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Small GTPases
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The RhoB small GTPase in physiology and disease
F ancisco M. Vega & Anne J. Ridley
To ci e his a icle: F ancisco M. Vega & Anne J. Ridley (2018) The RhoB small GTPase in
physiology and disease, Small GTPases, 9:5, 384-393, DOI: 10.1080/21541248.2016.1253528
To link o his a icle: h ps://doi.o g/10.1080/21541248.2016.1253528
© 2016 The Au ho (s). Published wi h
license by Taylo & F ancis© F ancisco M.
Vega and Anne J. Ridley
Published online: 22 No 2016.
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REVIEW
The RhoB small GTPase in physiology and disease
F ancisco M. Vega
a
,
b
and Anne J. Ridley
c
a
Ins i u o de Biomedicina de Se illa, IBiS (Hospi al Uni e si a io Vi gen del Roc

ıo/CSIC/Uni e sidad de Se illa), Se illa, Spain;
b
Depa men o
Medical Physiology and Biophysics, Uni e sidad de Se illa, Se illa, Spain;
c
Randall Di ision o Cell and Molecula Biophysics, King’s College
London, New Hun ’s House, Guy’s Campus, London, UK
ARTICLE HISTORY
Recei ed 28 Sep embe 2016
Re ised 22 Oc obe 2016
Accep ed 23 Oc obe 2016
ABSTRACT
RhoB is a Rho amily GTPase ha is highly simila o RhoA and RhoC, ye has dis inc unc ions in
cells. I s unique C- e minal egion is subjec o specific pos - ansla ional modifica ions ha con e
di e en localiza ion and unc ions o RhoB. Apa om he common ole wi h RhoA and RhoC in
ac in o ganiza ion and cell mig a ion, RhoB is also implica ed in a a ie y o o he cellula p ocesses
including memb ane a ficking, cell p oli e a ion, DNA- epai and apop osis. RhoB is no an
essen ial gene in mice, bu i is implica ed in se e al physiological and pa hological p ocesses. I s
mul iple oles will be discussed in his e iew.
KEYWORDS
cance p og ession;
de elopmen ; memb ane
a ficking; RhoB; Rho
GTPases
In oduc ion
The small Rho GTPase amily o signaling molecules a e
impo an egula o s o cell and issue mo phology and
unc ion, ac ing mainly h ough he cellula cy oskele on.
1,2
They a e key media o s du ing di e se cellula and physio-
logical p ocesses like cell di ision, cell mig a ion, wound
healing o immune su eillance. The amily consis s o 20
membe s in humans and he dys egula ion o hei unc-
ion ha e been linked o di e en human pa hologies.
RhoB, oge he wi h RhoA and RhoC, o ms he Rho
sub amily wi hin he Rho GTPase amily. These h ee
p o eins ha e a high deg ee o simila i y ( hey sha e
a ound 87% amino acid sequence iden i y) al hough
RhoB is he mos di e gen membe o he sub amily. In
con as o RhoA and RhoC, RhoB is encoded by a single
exon and i is belie ed o ha e a isen om a RhoA
e e se copy in eg a ion du ing e eb a e e olu ion.
While RhoA and RhoC genes a e p esen in all e e-
b a es analyzed o da e, he RhoB gene is ound in many
bu no all e eb a es, al hough i is p esen in some
amphibians, ep iles and bi ds.
3,4
RhoB egula ion and signaling
Mos o he amino acid di e ences be ween RhoB and
RhoA/RhoC a e nea he C- e minus, in he egion
known as he hype a iable egion (Fig. 1). The hype -
a iable egion o RhoB con ains mos ly pola esidues
compa ed o he basic esidues ound in RhoA and
RhoC. This a ec s he e ec o and egula o y p o eins i
binds o.
