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Cell Migration

Cell Migration. IBS-501, April 16, 2001 Barry D. Shur. Epithelial-mesenchymal transformation. Basal lamina controls epithelial phenotype Degradation of basal lamina leads to loss of cell polarity and mesenchyme transformation Collagen gels vs basal lamina

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Cell Migration

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  1. Cell Migration IBS-501, April 16, 2001 Barry D. Shur

  2. Epithelial-mesenchymal transformation • Basal lamina controls epithelial phenotype • Degradation of basal lamina leads to loss of cell polarity and mesenchyme transformation • Collagen gels vs basal lamina • Anti-E-cadherin antibodies break adhesions and lead to mesenchyme transformation

  3. Concept of epithelial-mesenchymal transformation

  4. What induces transformation? • TGFß induces loss of E-cadherin, increase in fibronectin synthesis, transformation • Scatter factor/hepatocyte growth factor, binds to c-met (tyrosine kinase) and induces epithelial dissociation • Metalloprotease degradation of basal lamina

  5. Biology of Cell Migration • Polarized insertion new membrane (with receptors) • Generate an intracellular force • Dissociation from substratum

  6. Polarized insertion of new membrane • In response to stimuli, MTOC reorients along with Golgi • Enables membrane insertion into leading edge

  7. MTOC reorientation

  8. Membrane vesicles travel on microtubules

  9. Polarized insertion of membrane glycoproteins • Vesicular stomatitis virus G protein in ER at non permissive temp, shift to permissive temp, G protein moves through Golgi and inserted into leading lamellipodia • Microtubule disrupting drugs (nocodazole) inhibit Golgi reorientation, membrane (G protein) inserted uniformly or randomly

  10. Membrane insertion

  11. Membrane insertion in three morphological stages

  12. GTPases regulate membrane insertion

  13. Generating an intracellular force • Lamellipodia projections need tension, infrastructure • Actin filament polymerization generates force • Cytochalasin B caps free end of F-filaments, inhibits lamellipodia formation/migration • Microinjected actin incorporated into leading edge, snd moves rearward • Photobleach spot of rhodamine-conjugated actin moves rearward

  14. Actin supplies tension to lamellipodia

  15. Actin polymerizes at leading edge

  16. Photobleached actin moves rearward

  17. Polymerized actin moves rearward

  18. Models of actin based movement

  19. Polarized insertion of membrane glycoproteins • Integrins inserted into leading edge • binds ligands (I.e., fibronectin) • ligand-induced clustering, • activates FAK, • recruits linker proteins to polymerize actin

  20. Integrin insertion leads to focal adhesion formation

  21. Integrin clustering activates FAK and recruitment of cytoskeleton components

  22. FAK activation

  23. Vinculin unfolds to facilitate actin attachment

  24. Actin polymerization at the leading edge

  25. Arp2/3 localizes to membranes where actin is polymerized

  26. Membrane insertion in three morphological stages …

  27. GTPases regulate membrane insertion

  28. GTPases regulate membrane insertion

  29. Actin filaments terminate in focal adhesions

  30. Actin filaments terminate in focal adhesions

  31. How do cells release from the substratum?

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