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Cell Signaling and Migration

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					Cell Signaling and Migration

        Erich Lidstone
        April 29, 2009
      Cell Signaling and Migration
•   Importance of cell migration
•   Major steps of migration
•   Signaling pathways
•   Lipid rafts
•   Adhesion-dependent trafficking
      Importance of Cell Migration
•   Embryonic development
•   Chemotaxis
•   Tissue turnover
•   Wound healing
•   Immunity
        Cell Migration and the
         Immune Response
• http://www.youtube.com/watch?v=MgVPLNu
  _S-w
    Importance of Cell Migration
• Pathological processes
  – Vascular disease
  – Osteoporosis
• Chronic inflammatory diseases
  – Rheumatoid arthritis
  – Multiple sclerosis
  – Cancer
  – Mental retardation
                      Cell Migration Cycle
Migration-promoting
event



                 Polarize, extend             Adhere to ECM or TM
                   protrusion                   receptor proteins


Transport necessary                 Disassemble                                       Move forward
    proteins to                      adhesions                                        over proteins
  movement front


                                          Microtubule dynamics promote efficient exploration of the peripheral cytoplasmic
                                          domain of a neuronal growth cone. An example of a single dynamically unstable
                                          microtubule undergoing assembly followed by disassembly (bottom). Microtubule
                                          behavior integrated over 10 minutes in the peripheral growth cone lamellipodium
                                          (top).

                                          Forscher Lab, Yale, Department of Molecular, Cellular, and
                                          Developmental Biology
                Actin Polymerization
• FAST-growing “barbed” end
• SLOW-growing “pointed” end

• Lamellipodia – branching dendritic
  network configuration
• Filipodia – long parallel bundles of
  filaments

• Mediated by Arp2/3 complex
• Causes branching of existing
  filaments
                Movement
• Leading edge moves by “Brownian ratchet”
• Uses thermal energy built up by deforming
  existing filaments
• Does not derive energy directly from actin
  polymerization
           Cell migration detection
•   Akt/PKB-GFP fusion
•   a4-integrin staining
•   PTEN-GFP fusion
•   FRET of GFP-V12Rac
    with an effector
    molecule
        Cell Migration Effectors
•Profilin
•Thymosin
•Cofilin
•Capping proteins
•Cortactin stabilizes
       branches
•Cross-linkers
   •filamin A
   •a-actinin
                        Cell Polarization




•Polarity intrinsic to migrating cell
•Vesicle trafficking toward the leading edge
•Localization of the MTOC and golgi apparatus
•PTEN resides at cell margins
•PI3K resides at the leading edge
•PIP3 production at the leading edge
Protrusion and Adhesion Formation
  Integrins and Adhesion in Migration
• Integrins support adhesion to ECM or neighboring cells
• Activate migration-related signaling molecules
• a- and b- subunits interact with signaling proteins ,
  undergo conformational changes
• Integrin clustering
• Downstream intracellular signaling
   –   Tyrosine phosphorylation
   –   GTPase activation
   –   Phospholipid biosynthesis
   –   Adhesion complex integrity
            Tractional Forces
• Integrins also function as sites of traction
• Cell uses them as a substrate over which it
  moves during migration
• Balance between adhesion at the leading edge
  and disassembly at the trailing edge
• Junction density
• Rate of disassembly
         Adhesion Disassembly
• Important at both the front and the rear of
  the cell
• Front – junctions disassembled as new ones
  are assembled in the formation of the
  protrusion
• Rear – junctions must be disassembled to
  provide materials and release cell from rear
  direction
       Cell Migration Summary
• Migration is promoted
• Cell undergoes polarization
• Leading edge reconfigures junctions, actin
  filaments, and microtubules
• Trailing edge undergoes junction disassembly
• Cell uses integrins for a combination of
  traction and intracellular signaling
• Cell reevaluates direction of migration
  Arf6 and Microtubules in Adhesion-
  Dependent Trafficking of Lipid Rafts
• Detailed analysis of adhesion modulation
• Lipid raft movement
• Cell movement
Cytoskeletal Regulation of
    Raft Endocytosis
    Identification of the
Intracellular Compartment
    Identification of the
Intracellular Compartment
Role of Arf6 in Raft Trafficking
Role of Arf6 in Raft Trafficking
Role of Arf6 in Raft Trafficking
Inhibition of Arf6 Function
Inhibition of Arf6 Function
Adhesion-dependent Activation of
  Arf6 Promotes Raft Exocytosis
Adhesion-dependent Activation of
  Arf6 Promotes Raft Exocytosis
Microtubules in Raft Exocytosis
Lipid Raft Trafficking Summary
References

				
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