5
RhoB also di e s om RhoA and RhoC in he
C- e minal CAAX box (C Dcys eine, A Dalpha ic amino
acid, X Dany amino acid), in which he Cys is modified
by isop enoid lipids. RhoB can be modified by bo h
ge anyl-ge anyl and a nesyl isop enoids, whe eas RhoA
and RhoC a e only ge anylge anyla ed. RhoB can also be
palmi oyla ed a Cys189 and 192. This a ie y o lipid
modifica ions on RhoB a ec s i s localiza ion and indeed
RhoB localizes a he plasma memb ane, as well as on
endosomes and mul i esicula bodies (MVB)
6,7
whe eas
RhoA and RhoC a e localized mainly on he plasma
memb ane o in he cy osol. RhoB has also been epo ed
o localize in he nucleus.
8
Like mos Rho GTPases, RhoB ac i i y is egula ed by
GTP/GDP loading. I cycles be ween a GTP-bound
ac i e s a e and a GDP-bound inac i e s a e. GTP-bound
Rho p o eins in e ac wi h hei downs eam e ec o s o
induce cellula esponses. GTP/GDP cycling is mainly
egula ed by guanine nucleo ide exchange ac o s
(GEFs), which exchange GDP o GTP, and GTPase-
ac i a ing p o eins (GAPs) ha p omo e apid GTP
hyd olysis. GEF and GAP p o eins specifically egula ing
CONTACT F ancisco M. Vega [email p o ec ed] Ins i u o de Biomedicina de Se illa, Uni e sidad de Se illa, Campus Uni e si a io Vi gen del Roc

ıo. A da,
Manuel Siu o s/n, Edificio IBiS, 41013 Se illa, Spain; Anne J. Ridley [email p o ec ed] King’s College London, New Hun ’sHouse,Guy’sCampus,
London SE1 1UL, UK.
Colo e sions o one o mo e o he figu es in his a icle can be ound online a www. and online.com/ksg .
© 2016 F ancisco M. Vega and Anne J. Ridley. Published wi h license by Taylo & F ancis.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion-NonComme cial-NoDe i a i es License (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/),
which pe mi s non-comme cial e-use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed, and is no al e ed, ans o med, o buil upon in any way.
SMALL GTPASES
2018, VOL. 9, NO. 5, 384–393
h ps://doi.o g/10.1080/21541248.2016.1253528
RhoB and no RhoA o RhoC ha e no so a been iden-
ified, e en hough he di e en localiza ion and lipid
modifica ions o RhoB compa ed o RhoA and RhoC
migh be expec ed o expose i o di e en GEFs and
GAPs. Mos GEFs and GAPs es ed ac on RhoA, RhoB
and RhoC, a leas in i o. The RhoGEF XPLN/ARH-
GEF3 binds o RhoA and RhoB bu no RhoC.
9
The chape one p o ein SmgGDS binds o polybasic
C- e minal egions in se e al GTPases and has GEF
ac i i y o RhoA and RhoC bu does no bind RhoB.
10
O he 3 Rho guanine nucleo ide dissocia ion inhibi-
o s (RhoGDIs), which a e nega i e egula o s o some
Rho GTPases,
11
only RhoGDI-3 has been desc ibed o
bind RhoB, whe eas RhoGDI1 binds RhoA and RhoC
bu no RhoB.
12
RhoB le els a e acu ely egula ed in esponse o a
a ie y o s imuli. RhoB is a ge o ubiqui in-media ed
p o easomal deg ada ion, wi h Smu 1 and he Cullin2-
RBX1 complex being i s bes known ubiqui in
ligases.
13,14
RhoA and RhoC a e also ubiqui yla ed,
howe e , RhoB p o ein is much mo e apidly deg aded
by he p o easome han RhoA o RhoC, and has a sho
hal -li e o abou 30 minu es.
