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Cell Signaling and Migration

Erich Lidstone

April 29, 2009

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Cell Signaling and Migration

• Importance of cell migration

• Major steps of migration

•

Signaling pathways• Lipid rafts

• Adhesion-dependent trafficking

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Importance of Cell Migration

• Embryonic development

• Chemotaxis

•

Tissue turnover• Wound healing

• Immunity

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Cell Migration and the

Immune Response

• http://www.youtube.com/watch?v=MgVPLNu

 _S-w 

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Importance of Cell Migration

• Pathological processes

 – Vascular disease

 – Osteoporosis

• Chronic inflammatory diseases

 – Rheumatoid arthritis

 – Multiple sclerosis

 – Cancer

 – Mental retardation

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Cell Migration Cycle

Polarize, extend

protrusion

Migration-promotingevent

Adhere to ECM or TM

receptor proteins

Move forward

over proteins

Disassemble

adhesions

Transport necessary

proteins to

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

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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

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Movement

• Leading edge moves by “Brownian ratchet” 

• Uses thermal energy built up by deforming

existing filaments

• Does not derive energy directly from actin

polymerization

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Cell migration detection

• Akt/PKB-GFP fusion

• a4-integrin staining

•

PTEN-GFP fusion• FRET of GFP-V12Rac

with an effector

molecule

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Cell Migration Effectors

•Profilin•Thymosin

•Cofilin

•Capping proteins

•Cortactin stabilizes

branches

•Cross-linkers

•

filamin A•a-actinin

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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

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Protrusion and Adhesion Formation

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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

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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

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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

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Cell Migration Summary

• Migration is promoted

• Cell undergoes polarization

•

Leading edge reconfigures junctions, actinfilaments, and microtubules

• Trailing edge undergoes junction disassembly

•

Cell uses integrins for a combination of traction and intracellular signaling

• Cell reevaluates direction of migration

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Arf6 and Microtubules in Adhesion-

Dependent Trafficking of Lipid Rafts

• Detailed analysis of adhesion modulation

• Lipid raft movement

•

Cell movement

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Cytoskeletal Regulation of 

Raft Endocytosis

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Identification of the

Intracellular Compartment

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Identification of the

Intracellular Compartment

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Role of Arf6 in Raft Trafficking

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Role of Arf6 in Raft Trafficking

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Role of Arf6 in Raft Trafficking

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Inhibition of Arf6 Function

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Inhibition of Arf6 Function

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Adhesion-dependent Activation of 

Arf6 Promotes Raft Exocytosis

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Adhesion-dependent Activation of 

Arf6 Promotes Raft Exocytosis

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Microtubules in Raft Exocytosis

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Lipid Raft Trafficking Summary

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References