Kidins220/ARMS as a unc ional media o o mul iple
ecep o signalling pa hways
Ve onika E. Neub and
1,
*, Fab izia Cesca
2,
*, Fabio Ben ena i
2
and Giampie o Schia o
3,`
1
Ins i u o de Pa asi ologı´a y Biomedicina Lo´pez-Ney a, IPBLN-CSIC, A da. Conocimien o S/N, 18100 A milla, G anada, Spain
2
Depa men o Neu oscience and B ain Technologies, Is i u o I aliano di Tecnologia, ia Mo ego 30, 16163 Geno a, I aly
3
Molecula Neu opa hology Labo a o y Cance Resea ch UK London Resea ch Ins i u e, 44 Lincoln’s Inn Fields, London, WC2A 3LY, UK
*These au ho s con ibu ed equally o his wo k
`
Au ho o co espondence ([email p o ec ed])
Jou nal o Cell Science 125, 1845–1854
!2012. Published by The Company o Biologis s L d
doi: 10.1242/jcs.102764
Summa y
An inc easing body o e idence sugges s ha se e al memb ane ecep o s – in addi ion o ac i a ing dis inc signalling cascades – also
engage in subs an ial c oss alk wi h each o he , he eby adjus ing hei signalling ou come as a unc ion o speci ic inpu in o ma ion.
Howe e , li le is known abou he molecula mechanisms ha con ol hei coo dina ion and in eg a ion o downs eam signalling. A
p o ein ha is likely o ha e a ole in his p ocess is kinase-D-in e ac ing subs a e o 220 kDa [Kidins220, also known as anky in epea -
ich memb ane spanning (ARMS), he ea e e e ed o as Kidins220/ARMS]. Kidins220/ARMS is a conse ed memb ane p o ein ha
is p e e en ially exp essed in he ne ous sys em and in e ac s wi h he mic o ubule and ac in cy oskele on. I in e ac s wi h
neu o ophin, eph in, ascula endo helial g ow h ac o (VEGF) and glu ama e ecep o s, and is a common downs eam a ge o se e al
ophic s imuli. Kidins220/ARMS is equi ed o neu onal di e en ia ion and su i al, and i s exp ession le els modula e synap ic
plas ici y. Kidins220/ARMS knockou mice show de elopmen al de ec s mainly in he ne ous and ca dio ascula sys ems, sugges ing a
c ucial ole o his p o ein in modula ing he c oss alk be ween di e en signalling pa hways. In his Commen a y, we summa ise
exis ing knowledge ega ding he physiological unc ions o Kidins220/ARMS, and highligh some in e es ing di ec ions o u u e
s udies on he ole o his p o ein in heal h and disease.
Key wo ds: Kidins220/ARMS, Neu onal di e en ia ion, Neu o ophins, RTK signalling, Synap ic plas ici y
In oduc ion
The co ec de elopmen o he ne ous sys em elies on
he abili y o axons and dend i es o ecognise hei a ge s.
Du ing his highly egula ed p ocess, neu ons mig a e and o m
unc ional connec ions in esponse o g adien s o g ow h ac o s
ha egula e mul iple neu onal unc ions, including cell
su i al, di e en ia ion and synap ic plas ici y (Bibel and
Ba de, 2000; Chao, 2003; Huang and Reicha d , 2003). The
neu o ophin (NT) amily is one o he bes -cha ac e ised g oups
o neu o ophic ac o s and includes ne e g ow h ac o (NGF),
b ain de i ed neu o ophic ac o (BDNF), and neu o ophin-3
(NT3) and -4 (NT4, also known as NT4/5) (Huang and
Reicha d , 2001). Neu o ophins bind wi h high a ini y o
h ee ela ed opomyosin ecep o kinases (T ks): NGF binds
mainly o T kA, whe eas BDNF and NT4/5 bind mainly o
T kB, and NT3 o T kC. In addi ion, all neu o ophins also bind
o he p75 neu o ophin ecep o (p75
NTR
, also known as
NGFR), a membe o he umou nec osis ac o (TNF)- ecep o
supe amily (Bibel and Ba de, 2000). O he g ow h ac o s ha
a e pa amoun in neu onal g ow h and de elopmen a e he
glial-cell-line-de i ed neu o ophic ac o (GDNF), which ac s
h ough he Re y osine kinase ecep o , and he GDNF amily
ecep o a(GFRa) (Pa a cha and Ledda, 2008). In addi ion,
ophic ac o s such as he VEGF and he eph in–eph in- ecep o
(eph in–Eph) amilies ha e c ucial oles bo h inside and ou side
he ne ous sys em (Klein, 2009; Ruiz de Almodo a e al.,
2009).