15
RhoB p o ein is no -
mally a low s eady-s a e le els in cells, bu can be ap-
idly and ansien ly up egula ed by se e al s imuli,
including UV i adia ion, g ow h ac o s, cy okines and
du ing he cell cycle (see below). RhoB mRNA can be
egula ed by se e al miRNAs in cance cell lines and
endo helial cells. Fo example miRNA21 egula es p o-
li e a ion, mig a ion and in asion o colo ec al cance
cells and miR19a p omo es panc ea ic cance in i o
and in i o, in bo h cases by a ge ing RhoB.
16,17
In e -
es ingly, se e al s udies ha e shown ha RhoB exp es-
sion is inc eased a e he down egula ion o RhoA o
RhoC,
18-21
al hough i is no clea i his is ia miRNAs
o changes in p o ein s abili y. RhoB may also be egu-
la ed by phospho yla ion. RhoB, bu no RhoA o
RhoC, is phospho yla ed and inhibi ed by casein kinase
1 (CK1) on Se 185 (Fig. 1).
22
RhoB has been epo ed
o be phospho yla ed on y osine esidues bu he unc-
ional ele ance is no clea (Fig. 1).
23
Mos e ec o s es ed in i o bind equally well o RhoA,
RhoB o RhoC. ROCK o example is ac i a ed by all 3 p o-
eins, al hough a di ec binding migh no be equi ed.
24
By
con as , he PRK amily o p o ein kinases has a highe
a fini y o RhoB han RhoA o RhoC, and o PRK3 his
in ol es in e ac ion wi h he C- e minal egion o RhoB.
25
In e es ingly, PRK1 is localized o endosomes by RhoB in
cells,
26
indica ing ha PRKs a e likely o p e e en ially
in e ac wi h RhoB in i o as well as in i o.
RhoB ac i i y in cells can be analyzed using he Rho-
binding domain (RBD) o he Rho e ec o Rho ekin,
which in e ac s wi h RhoA, RhoB and RhoC, ollowed by
wes e n blo ing wi h RhoB-specific an ibodies. Specific
molecula FRET biosenso s o he s udy o RhoA and
RhoC ac i i y ha e been desc ibed.
27
In e molecula
FRET be ween RhoB and i s a ge mDia2 has been used
in he pas o he isualiza ion o RhoB ac i i y on
endosomes.
28
Mos ecen ly, a specific molecula FRET
biosenso o he de ec ion o RhoB ac i i y in in ac cells
Figu e 1. Schema ic o RhoB p o ein s uc u e highligh ing he di e en p o ein domains and known phospho yla ion si es. A
compa ison be ween he hype a iable egion sequence o RhoA, RhoC and RhoB is shown in he box. Red amino acid esidues in RhoA
and RhoC indica e di e gence om he RhoB sequence. CAAX box is also highligh ed. CK1: Casein kinase 1; GG: ge anylge anyla ion;
P: palmi oyla ion; F: a nesyla ion.
SMALL GTPASES 385
has been epo ed and used, oge he wi h RhoA/C
p obes, o analyze he spa io empo al ac i i y egula ion
o hese molecules in endo helial cells.
29
One o he specific cellula unc ions o RhoB, ela ed
o i s localiza ion o in acellula memb ane esicles, is
he egula ion o endosomal dynamics
30
(Fig. 2). By con-
olling in acellula anspo , i egula es signaling by
he ecep o s EGFR and CXCR2, and he in acellula
kinases S c and Ak ,
31-34
hus a ec ing a a ie y o
physiological p ocesses as desc ibed below (Fig. 2).
RhoB unc ion du ing de elopmen
RhoB is no essen ial o de elopmen in mice: RhoB
knockou mice a e iable and e ile.
35
I is possible ha
signalingbyo he RhoGTPases is al e ed in RhoB-null
mice, he eby compensa ing o loss o RhoB. Close anal-
ysis o RhoB-null mice howe e e eals de ec s in specific
sys ems and a ole o RhoB in se e al de elopmen al p o-
cesses. Fo example, RhoB knockou mice show a educed
hymus weigh and cellula i y and an inc ease in TGFb
signaling in he hymic medulla y epi helium, whe e
RhoB is no mally exp essed, implying ha RhoB con ib-
u es o hymus de elopmen and main enance.
