Rho GTPases Flashcards
1
Q
How are invasive single cells increased in cancer?
A
- HGF production causes the loss of adherens junctions leading to weakened cell-cell adhesions
- single cells break away and become invasive + migratory
2
Q
What other non-cancer diseases can mutations in Rho GTPases cause?
A
- neurological diseases that affect synapse formation in the brain during development
- immune cell diseases
3
Q
What are the basic steps of cancer metastasis?
A
- primary tumour
- invasion of surrounding tissues
- enters the blood stream
- leaves the blood vessels and forms a second tumour site
4
Q
What are the most frequent sites of metastasis?
A
- those with lots of blood vessels such as the liver, bone, liver
- certain cancers have locations they’re more likely to migrate to for example prostate often goes to the bone they may be nutrients in the bone that support prostate cancer cells well
5
Q
How can cancer cells migrate?
A
- as single cells
- as groups (epithelial)
- may fall apart into single cells as they move through the bloodstream
6
Q
What are rho GTPases?
A
- signalling proteins involved in migration and invasion
- rac1, rhoA, Cdc42
7
Q
How do Rho GTPases facilitate cancer cell migration?
A
- Rac1 and Cdc42 facilitate the formation of filopodia extending forwards
- Rac1 also facilitates attachments to the ECM to allow directional movement
- RhoA ia involved in the removal of these attachments at the back as the cell moves forward and in contraction of the back of the cell to allow movement
- Cdc42 can also produce filapodia that can sense directionality signals
8
Q
What kinds of receptors can activate Rho GTPases (4)?
A
- GPCR
- tyrosine kinase receptors
- integrins
- cadherins
9
Q
What is an example of a factor that leads to teh activation of GEFs for Rho GTPases?
A
- HGF
- hepatocellular growth factor
10
Q
How does RhoA cause actin to perform its function?
A
- activates ROCK which leads to actin + mypsin contraction by phosphorylating the reguatory chain of myosin and actiavting it
- activates mDia which leads to actin polymerisation and filament formation
11
Q
How do Rac1 and Cdc42 form different actin polymers?
A
- Rac1 activates the WAVE complex with activates Arp1/2
- thid directly stimulates new actin filaments branching from existing filaments called lamellipodia
- Cdc42 binds Mdia leading to formatino of new parrallel actin filaments called filapodia
12
Q
How does Rac1 facilitate ECM adhesion?
A
- rac1 activates PAK kinase by binding its inhibitory region
- kinase phosphorylates targets involved in integrin-mediated adhesion and turnover to ensure that new adhesions are made and lost as the cell moves forward
13
Q
What kind of mutations are seen in cancers of Rho GTPases?
A
- Rac1 in melanomas
- fast GDP/GTP exhange - cna release GDP without GEFs
- Rhoa mutations whereby they can’t sequester GEFs are seen in lymphomas
