Rho Family of GTPases

Rho Family of GTPases

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Contents

The

Dynamic

Cytoskeleton

Actin-based

extensions

&

motility

Filopodia

Lamellipodia

Stress

fibers

Filopodia

specific information is found

HERE

Rac

Lamelliopodia/lamellum

specific

information

is

found

HERE

RacGTPase

Stress fiber

specific information is found

HERE

activity

is

Dentritic spine

specific information is found HERE

primarily

associated with

actin

dynamics

The

Rho

(

< br>R

as-

ho

mologous )

family

areRas-related

small

and actin-based

GTPases

that

use

the

energy

from

GTP

hydrolysis

to

structures

in

modulate and control numerous aspects of actin filament

the

dynamics and cytoskeleton structure. Rho GTPases link

lamellipodium

many

cytoplasmic

signaling

effectors

to

the

actin

(including

cytoskeleton

[1]

(reviewed

in

[2,3])

and

Rho

GTPase

membrane

activity

influences

diverse

processes

such

as

cell

ruffles).

Rac

growth,

migration,

cell

shape

and

cell

fate

(reviewed

in

associates with

[3-5]). The specific mechanical and chemical cues that

enzymes

(e.g.

modulate

the

activity

of

the

more

prominent

family

phosphatidylinos

members,

Rho

,

Rac

,

and

Cdc42

,

to

each

of

the

above

itol

4-phosphate

mentioned processes is likely to vary between different

5-kinase

[19])

cell

contexts,

cell

or

tissue

types,

receptors,

or

that

produce

stimuli. Although Rho GTPases integrate many signaling

secondary

events by their interaction with multiple components,

signaling

these GTPases may act more as permissive factors for

molecules

such

cytoskeleton

reorganization

rather

than

as

direct

as PIP

2

, which in

mediators (reviewed in [6]).

turn

binds

directly

to

The

Rho

family

members

contribute

to

higher-order

several

actin-based

structures

such

as

stress

fibers

,

actin- regulating

lamellipodium

, dendritic spines, and

filopodia

[1]. The

proteins

to

spatial localization of these GTPases is controlled in

modulate

their

different regions of the cell because in certain cases,

activities

the activity of one Rho family member antagonizes the

(reviewed

in

activity

of

another

family

member

(e.g.

Rac1

antagonizes

[3]).

RacGTPase

RhoA

signaling

[7]).

Conversely,

activation

of

one

family

activity

also

member

(e.g.

Cdc42)

can

also

lead

to

the

stepwise

stimulates

activation

of

other

members

(,

Rho)

[8].

Thus,

this

Arp2/3

significant

feedback

and

crosstalk

between

the

Rho

family

complex- mediate

members

complicates

the

task

of

constructing

one

paradigm

d

assembly

of

or linear pathway for Rho-mediated mechanotransduction

actin filaments

(reviewed in [9,10]).

through

the

WAVE

family

of

NPFs

Regulation of Rho GTPase activity:

[20]

(reviewed

in

[21]);

Rho GTPases cycle between inactive GDP-bound and active

however,

this

GTP-bound

conformations;

the

activation

state

is

activity can be

controlled

by

GAPs

(reviewed

in

[11]),

GEFs

[12,13],

and

altered

to

drive

GDIs

(reviewed

in

[14]).

GTP-binding

also

influences

the

filopodia

and

cellular

localization

of

the

Rho

GTPases,

with

the

growth

cone

GDP-bound state existing solely in the cytoplasm due to

collapse

[22].

their

association

with

GDIs.

Cellular

signals

(e.g.

Rac1

is

growth factors) influence the activity of GEFs at the

activated

by

plasma

membrane,

which

in

turn,

catalyze

the

exchange

of

integrin-ECM

GDP

for

GTP

on

Rho

GTPases,

thus

promoting

their

binding

[23]

and

activation.

Although

Rho

GTPases

form

homophillic

dimers

Rac1

activity

is

in both the GTP- and GDP-bound state, homodimerization

required

for

the

of

only

the

GTP- bound

form

causes

a

significant

increase

initial

in

GTPase

activity

[15].

The

Rho

GTPases

stimulate

actin

formation

filament assembly by helping the

WASp

family overcome

of

integrin

-dep

their

inhibition

in

cooperation

with

membrane

endent

phospholipids

such

as

phosphatidylinositol

adhesions

in

4,5-bis-phosphate (PIP

2

) [16-18].

growth

cone

lamellipodial

and

filopodial

protrusions

[24].

Rho

Rho

GTPase

activity

is

primarily

associated with

the

formation

of

stress

fibers

and

contractile

bundles

;

its

activity

influences

myosin

light

chain

kinase

(MLCK),

which

in

turn,

causes

increased

myosin

activity

and

contraction.

Rho

members

RhoA

and

RhoB

are

enriched

at

nascent

adhesion

sites

[25]

and

the

RhoA

effector,

Rho kinase (aka

ROCK),

is

necessary

for

focal

adhesion

maturation

and

myosin-II based

contraction

in

fibroblasts

[26].

ROCK

activity

also

promotes

rapid

neurite

outgrowth

through

stabilization

of

lamellipodial

and

filopodial

Figure:

Rho

GTPases

regulate

actin

filaments

and

membrane

cytoskeletal

organization.

Cdc42

generally

controls

the

protrusions and

cell

polarity

and

the

formation

of

filopodia

and

nascent

maturation

of

focal complexes

(shown as yellow dots).

Rho

influences

adhesion

sites

cell adhesion assembly and maturation, in addition to

[24].

Lastly,

controlling

stress

fiber

formation

and

contractile

Rho

activity

activity.

Rac1

primarily

controls

actin

assembly

and

removes

the

adhesion in the lamellipodium.

autoinhibition

of

formin

dimers

to

promote

their

actin

nucleating

activity

and

the

formation

of

unbranchedactin