36
In addi-
ion, RhoB-null mice ha e e a ded ascula de elopmen
and impai ed essel sp ou ing in he e ina, an e ec
a ibu ed o a ole o RhoB in endo helial cell su i al
ia Ak s abiliza ion in he nucleus.
31
RhoB is exp essed du ing mouse de elopmen in bo h
neu al c es and neu al issues including mo o neu ons
and he floo pla e o he neu al ube. I is also exp essed
in he de eloping endoca dial cushions o he a io en-
icula and ou flow egions o he de eloping hea and
i s exp ession inc eases as he epi helial-mesenchymal
ansi ion (EMT) necessa y o gene a ing he al es and
sep a o he hea p og esses.
37
This sugges s a possible
ole o RhoB in he o ma ion o he hea memb ane
al es, al hough his has no been es ed. RhoB is also
exp essed in glial M€
ulle cells o main ain cellula
mo phology, in bo h adul mouse and chick e ina.
38
In addi ion o mice, s udies in o he o ganisms ha e
demons a ed a ole o RhoB in no mal de elopmen .
Fo example, RhoB ac i i y is necessa y o he ac in
eo ganiza ion equi ed o ea he bud o ma ion and
pa e ning downs eam o Eph in signaling in chick
emb yos.
39
Whe e a ole o RhoB has been mos clea ly delin-
ea ed is in he de elopmen o he chick neu al c es .
RhoB is implica ed in he delamina ion o he neu al
c es downs eam o he ansc ip ion ac o Slug.
35,40
RhoB has also been desc ibed o be induced indepen-
den ly o Slug by he ansc ip ion ac o Sox5 in he
p e-mig a o y chick cephalic neu al c es .
41
The exp es-
sion o RhoB is also de ec ed in mig a ing neu al c es
cells in Xenopus
42
RhoB is p oposed o induce neu al
c es delamina ion by s imula ing cy oskele al emodeling
Figu e 2. Roles o RhoB in in acellula anspo . Endosome-associa ed RhoB egula es he a ficking and ecycling o ecep o y osine
kinases such as EGFR and o he ecep o s like CXCR2 o TNFR, a ec ing hei ac i i y. I also egula es S c ac i a ion and anspo o
memb anes and Ak ac i a ion and anspo o he nucleus. RhoB media es he PDGF o inflamma o y esponses by a ge ing o he
Rho GTPases like Rac o Cdc42 o he plasma memb ane. See ex o e e ences.
386 F. M. VEGA AND A. J. RIDLEY
and he o ma ion o ocal adhesions ha allow he
acquisi ion o a mig a o y pheno ype in p e-mig a o y
and mig a o y neu al c es cells
43
al hough hese ea ly
s udies elied on he Clos idium bo ulinum exoenzyme
C3 ans e ase, which inhibi s RhoA, RhoB and RhoC.
RhoB is also in ol ed in neu al c es mig a ion i sel ,
al hough i s o e exp ession alone is no su ficien o elici
a mig a o y pheno ype.
37,42,44
In conclusion, RhoB
exp ession in he neu al c es sugges s a p ominen ole
in neu al c es o ma ion and mig a ion o a ge issues,
al hough he mechanism and exac ole ha e no been
ully elucida ed ye .
RhoB in inflamma ion and asculogenesis
Se e al s udies ha e implica ed RhoB in inflamma o y
esponses, pa icula ly in mac ophages and endo helial
cells. RhoB bu no RhoA is epo ed o be in ol ed in
mannose ecep o -media ed phagocy osis in human
al eola mac ophages.
45
RhoB also egula es he sec e-
ion o TNFaand ni ic oxide by mac ophages in a
model o LPS-induced inflamma ion in mice, possibly
h ough a pa hway in ol ing NFkB.
