Integrins And Invasion Flashcards
What effect does constitutive activation of MAPK signalling have?
Downregualted E-cadherin, freeing melanoma cells from keratinocyte-mediated control
Upregulated/altered integrin expression promoting survival and invasive growth in ECM
What happens to N-cadherin when the level of E-cadherin goes down?
N-cadherin goes up- this is used as a diagnostic test for metastatic potential
Focal adhesions
Point of interaction between ECM, integrins and the cytoskeleton
Describe the molecular architecture of focal contacts
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
Focal adhesion
Tension across actin stress fibres that produces cell shape
Focal contacts are static structures of structural (integrins alpha and beta) and regulatory proteins. True or false?
They are dynamic
Describe the role of integrins
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
Expression of _____ and _____ integrins is ________ in melanomas. ______ and _____ upregulated in some other cancers
Beta 1 and 3
increased
Alpha6Beta4 or AlphavBeta3
What happens to normal cells that lose contact with the ECM/basal lamina?
Apoptose- anchoring is critical to survival
Integrins interact with the ECM via ________. This leads to ___________ and _________
Extracellular domain
Conformational change
Recruitment of molecules involved in downstream signalling
Integrins can bind _____ but ______ ______ subsets of the ECM and activate _____ but ______ ______ signalling cascades
Distinct
Partially overlapping
Distinct
Partially overlapping
Which integrin subunit is thought to be critical? And what response results from interaction between this and other subunits?
Beta 1
Alpha 3: bind to laminin 5
Alpha 5: bind to fibronectin
Alpha 9: bind to tenascin
These forms are prevalent in melanomas
Integrin receptors have no _____ activity, they are solely ______.
Kinase
Scaffolds
alphav-beta3 _______ activates _______ and ____
Strongly
ERK
Src
alphav-beta1 activates_____ and _____
JNK
Lipid dependent kinases
Lipid rafts
Involved in fluidity changes
Integrins interact with RTK signalling to bring about:
Activation of SFK, PI3K activation, P130cas activation, tumour growth and invasion
Cells can switch expression of their integrins. True or false?
True- this is a transcriptional change
Canonical (classical) integrin signalling
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
Non-canonical integrin signalling
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
__________ 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 ________
Humanised mAbs Vitaxin Volociximab Cilengitide Phase II Resistance
Describe FAK and its role in signalling
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 migrationDescribe the relationship between FAK levels and cancer
Levels elevated in many highly malignant cancers
Integrins assemble a signalling complex:
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
