lecture 10 Flashcards

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1
Q

what happens when cell migration goes wrong

A

metastatic cancer

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2
Q

how do cells move?

A

mesenchymal cell migration, amoeboid cell migration

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3
Q

what are both migrations driven by

A

lamellipodial protrusions at leading edge

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4
Q

what is diff b/w ameboid and mesenchymal

A

ameboid is less adhesive

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5
Q

how do cells bind to extracellular env.

A

integrin receptors / extracellular matrix

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6
Q

descibe mesenchymal migration

A

fibroblasts; adhesion, harder to move, stuck to environment

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7
Q

describe ameboid migration

A

immune cells; move quicker, slip through to chase down pathogens

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8
Q

2 main ways for cells to move

A

lamellipodia (high or low adhesion), blebbing migration

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9
Q

step 1 of cell moving

A

adhere to surface (integrin receptors)

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10
Q

step 2 of cell moving

A

flatten and spread (integrin, actomyosin)

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11
Q

step 3 of cell moving

A

become polarized (tell front from back; microtubules)

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12
Q

step 4 of cell moving

A

generate protrusions (actin filaments; facilitates polarization)

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13
Q

step 5 of cell moving

A

form new adhesions, release old ones (combo of all 3)

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14
Q

step 6 of cell moving

A

directionally migrate intracellular signaling

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15
Q

how are epithelial cells that line surface anchored to underlying matrix

A

integrin adhesions

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16
Q

what happens if you disrupt integrin adhesions

A

would wipe cells right off dermis

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17
Q

what is cell matrix adhesion mediated by

A

integrin receptors

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18
Q

what happens when u see fiber laying across cell

A

it’s bound by integrins entire length of filament

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19
Q

what are integrins

A

transmembrane heterodimers that link ECM to cytoskeleton

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20
Q

what is collagen

A

glue that holds tissue and organs together

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21
Q

what binds to collagen fiber

A

integrin receptors

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22
Q

on cytoplasmic face, what connects to adhesions

A

actomyosin filaments

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23
Q

what does this mean for contractility

A

as actomyosin force is applied, attached to integrin, so pulling force is gonna be applied to outside env. (ECM)

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24
Q

what does alpha subunit do

A

participates in adhesion; facilitates adheion strength

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25
Q

what does beta subunit do

A

connects complex to actin filaments inside cell

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26
Q

vinculin

A

force sensor that triggers signaling

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27
Q

what does actin bind to

A

vinculin, talin (connects everything to integrin)

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28
Q

what does this machinery represent

A

continuous mechanical connection from ECM (outside) to cytoskeleton (inside)

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29
Q

describe integrin activation

A

can be off or on

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30
Q

describe integrin at surface

A

active

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31
Q

what happens once integrin active

A

at cell surface, binds to matrix and talin

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32
Q

what happens through talin

A

binds to vinculin (adaptor protein that links integrin complex to actin filaments)

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33
Q

what happens when you get force/contractility

A

positive feedback loop, more integrins, more actomyosin filaments, bigger+stronger adhesions, more effective force

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34
Q

does this positive feedback loop happen in fibroblasts or immune cells

A

fibroblasts

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35
Q

what happens when integrin binds to talin

A

talin recriuts vinculin

36
Q

how is force sensed by adhesion complexes

A

talin

37
Q

what is talin

A

mechanosenser responsible for detecting pulling force on connecitions

38
Q

what happens when it detects force

A

trigger that regruits more actomyosin contractility in positive fedback loop, to ramp up contractility to allow adhesions to grow and strengthenh

39
Q

how does protein sense force

A

force causes change in confomration of protein, revealing a hidden binding site

40
Q

what happens when they pull on talin

A

talin unfolds (force dependent conformational chaneg)w

41
Q

what happens when talin unfolds

A

reveals binding site for vinculin

42
Q

what happens when vinculin is binded

A

joins talin; more actomyosin filaments come w/ vinculin –> positive feedback loop controlled by talin

43
Q

where does integrin recruit intracellular signaling proteins

A

sites of cell-matrix adhesion

44
Q

what gives increased contractility that helps in adhesion formation

A

rhoA activaetes ROCK, phosphorylates myosn light chain , activates myosin 2 protein

45
Q

what’s happening at bottom/back of cell

A

adhesions falling apart, disassembed, recycled into cytoplasmw

46
Q

what wud happen if cell douln’t dissasmeble adhesions in the back

A

cell would get stuck;