46
RhoB a ec s cell adhesion and mig a ion o mac o-
phages by educing cell su ace exp ession o b2 and b3
in eg ins bu i is no equi ed o he assembly o podo-
somes, based on s udies wi h p ima y mac ophages om
RhoB-null mice.
47
Mac ophages lacking bo h RhoB and
RhoA (RhoC is no exp essed in mac ophages) ha e
impai ed lamellipodial e ac ion and al e ed cell shape.
Simila o RhoB-deple ed mac ophages
47
hey mig a e
as e in i o, which co ela es wi h inc eased ec ui -
men in esponse o pe i oneal inflamma ion in i o.
48
RhoB exp ession is up egula ed in mouse mac o-
phages du ing he inflamma o y esponse o hypoxia in
a mechanism in ol ing JNK, ERK and he hypoxia-
inducible ansc ip ion egula o HIF1a. RhoB deple ion
in hese cells impai s p oduc ion o inflamma o y cy o-
kines bo h in no moxia and in esponse o hypoxia.
49
RhoB is also apidly ac i a ed by hypoxia and is equi ed
o HIF1as abiliza ion in endo helial cells and o he cell
ypes.
50,51
Ac i a ion o RhoB by hypoxia inc eases
pulmona y endo helial cell con ac ili y, induces endo-
helial pe meabili y and p omo es cell g ow h in i o,
media ing adap i e changes o ch onic hypoxia in he
pulmona y ascula u e in i o.
51
The a nesyla ed bu no he ge anylge anyla ed o m
o RhoB can ac i a e NFkB in se e al cell ypes ia i s
downs eam a ge ROCK-I,
52
al hough whe he i con-
ibu es o inflamma o y esponses media ed by NFkBis
no known. RhoB is also needed o e ficien human
cy omegalo i us p oduc ion and in ec ion o fib oblas s,
whe e i con ibu es o he ac in assembly needed o
i us sp ead.
53
RhoB also egula es endo helial cell esponses o
inflamma o y signals. RhoB is s ongly up egula ed in
p ima y human endo helial cells by he p o-inflamma-
o y s imuli TNFa, IL1band LPS. I specifically egula es
some esponses o he TNF ecep o by con olling i s
in acellula a fic, o example TNFa-media ed ac i a-
ion o p38MAP kinase and JNK, he la e p esumably
in a coo dina ed manne wi h RhoA.
54
Significan RhoB
ac i a ion in endo helial cells a e TNF s imula ion has
also been de ec ed using a specific RhoB biosenso .
29
The
inflamma o y esponse in endo helial cells deple ed o
RhoB is impai ed, as measu ed by exp ession o he leu-
kocy e ecep o ICAM-1 o p oduc ion o he cy okines
IL6 and IL8. Du ing inflamma ion, endosomal RhoB in
he endo helium is up egula ed in esponse o inflamma-
o y cy okines, and RhoB ac i i y egula es Rac1 a fick-
ing o he plasma memb ane o con ol endo helial
ba ie in eg i y.
21
RhoB is no only implica ed in endo helial cell inflam-
ma o y esponses bu also in he egula ion o ascula
unc ion and angiogenesis. Using siRNAs, RhoB has
been shown o be equi ed o endo helial cell mig a ion,
sp ou ing and capilla y mo phogenesis.
55
The mic o-
RNA miRNA-21 a ge s RhoB in endo helial cells o
inhibi mig a ion and ubulogenesis.
56
How RhoB exe
hese unc ions in endo helial cells is no comple ely
clea . One possibili y is ha i ac s h ough i s e ec s on
he ac in cy oskele on, since RhoB is he main egula o
o s ess fibe o ma ion in endo helial cells unde some
condi ions.
