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biology of cancer > Cell motility > Flashcards

Cell motility Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q

why is cell motility important?

A

aids in:
- wound healing
- chemotaxis
- development

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2
Q

what are Rho GTPases?

A

family of small signalling G proteins.
- serve as molecular switches of intracellular signal transduction

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3
Q

what molecules are involved in the biochemistry of Rho GTPases?

A

GAP: GTPase activating factor
GEF: GTPase exchange factor
GDI: GTPase dissociation inhibitor
Effectors: proteins that mediate the cellular effects of a signal transduction pathway

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4
Q

Rho and the cytoskeleton

A

participates in regulation of the actin cytoskeleton and cell adhesion through specific targets

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5
Q

whay regulates Rho GTPases?

A

growth factors and G-proteins

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6
Q

what is actin treadmilling?

A

continuous addition at one end and dissociation from the other end of the G-actin monomers.
- crucial in cell migration, endocytosis and exocytosis

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6
Q

what is the process of actin treadmilling?

A

a segment of filament ‘moves’ through a stratum or the cytosol. when one end of the filament lengthens, the other shortens.

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7
Q

what regulates actin cytoskeleton contractility?

A

MLC contracted + MP = relaxed
MLC relaxed + MLCK = contracted

molecules:
- MLC; myosin light chain
- MLCK; myosin light chain kinase
- MP; myosin phosphatase

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8
Q

what does RhoA do?

A

Ras homolog A: small GTPase protein that has a key role in actin cytoskeleton reorganisation, regulation of cell shape, adhesion and migration and transformation of cellular phenotypes

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9
Q

how is RhoA activated?

A

activation mediated by guanin nucleotide exchange factors (GEFs) that catalyse exchange of GDP for GTP

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10
Q

describe the RhoA cycle

A

RHO-GDP + serum, GFs and integrins becomes RHO-GTP.
splits into two pathways:
- actin stabilisation;
+ ROCK + LMK p -> Cof (cofilin; actin regulatory protein that severs actin filaments and accelerates actin assembly)

  • actin assembly;
    + diaphanous
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11
Q

describe the regulation of stress fibre formation by RHOA

A

Rho-GTP –> ROCK –> transition of MP to MP+P which affects the MLC contraction and relaxation equilibrium

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12
Q

overview of the process by which RAC and CDC42 regulare actin polymerisation

A
  • activation of RAC and CDC42
  • effector proteins
  • actin nucelation and polymerisation
  • actin bundling and filament stability
  • spatial and temporal regulation
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13
Q

how are RAC and CDC42 activated?

A

both are activated by guanine nucleotide exhcange factors (GEFs) by extracellular signalling.
GEFs cataluse the exchange of GDP for GTP thereby activating RAC and CDC42

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14
Q

what is the role of the effector proteins?

A

relay signal to downstream pathways involved in actin polymerisation.
effector proteins include; kinases, phospholipases and scaffolding proteins

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15
Q

what role does RAC and CDC42 play in actin nucelarion and polymerisation?

A

regulate actin polymerisation through their effectors by promoting formation of actin filaments.
- one key pathway: involves activation of ARP2/3 complex (actin related protein).
this promotes actin nucleation = formation of branched actin networks.

16
Q

what role does RAC and CDC42 play in actin bundling and filament stability?

A

activate formins, proteins that facilitate elongation of actin filaments and promote formation of linear actin bundles.
- this contributes to organisation and stability of actin structures within the cell.

17
Q

how is RAC and CDC42 activity regulated?

A
  • tightly regulated spatially and temporally within the cell.
  • ensures that actin polymerisation occurs in coordinated manner in response to specific signals and at precise parts of the cell.
  • allowing for processes such as cell migration, adhesion and division.
18
Q

what is FAK?

A

FAK: focal adhesion kinase is a key protein involved in regulating cell adhesion, migration and cytoskeletal dynamics.

19
Q

How does FAK regulate cytoskeletal fluidity?

A
  • activation of signalling pathways
  • interaction with cytoskeletal proteins
  • regulation of Rho GTPases
  • stress fibre formation
  • cell migration and spreading
20
Q

what role does FAK have in regulating Rho GTPases?