47
Q

what does myosin contraction and cell adhesoin allow

A

allows cell to pull itself forward

48
Q

what happens if nothing to anchor the netowrk

A

not gonna be able to push network forward, rather it pushes it back (cuz it’s not yet attached to actomyosin machinery)

49
Q

what happens when pos feedback loop

A

vinculin & talin grab actin filaments, harness contractile power to anchor filaments, now it can actually push it forward

50
Q

retrograde flow

A

if filaments aren’t anchored, netowrk is pushed backward

51
Q

what happens if filaments aren’t anchored

A

network pushed backward

52
Q

what happens if filaments anchored

A

resist backward pushing force, exert force to make cell migration

53
Q

what happens if cell bound to integrin

A

migrates; does work

54
Q

what happens when new adheson forms

A

small, low contractility; need massive increase in contractility (vinculin, talin)

55
Q

what needs to happen for recycling

A

not bound to talin; detach from it

56
Q

what happens if rhoA is inhibited

A

contractility drops, breaks positive feedback loop, everything falls apart

57
Q

what happens if vinculin mutated

A

you’d never get positive feedback loop initiated in first place

58
Q

what happens if talin mutated

A

binding site always exposed; positive feedback all the time

59
Q

role of myosin

A

help unfold talin, and strengthen adhesions through additional vinculin binding

60
Q

what happens when integrins bind to ECM

A

talin unfolded, positive feedback loop for actomyosin contractility

61
Q

what is any movement in ECM from

A

contractile forces in cell

62
Q

what gives cell ability to propel itself forward

A

force is being transmitted from actomyosin filaments in cytoplasm, connected to alpha beta integrins via vinculin-talin, those integrins are connected to extracellular matrix

63
Q

describe actin-integrin

A

continuous mechanical connection that allows cellular forces to pull on those extracellular fibers to allow for productive cell migration

64
Q

2 major outcomes of force coupling

A

protrusion, traction forces against extracellular env.

65
Q

what motor protein delivers cargo at MT tracks

A

kinesin 1; takes vesicles at golgi to plus ends

66
Q

describe mesencyhmal cell migration

A

rac1 activates arp2/3, leads to actin polymerization, causes lamellipodial protrusion

67
Q

what happens if RAC1 arp2/3 pathway is active W/O coupled at adhesions

A

no protrusion, just retrograde flow

68
Q

what happene whenever rac1 activated

A

lamellipodia is formed

69
Q

is contractility at leading or lagging edge

A

leading edge; adhesions

70
Q

describe contractility at back of cell

A

RhoA, contractile forces that allow leading edge to contract and keep up w/ front

71
Q

what contracts in the back?

A

actomyosin filaments that are attached to plasma membrane, as they are acted on by mosin 2 they become more tightly cross-linked, the spaces shrink, just continuously pulls plasma membrane forward

72
Q

what is front rhoA contractility

A

plugs talin via vinculin to strengthen adhesions

73
Q

what is back rhoA stuff

A

no adhesions; just contracting the actomyosin network underneath plasma membrane to contract the rear and allow it to move in synch w/ front of cell

74
Q

what allows for continuous lamellipodia and cell migration

A

cofilin, at back of lamellipodial network (still front of cell), recycles monomers

75
Q

describe how back of cell pulls itself forward

A

rhoA –> ROCK –> myosin 2

76
Q

how does back of cell keep up w/ front

A

contraction in back

77
Q

what does rhoA control

A

actomyosin contraction

78
Q

what does rac1 control

A

lamellipodia (arp 2/3)

79
Q

what does high contractility mean

A

low lamellipodia formation

80
Q

what separates front from back of cell

A

cross talk b/w rac and rho

81
Q

what do we need at front of cell fo r adhesion formation

A

rhoA

82
Q

what does Rac1 do

A

activates arp2/3 for branched actin networks, turns on Pak, turns off actomyosin stressfibers

83
Q

what does rac1 do to rhoA in front

A

suppresses rhoA response

84
Q

describe cross-talk

A

chemoattractant binds GPCRs –> activate rac1 –> turn off rhoA

85
Q

what happens as you get farther from cell

A

rac1 suppresses rhoA less and less; rhoA does actomyosin contractility more at the back

86
Q

what is blebs

A

increase pressure to cause protrusion (no actin polymreization)

87
Q

do blebs have actin

A

nah; just pressure driven