56,57
I is also possible ha RhoB egula es he
ac i i y o o he Rho GTPases, like RhoA, o ha i
a ec s endo helial cell mo phogenesis by egula ing
g ow h ac o ecep o a ficking and signaling, as
VEGF induces RhoB exp ession.
55
Loss o RhoB also dec eases pa hological angiogenesis
in ischemic e ina and educes angiogenesis in esponse
o wounding. Con e sely, loss o RhoB inc eased lym-
phangiogenesis a e wounding o inflamma ion, indica -
ing ha RhoB has di e en e ec s in blood essel e sus
lympha ic endo helial cells.
8
Bo h e ec s we e linked o
RhoB-media ed egula ion o gene exp ession h ough
he ansc ip ion ac o VEZF1.
RhoB in cance
Rho GTPases, including RhoB, ha e been ex ensi ely
s udied o hei con ibu ion o cance p og ession,
gi en hei majo oles in egula ing cell mig a ion and
p oli e a ion.
58-61
RhoB was fi s desc ibed o con ibu e o fib oblas
ans o ma ion downs eam o he Ras onco-p o ein,
62
SMALL GTPASES 387

bu has subsequen ly been desc ibed o ac p edomi-
nan ly as a umo supp esso . Indeed, RhoB le els
dec ease wi h umo p og ession in a ious solid human
umo ypes,
58
and RhoB knock-ou mice a e mo e p one
o ca cinogen-induced skin cance .
35
This could eflec
he ole o RhoB in egula ing cell cycle p og ession and
apop osis. Fo example, RhoB is equi ed o he apop o-
ic esponse o ans o med fib oblas s o DNA damage
o axol,
63
and ea men o anaplas ic hy oid ca cinoma
cells wi h an agonis o PPARg(Pe oxisome-p oli e a-
o -ac i a ed- ecep o -g) induces cell cycle a es by
RhoB-media ed ac i a ion o he cell cycle inhibi o
p21.
64
RhoB also inhibi s mig a ion, in asion, me as asis
and umo g ow h in some models.
65,66
By con as ,
RhoB con ibu es o umo igenesis in ce ain umo
models. Fo example, RhoB knockdown has been
desc ibed o induce an apop o ic esponse in enal cells
67
and a ecen epo shows ha , in gliomas, RhoB deple-
ion leads o cell cycle a es , apop osis and educed
umo igenic po en ial in i o, possibly h ough p53
ac i a ion.
68
Howe e , o e exp ession o RhoB did no
induce cell g ow h in glioma cells, a guing agains a
umo -ini ia ing unc ion o RhoB.
As men ioned abo e, RhoB exp ession is apidly
up egula ed in cance cells by mul iple s imuli including
UV i adia ion, cy okines, g ow h ac o s o oxin
ea men ( e iewed in e . 58). These changes in RhoB
le els a e media ed by gene ansc ip ion (as a e oxin
A o s e oid ho mones ea men and a e y osine
kinase s imula ion), mRNA s abiliza ion (like a e
TGFbs imula ion o du ing cell cycle p og ession) o
bo h ( o example a e UV ligh induc ion). mRNA s a-
bili y is con olled by he RNA-binding p o ein HuR, a
subs a e o he DNA damage-ac i a ed checkpoin
kinase Chk2.
69,70
Epigene ic changes ha e also been p o-
posed o egula e he RhoB p omo e : his one deace y-
lase-1 (HDAC1) ep esses RhoB exp ession and HDAC
inhibi o s, known o kill umo cells, ac ually induce
RhoB exp ession.
71,72
In addi ion, combined inhibi ion
o HDACs and phosphoinosi ide 3-kinases (PI3Ks) in
Bu ki lymphoma cells inc eases RhoB exp ession, co -
ela ing wi h educed cell p oli e a ion and mig a ion.
73
In e es ingly, RhoB con ibu es o ei he cell cycle a es
o apop osis depending on which HDAC iso o m is
inhibi ed,
74
sugges ing ha RhoB may ac oge he wi h
o he HDAC iso o m-selec i e a ge s o a ec cellula
esponses. On he o he hand RhoB exp ession is
educed by se e al oncogenes including Ras, EGFR o
Ak .