A
  • influences activity of Rho, Rac, CDC42 by directly phosphorylating and activating them.
21
Q

what does Rac do?

A
  • promotes formation of lamellipodia, flat sheet like membrane portrusions rich in branched actin network.
  • activated Rac stimulates activationg of WAVE regulatory complex = nucleation of actin filaments and formation of branched actin networks at leading edge of migrating cells.
22
Q

what is the role of CDC42?

A
  • regulates formation of filopodia, thin, finger like portrusions with lots of actin filaments
  • activated CDC42 interacts with proteins to promote actin polymerisation and bundling.
23
Q

role of small GTPases in actin nucleation and polymerisation?

A
  • regulate via interaction with actin binding proteins and actin nucleation promoting factors (NPFs)
24
Q

how do Rho GTPases regulate microtubule stability?

A
  • can influence indirectly via downstream effectors
  • Rho can = phospho. and inactivation of MAPs which = microtubule destabilisation
  • Rho inactivation can = microtuble stability by allowing active stathmin to bind and sequester tubulin dimers, preventing microtubule depolymerisation.
25
Q

interactions of Rho GTPases and effects

A
  • Rho > Diaphanous > stabilisation
  • RAC > p65PAK > elongation
  • CDC42 > Par6/PKCy > elongation
26
Q

how does Rho contribute to cell proliferation?

A
  • regulation of cell cycle
  • control of cell cycle checkpoints
  • influence on mitotic spindle
  • regulation of cell adhesion and migration
  • integration with growth factor signalling
27
Q

how does Rho regulate the cell cycle?

A
  • modulates activity of cyclin-dependent kinases and their regulators.
  • RhoA signalling has been shown to promtoe expression of cyclin D1 (regulator of G1/S phases).
  • RhoA inhibition = G1 cell cyle arrest
28
Q

implications of Rho GTPase in cancer

A
  • dysregulation where activation of Rho GTPases = uncontrolled cell proliferation, tumor growth and metastasis.
29
Q

Rho in tumorigenesis

A
  • inactivated Rho, RAC and CDC42 prevents RAS activation
30
Q

which Rho GTPases have been found in cancers?

A
  • RhoA; overexpressed in colon, breast, lung carcinomas
  • RhoC: overexpressed in breast and pancreatic cancers
  • RAC1: overexpressed in breast cancer
  • RAC1B: splice variants in breast and colon cancer
  • CDC42: overexpressed in breast cancer
  • RhoH: rearranged in lymphomas and myelomas
31
Q

what GFs are present in tumor microenvironment that can activate Rho?

A
  • EGF
  • HGF
  • LPA
  • PDGF
  • TGF-b
32
Q

Rho GTPases in maintenance of normal epithelial polarity

A
  • cell polarity: RhoA, RAC1, CDC42
  • cell junctions; RhoA, RAC1
33
Q

what happens to cell polarity in bening tumours?

A

loss of polarity and multilayering
- loss of polarity; RAC1, RhoA
- multilayering; RhoE

34
Q

what do invasive tumors present in cell polarity changes?

A
  • loss of cell junctions: RAC1. RhoA, ROCK
  • motility; RhoA, ROCK, RAC1, CDC42
  • protease expression; RhoA, RAC1
35
Q

what is needed for metastasis of a tumor?

A
  • intravasation and extravasation; Rho, ROCK
  • vascularisation; RhoC
36
Q

Rho proteins as therapeutic targets

A

compounds that:
- inhibit lipid mods; geranylgeranyl transferase inhibitors (inhibit growth of tumor cells invitro & anti tumor efeects in animals)
- prevent GEF action
- inhibit Rho-GTP interaction with effectors
- inhibit effector activity; Y-27632 a ROCK inhibitor that reduces metastatic potential in vivo

37
Q

what other biological process can Rho GTPases control?

A
  • mitosis
  • cytokines
  • enzymatic activities; lipid metabolism & ROS
  • vesicle trafficking
  • phagocytosis
  • endosomal transport
  • apoptosis

biology of cancer (13 decks)

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