The as majo i y o hese ligands pe o m hei physiological
unc ions h ough plasma memb ane ecep o s ha ha e y osine
kinase ac i i y – he ecep o y osine kinases (RTKs) – which
esul s in dis inc signalling ou pu s and cellula e ec s.
Howe e , how RTKs media e such di e se biological
ou comes by s a ing om a common subse o signalling
molecules – such as he Ras p o ein amily, he ex acellula
egula ed kinases (ERKs; also known as mi ogen ac i a ed
p o ein kinases, MAPKs), Ak and phospholipase Cc(PLCc)–
is p esen ly unclea . The signal speci ici y o NT ecep o s is
uned by a numbe o ac o s, including he epe oi e o T k
ecep o s and he le el o p75
NTR
exp essed by a pa icula
neu on, which de e mine he subse o neu o ophins o which a
pa icula neu on would espond (Cla y and Reicha d , 1994;
S ohmaie e al., 1996; Hapne e al., 1998; Palko e al., 1999;
S oilo e al., 2002). Upon binding o NTs, T k ecep o s dime ise
and c oss-phospho yla e each o he . Ac i a ed T k ecep o s a e
hen able o ec ui a numbe o adap o s h ough hei
phospho yla ed esidues. A he in acellula le el, a ailabili y o
di e en subs a es o adap o s could, hus, con ol signalling
downs eam o T k ecep o s (Lee e al., 2001). Addi ionally, he
esponse o neu o ophin signals depends on he empo al and
spa ial pa e n o s imula ion. Thus, ansien o sus ained
ac i a ion o he MAPK, phosphoinosi ide kinase-3 (PI3K) o
Ak pa hways media es dis inc cellula e ec s, o example by
p omo ing a local and as esponse a he g ow h cone
compa ed wi h a slowe esponse a dis al si es, such as he
Commen a y 1845
Jou nal o Cell Science
soma (Ma shall, 1995; Ku u illa e al., 2000; Wa son e al.,
2001). To add a u he le el o complexi y, di e en ecep o s
can in e ac wi h each o he . Fo example, p75
NTR
is ound in
complex wi h T k, so ilin-1 (So l1) o Nogo (RTN4R) ecep o s
(B on man and Fainzilbe , 2004), whe eas T kB in e ac s wi h
eph in-A7 and EphA5 (Fi zge ald e al., 2008; Ma le e al.,
2008). Simila ly, GDNFaR, Re y osine kinase and
p o ocadhe ins coope a e o egula e neu onal su i al
(Schalm e al., 2010), and he in e ac ion be ween EphB and
N-me hyl-D-aspa a e (NMDA) ecep o s – an impo an class
o glu ama e ecep o s – is c ucial o he modula ion o synap ic
plas ici y (Dal a e al., 2000; Hende son e al., 2001). Thus, a
complex in e play be ween he epe oi e o ecep o s and he
a ailabili y o downs eam e ec o s ul ima ely de e mines he
esponse o a neu on o a gi en s imulus.
A common downs eam e ec o o hese pa hways is he
sca olding p o ein Kidins220/ARMS. In mice, emb yos ha lack
Kidins220/ARMS die a bi h, indica ing ha his p o ein is
essen ial o li e. In addi ion o a a ie y o neu onal pheno ypes,
hese emb yos show se e e de ec s in ascula de elopmen and
ca diac mal o ma ions, which a e likely o be he cause o dea h
(Cesca e al., 2011; Cesca e al., 2012). Mu an s o Kidins220/
ARMS ha e been desc ibed in Caeno habdi is elegans ( ag-114)
and D osophila melanogas e (Dmel CG42672) (see also h p://
www.wo mbase.o g/ and h p:// lybase.o g/). Howe e , only a
pa ial pheno ypic cha ac e isa ion o hese mu an s has been
p o ided so a , making he analysis pe o med in mice he mos
in o ma i e o da e.
