Integrins And Invasion

Question 1

What effect does constitutive activation of MAPK signalling have?

Answer 1

Downregualted E-cadherin, freeing melanoma cells from keratinocyte-mediated control
Upregulated/altered integrin expression promoting survival and invasive growth in ECM

Question 2

What happens to N-cadherin when the level of E-cadherin goes down?

Answer 2

N-cadherin goes up- this is used as a diagnostic test for metastatic potential

Question 3

Focal adhesions

Answer 3

Point of interaction between ECM, integrins and the cytoskeleton

Question 4

Describe the molecular architecture of focal contacts

Answer 4

Cell attaches to ECM via integrins
Integrins can assemble/disassemble ‘foot’ to allow cell to move
Complex involved p130cas, src, FAK and proteins involved in assemble/disassembly of actin cytoskeleton

Question 5

Focal adhesion

Answer 5

Tension across actin stress fibres that produces cell shape

Question 6

Focal contacts are static structures of structural (integrins alpha and beta) and regulatory proteins. True or false?

Answer 6

They are dynamic

Question 7

Describe the role of integrins

Answer 7

Transmit mechanical and chemical signals
Give polarity to the cell
Organise and remodel cytoskeleton during adhesion and migration
Signal to exert stringent control over cell survival and proliferation

Question 8

Expression of _____ and _____ integrins is ________ in melanomas. ______ and _____ upregulated in some other cancers

Answer 8

Beta 1 and 3
increased
Alpha6Beta4 or AlphavBeta3

Question 9

What happens to normal cells that lose contact with the ECM/basal lamina?

Answer 9

Apoptose- anchoring is critical to survival

Question 10

Integrins interact with the ECM via ________. This leads to ___________ and _________

Answer 10

Extracellular domain
Conformational change
Recruitment of molecules involved in downstream signalling

Question 11

Integrins can bind _____ but ______ ______ subsets of the ECM and activate _____ but ______ ______ signalling cascades

Answer 11

Distinct
Partially overlapping
Distinct
Partially overlapping

Question 12

Which integrin subunit is thought to be critical? And what response results from interaction between this and other subunits?

Answer 12

Beta 1
Alpha 3: bind to laminin 5
Alpha 5: bind to fibronectin
Alpha 9: bind to tenascin

These forms are prevalent in melanomas

Question 13

Integrin receptors have no _____ activity, they are solely ______.

Answer 13

Kinase

Scaffolds

Question 14

alphav-beta3 _______ activates _______ and ____

Answer 14

Strongly
ERK
Src

Question 15

alphav-beta1 activates_____ and _____

Answer 15

JNK

Lipid dependent kinases

Question 16

Lipid rafts

Answer 16

Involved in fluidity changes

Question 17

Integrins interact with RTK signalling to bring about:

Answer 17

Activation of SFK, PI3K activation, P130cas activation, tumour growth and invasion

Question 18

Cells can switch expression of their integrins. True or false?

Answer 18

True- this is a transcriptional change

Question 19

Canonical (classical) integrin signalling

Answer 19

Integrins interact with the ECM, activate FAK, src and PI3K and interacting with cas
This leads to survival, proliferation, adhesion, migration and invasion
ST response

Question 20

Non-canonical integrin signalling

Answer 20

Mutant integrins activate ras, NFkB, src, SLUG (through upregulation/aberrant expression)
Involved in stemness, metastasis, drug resistance and reprogramming
Alpha6ABeta1 leads to maintenance of epithelial phenotype
Alpha6BBeta1 leads to stemness and mesenchymal phenotype

Question 21

__________ can be used to target integrins. ________ targets avBeta3, ________ targets Alpha5Beta1 integrins and ______ inhibits AlphaVBeta3 and AlphaVBeta5 integrins. These are all in phase _____ trials and are subject to rapid onset ________

Answer 21

Humanised mAbs
Vitaxin
Volociximab
Cilengitide 
Phase II
Resistance

Question 22

Describe FAK and its role in signalling

Answer 22

Activation is central to integrin signalling
Can be activated by GFRs and integrins
Can influence cadherins
Assemble/disassemble focal contacts
Works as a kinase and adaptor molecule and can switch on molecules involved in microtubule stabilisation
Can activate Rho family GTPases:
      -RhoA involved in stress fibres
      -Rac involved in lamellipodia 
      -cdc42 involved in filopodia 
     These all influence cell migration

Question 23

Describe the relationship between FAK levels and cancer

Answer 23

Levels elevated in many highly malignant cancers

Question 24

Integrins assemble a signalling complex:

Answer 24

Allows recruitment and activation of FAK
Brings structural and adaptor proteins with it, inc. STATs, Ras, MEK=ERK, PI3K, RhoGAP and other migration-modulating proteins

Question 25

Describe the phosphorylation events required for maximum FAK catalytic activity

Answer 25

Ty576 and 577

Question 26

FAK is recruited to activated integrin receptors via its _____ by associating with integrin-associated proteins ______, _____ and to RTK through _____ domain

Answer 26

FAT (focal adhesion targeting) domain
Paxillin
Talin
FERM

Question 27

FAK is never fully inactive- true or false?

Answer 27

True