66,75
Simila ly, hy oid ho mone ecep o e-exp es-
sion in hy oid cance cells ac i a es RhoB ansc ip ion
inducing cell cycle a es and educing in asion.
76
In addi ion o inc easing RhoB exp ession, geno oxic
s ess apidly ac i a es RhoB. This appea s o be
media ed by he nuclea GEFs Ec 2 and Ne 1, as down e-
gula ion o hese p o eins, and no 2 cy oplasmic RhoB
GEFs, ab oga es DNA damage-media ed RhoB
ac i a ion.
77
Dis inc lipid modifica ions on RhoB may play a ole
in i s umo supp essi e ole. Fa nesyl an e ase inhibi-
o s (FTIs) induce accumula ion o ge anylge anyla ed
RhoB, which has been p oposed o media e FTI-induced
inhibi ion o p oli e a ion
78
. RhoB is ce ainly equi ed
o he apop o ic esponse o FTIs, which is in pa
media ed by supp ession o Cyclin B1 ac i i y.
63,79,80
Fo some ime, i has been known ha RhoB dele ion
con e s esis ance o DNA damaging agen s in i o.
63
New e idence e eals ha RhoB a ec s DNA damage
epai and how his could a leas in pa explain i s
umo supp essi e ole (Fig. 3). A di ec link be ween
double s and b eaks (DSBs) and RhoB exp ession has
been desc ibed, in ol ing RhoB mRNA s abiliza ion by
Chk2 ia i s subs a e HuR.
70
RhoB-deficien cells ail o
epai DNA DSBs e ec i ely by homologous ecombina-
ion, and his is a ibu ed o educed de-phospho yla-
ion o he his one gH2AX by he phospha ase PP2A.
RhoB can also be induced downs eam o he DNA-
damage ac i a ed kinases ATR and Chk1, which sup-
p ess RhoB deg ada ion by he ubiqui in ligase Smu 1,
he eby p omo ing RhoB s abiliza ion and apop osis.
13
These mechanisms oge he o e an explana ion o he
associa ion be ween RhoB deple ion, genomic ins abili y
and umo p og ession.
In addi ion o egula ing he DNA damage
esponse, RhoB can a ec cell p oli e a ion and umo
g ow h by egula ing in acellula a ficking (see
Fig. 2). Fo example, RhoB is esponsible o EGFR
so ing o lysosomes and ecycling, hus modula ing
he esponses media ed by EGF.
7
I also influences
a fickingo o he signalingmoleculesincluding he
kinases Ak and S c
31,33
The e ec o s ha media e
hese unc ions downs eam o RhoB a e s ill no
known, al hough PRKs could be in ol ed since RhoB
ec ui s PRK1 o endosomes.
26
RhoB can also influence umo p og ession by egu-
la ing cance cell mig a ion, in asion and adhesion
(Fig. 4). The e ec o RhoB on cell mig a ion is cell ype
and con ex -dependen , p obably because i a ec s bo h
in acellula p o ein a ficking and ac in o ganiza ion.
Bo h RhoB dele ion and o e exp ession appea s o be
able o educe mig a ion in i o, highligh ing he
impo ance o a igh con ol on RhoB exp ession and
unc ion.
35,66
Howe e , RhoB deple ion can also inc ease
mig a ion speed o p os a e cance cells.
81
RhoB a ec s
b-in eg in exp ession and localiza ion, he eby modula -
ing cance cell adhesion and mig a ion.
81,82
RhoB
egula es signaling media ed by he U okinase- ype
388 F. M. VEGA AND A. J. RIDLEY
plasminogen ac i a o (uPA), a ec ing uPA-induced cell
adhesion, mig a ion and in asion o p os a e cance
cells.