Kidins220/ARMS is a mul i unc ional sca olding p o ein
Kidins220/ARMS was ini ially iden i ied as a subs a e o
p o ein kinase D (PKD) in neu al cells (Iglesias e al., 2000), and
independen ly cha ac e ised as a downs eam a ge o he
signalling media ed by neu o ophins and eph ins (Kong e al.,
2001). Kidins220/ARMS is an in eg al memb ane p o ein,
con aining ou ansmemb ane segmen s in he cen al pa o
he molecule, and N- and C- e minal ails bo h exposed o he
cy oplasm (Fig. 1). Sequence analysis o Kidins220/ARMS
e ealed he p esence o nume ous domains ha media e
p o ein–p o ein in e ac ions. The N- e minus o Kidins220/
ARMS con ains ele en anky in epea s ( esidues 37–398 in he
mouse sequence), which o m a conca e binding su ace ha is
accessible o molecula pa ne s, such as he Rho–guanine
nucleo ide exchange ac o (RhoGEF) T io (Neub and e al.,
2010). Kidins220/ARMS has been included in he Kidins220/
ARMS and Pi A (KAP) amily o P-loop nucleo ide phospha ases
(NTPases). P-loop NTPases con ain Walke A and Walke B
mo i s (WA and WB, espec i ely) (Higgins e al., 1988), which
a e o en in ol ed in he binding o nucleo ides and ha e been
iden i ied in he jux amemb ane egions lanking he N- and C-
e minus o Kidins220/ARMS. Membe s o his amily a e
p edic ed o media e he assembly o p o ein complexes ha a e
associa ed wi h he inne su ace o cell memb anes (A a ind
e al., 2004). In e es ingly, Kidins220/ARMS binds ATP
(Te esa Iglesias and G.S., unpublished), al hough a unc ional
ole o i s Walke mo i s has so a no been es ablished. Thus,
u he wo k is equi ed o es ablish whe he Kidins220/ARMS
Anky in epea
Walke A, B
P oline- ich domain
SAM domain
KIM
PDZ-binding mo i
Phospho yla ion si e
Caspase-3 si e
Ubiqui yla ion si e
T ansmemb ane
egion
EphA4
eph in-A1
p75NTR
C kL
Y1096
PKD S919
Kinesin-1
α
α-syn ophin
T ks
NMDAR
AMPAR
T io
SCG10
SCLIP MAP1a, 1b, 2
Neu onal su i al and/o
dea h upon exci o oxici y
S-SCAM
T k signalling
om endosomes
Connec ion o ac in
and MT cy oskele on
Exi om TGN
Localisa ion
o lipid a s
Sus ained MAPK
ac i a ion
Neu onal di e en ia ion
MT cy oskele on
Jak–S a signalling
Synapse de elopmen
VEGFRs
Vascula
de elopmen
VEGF
NT
Glu
K891
Key
Fig. 1. Kidins220/ARMS engages in mul iple p o ein–p o ein in e ac ions. Schema ic s uc u e o Kidins220/ARMS wi h i s di e en domains and si es o
pos - ansla ional modi ica ions. Also shown a e he molecula pa ne s iden i ied o da e, oge he wi h he cellula e en s ha a e igge ed by hei
binding o Kidins220/ARMS (a ows). The domains o Kidins220/ARMS media ing he in e ac ion wi h he a ious pa ne s a e lis ed in Table 1. AMPAR,
AMPA ecep o ; Glu , glu ama e; MT, mic o ubule; NT, neu o ophins, NMDAR, NMDA ecep o .
Jou nal o Cell Science 125 (8)1846
Jou nal o Cell Science
has a de ec able NTPase ac i i y, o whe he ATP binding is
equi ed o i s unc ion.
The C- e minus o Kidins220/ARMS includes se e al p o ein–
p o ein in e ac ion domains; o example a p oline- ich egion
( esidues 1080–1092) ha binds he adap o p o ein C kL
(A e alo e al., 2006), and a s e ile alpha mo i (SAM; esidues
1231–1300) (Iglesias e al., 2000; Kong e al., 2001) ha migh
be in ol ed in bo h in e - and in a-molecula in e ac ions. In
addi ion, he kinesin ligh chain (KLC)-in e ac ing mo i (KIM)
( esidues 1387–1426) binds he kinesin-1 mo o complex
(B acale e al., 2007). The las ou amino acids o Kidins220/
ARMS cons i u e a PDZ-binding mo i ha binds he PDZ
domain o a-syn ophin, he eby o ming a complex ha is
associa ed wi h he EphA4 ecep o a he neu omuscula
junc ion (Luo e al., 2005).
The obse a ion ha Kidins220/ARMS in e ac s wi h all h ee
T k ecep o s and wi h p75
NTR
(A e alo e al., 2004; Chang e al.,
2004) p omp ed a se ies o s udies on he ole o Kidins220/
ARMS in a ious aspec s o neu o ophin physiology, mos ly
ocusing on he molecula mechanisms by which Kidins220/
ARMS media es T k signalling (A e alo e al., 2004; A e alo
e al., 2006). Wi h i s mul iple domains, Kidins220/ARMS is a
well-sui ed candida e o ac as a signalling pla o m, by ec ui ing
cell-speci ic adap o s and e ec o s o ac i a ed T k ecep o s.
Kidins220/ARMS is also in ol ed in unc ional in e ac ions wi h
se e al o he ecep o s, such as glu ama e, Eph and VEGF
ecep o s (VEGFRs) (Luo e al., 2005; Lopez-Menendez e al.,
2009; A e alo e al., 2010; Cesca e al., 2012), hus ep esen ing
an example o how di e en ophic pa hways can con e ge and,
possibly, be in eg a ed a he le el o a single adap o molecule.
A lis o he Kidins220/ARMS in e ac o s iden i ied o da e is
p esen ed in Table 1.
