosin, ADF / cofilin
29
Q

Name some + end capping proteins

A
  • CapZ
  • Gelsolin
  • Fragmin/severin
30
Q

Name some – end capping proteins

A
  • Tropomodulin
  • Arp2/3
31
Q

Name some severing proteins

A
  • Gelsolin
  • Fragmin / severin
  • ADF / Cofilin
32
Q

Why might it be desirable to sever actin filaments?

A
  • Actin filaments can grow and shrink more rapidly when severed - more bits for polymerisation to act on
33
Q

What can happen to single filaments of actin to improve their structural integrity?

A
  • They can be bundled or cross-linked
34
Q

Name some proteins involved in the processes of bundling and cross-linking actin filaments

A
  • Alpha-actinin
  • Fimbrin
  • Filamin
  • Spectrin
  • Villin
  • Vinculin
35
Q

Which protein allows branching of the actin filaments?

A
  • Arp2/3
36
Q

At what angle do actin filaments branch in the lamellar?

A
  • 70 degrees
37
Q

Summarise the actions of Arp2/3

A
  • They initiate nucleation
  • They cap filaments
  • They cause branching
38
Q

What is the gel-sol transition (including what the gel and sol states are) and how is it carried out? Also why is this useful?

A
  • The actin filaments can be severed to break the cross-linking proteins holding the mesh-like gel structure and makes the cell more fluid and able to flow as a sol structure
  • This, alongside actin polymerisation, is important in rearranging cell polarity for directional motility
39
Q

Describe the actin processes that take place during the protrusion of lamellipodia

A
  • There is disassembly of actin filaments at the back end of the cell from F-actin (filamentous) to G-actin (monomeric actin)
  • There is then migration of the G-actin to the end where lamellipod protrusion will occur (leading edge) and assembly of the actin filament
  • Branching and capping also occurs
  • There is net filament assembly at the leading edge
40
Q

Describe the actin processes that take place during the formation of filopodia

A
  • Actin polymerisation
  • Bundling and cross-linking (NO branching because there is only parallel arrangement of actin fibres at the lamellipod)
  • Elongation for the protrusion in a localised position
  • As soon as the finger wants to retract (e.g. due to removal of a stimulus), capping occurs to stop elongation and the filopod will collapse at the base
41
Q

State four signalling mechanisms that regulate the actin cytoskeleton

A
  1. Ion flux changes (e.g. calcium levels)
  2. Phosphoinositide signalling
  3. Kinases/phosphatases
  4. Small GTPases
42
Q

What are the three most important small GTPases in terms of the actin cytoskeleton and what does activation of each cause?

A
  • Cdc42 – filopodia - binds WASP, which in turn activates Arp-2,3 to control polarised motility and actin mobilisation in filopodia
  • Rac – lamellipodia - activates WAVE and Arp-2,3 to induce polymerisation
  • Rho – stress fibres - induces stress fibre contraction to aid mobility
  • NOTE: these are all part of the Ras super-family of GTPases
43
Q

Explain how Rac causes actin polymerisation/organisation

A
  • Rac binds to and activates WAVE
  • WAVE then activates Arp2/3, which is important in actin organisation
44
Q

Explain how Cdc42 causes actin polymerisation/organisation

A
  • Cdc42 binds to WASP
  • WASP also activates Arp2/3
45
Q

Which small GTPases are involved in lamellipodia protrusion?

A
  • Rac
46
Q

Which small GTPases are involved in focal adhesion assembly?

A
  • Rac and Rho
47
Q

Which small GTPases are involved in contraction?

A
  • Rho (stress fibres are important for contraction)

Y2 - CANCER (14 decks)

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