82
RhoB can also egula e he unc ion o o he Rho
GTPases a ec ing cell mig a ion. Fo example, RhoB
con ols he a ficking o Cdc42 and Rac o he cell
memb ane in esponse o PDGF, media ing cell
mo emen .
83
Gi en i s ole in neu al c es de elopmen and
delamina ion,
35,40
he possible in ol emen o RhoB in
epi helial-mesenchymal ansi ion (EMT) mechanisms
du ing cance p og ession has been in es iga ed. RhoB
deple ion in enal cells did no a ec EMT, whe eas
RhoA and RhoC did con ibu e o EMT in he same
model.
67
Howe e , RhoB deple ion dis up ed cell-cell
in e ac ion in p os a e cance cells by al e ing E-cadhe in
dis ibu ion and le els.
84
RhoB deple ion p omo ed
Rac1-dependen mesenchymal cell in asion o lung
ca cinoma cells by media ing induc ion o he EMT
ansc ip ion ac o Slug and E-cadhe in ep ession.
Down egula ion o RhoB also induced Ak ac i a ion
which in u ns ac i a es Rac1 ia he GEF T io. The
phospha ase PP2A was iden ified he e as a RhoB e ec o
leading o Ak dephospho yla ion.
85
In summa y, RhoB con ibu es o cance p og es-
sion in mul iple ways, by egula ing DNA damage
esponses, apop osis, cell cycle p og ession, mig a ion
and in asion.
Conclusions and pe spec i es
Despi e he sequence simila i y wi h he closely ela ed
Rho GTPases RhoA o RhoC, RhoB has p o en o ha e
specific and pleio opic unc ions in o ganisms om
mammalian de elopmen o DNA damage su i al
esponses. Al hough some o hese oles o RhoB can be
a ibu ed o egula ion o in acellula a ficking o
signaling and adhesion molecules, he unc ion o RhoB
Figu e 4. Roles o RhoB in cell mig a ion and adhesion. RhoB ac s
on se e al a ge s (in yellow boxes) and a ec s he unc ion o
adhesion molecules, ecep o s and/o GTPases o egula e cell
mig a ion, in asion and adhesion p ocesses.
Figu e 3. RhoB in DNA-damage esponses. Bo h a e ionizing adia ion o UV-induced DNA-damage, RhoB exp ession is inc eased due
o inc eased mRNA s abili y, di ec p omo e ac i a ion and educed deg ada ion. Ac i e RhoB in u n pa icipa es in DNA epai and
induces cell cycle a es o apop osis in damaged cells. UV: ul a iole adia ion; IR: ionizing adia ion. See ex o e e ences.
SMALL GTPASES 389
ex ends beyond his. Mo e in o ma ion on how RhoB
ac i i y is egula ed and iden ifica ion o RhoB-specific
e ec o s will p o ide new insigh in o RhoB unc ion a
he cellula le el. A he physiological le el, i will be
impo an o de e mine whe he RhoB down egula ion
d i es umo p og ession and i i s signaling could be
exploi ed he apeu ically. Gi en he oles o RhoB in as-
cula biology and inflamma ion, i s di ec in ol emen
in o he human pa hologies should also be explo ed.
Funding
This wo k was suppo ed by Cance Resea ch UK unde G an
C6620/A15961 o Anne J Ridley; Andaluc
ıa Talen Hub P o-
g am g an launched by he Andalusian Knowledge Agency,
co- unded by he Eu opean Union’s Se en h F amewo k P o-
g am, Ma ie Sk»odowska-Cu ie ac ions (COFUND –G an
Ag eemen no 291780) and he Minis y o Economy, Inno a-
ion, Science and Employmen o he Jun a de Andaluc
ıa o
F ancisco M Vega.
ORCID
F ancisco M. Vega h p://o cid.o g/0000-0002-9015-864X
Anne J. Ridley h p://o cid.o g/0000-0001-8186-5708
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