Kidins220/ARMS in e olu ion
Bioin o ma ic analysis e ealed Kidins220/ARMS o hologues in
se e al me azoans (Fig. 2A; Table 2) [(Iglesias e al., 2000;
Kong e al., 2001) and (P obi Chak a a y, unpublished)]. In a
phylogene ic ee, mammalian, a ian and ep ilian p o eins a e
clus e ed oge he , and ha e a high deg ee o sequence simila i y
(94-80% among mammals; 94-75% o e all). F og and ish
p o ein sequences ha e an in e media e le el o simila i y
(70-75% and 61-66%, espec i ely) compa ed wi h hose o
mammalian p o eins, whe eas Kidins220/ARMS amino acid
sequences in nema oda, unica a and cnida ia a e conside ably
di e en om hose in he o he g oups (Fig. 2A). Ano he
phylogene ic clus e o Kidins220/ARMS homologues is
ep esen ed by insec s, whose p o ein sequences a e mo e
simila o each o he han o any o he o ganism. Wi h he
excep ion o he D. melanogas e Kidins220/ARMS sequence
(which has an addi ional N- e minal ex ension) and ha o
Bombus e es is ( o which an N- e minal ex ension is also
p edic ed), he N- e minal egion o Kidins220/ARMS is highly
conse ed, whe eas i s C- e minal pa is mo e di e gen
(Fig. 2B). On he basis o his analysis, i is possible ha
cy oskele al emodelling, which is he main unc ion associa ed
wi h he N- e minus (Higue o e al., 2010; Neub and e al., 2010;
Pa k e al., 2010), is he mos ‘ancien ’ unc ion o Kidins220/
ARMS. This ole has been main ained h ough e olu ion in
o ganisms such as D. melanogas e and C. elegans, o which a
canonical neu o ophin pa hway has no ye been iden i ied. As
Kidins220/ARMS is p esen in cells o he immune sys em (Riol-
Blanco e al., 2004; Ni e al., 2010; Jean-Mai e e al., 2011; Ni
e al., 2011) and i is likely o be exp essed in he ca dio ascula
sys em – hypo hesised on he basis o unc ional da a (Cesca e al.,
2011; Cesca e al., 2012) – he C- and N- e minal pa s o
Kidins220/ARMS migh ha e di e ged, e lec ing he di e en
specialisa ion o issues and o gans in he a ious phylogene ic
g oups. In e es ingly, he eph in–Eph and VEGF–VEGFR
pa hways a e mo e conse ed in e olu ion han he neu o ophin-
T k sys em, and ha e also been iden i ied in in e eb a es
(D esche , 2002; Shibuya, 2002; Seipel e al., 2004; Mello and
Bu ke, 2008). The e o e, he neu o ophic unc ion o Kidins220/
ARMS migh be a ea u e in o ganisms wi h a mo e complex
ne ous sys em, whe eas in lowe o ganisms, Kidins220/ARMS
migh con ibu e o he de elopmen o o he issues by modula ing
eph in–Eph and VEGF–VEGFR pa hways.
Kidins220/ARMS and neu o ophin signalling
As p e iously men ioned, Kidins220/ARMS in e ac s wi h T k
ecep o s (A e alo e al., 2004), o ming a e na y complex wi h
p75
NTR
(Chang e al., 2004). The in e ac ion be ween Kidins220/
ARMS and T kA is media ed by he ou h ansmemb ane
Table 1. Kidins220/ARMS binding pa ne s
Binding pa ne Kidins220/ARMS binding si e Re e ences
AMPAR–GluA1 T ansmemb ane domains (A e alo e al., 2010)
a-syn ophin PDZ-binding mo i (Luo e al., 2005)
C kL P oline- ich domain (A e alo e al., 2006)
EphA4 n.d. (Luo e al., 2005)
Kinesin 1 KIM mo i (B acale e al., 2007)
MAP1a, MAP1b, MAP2 Residues 760–1762 (Higue o e al., 2010)
NMDA ecep o n.d. (Lopez-Menendez e al., 2009)
p75
NTR
Residues 1512–1762 (Kong e al., 2001)
PDZ–GEF1 Indi ec binding h ough S-SCAM (Hisa a e al., 2007)
PKD n.d. (Iglesias e al., 2000)
SCG10 Anky in epea s (Higue o e al., 2010)
SCLIP Anky in epea s (Higue o e al., 2010)
Sep in 5 Residues 1603–1715 (Pa k e al., 2010)
S-SCAM PDZ-binding mo i (Hisa a e al., 2007)
T io, kali in Anky in epea s (Neub and e al., 2010)
T kA, T kB, T kC T ansmemb ane domain (Kong e al., 2001;
(A e alo e al., 2004)
VEGFR2, VEGFR3 n.d. (Cesca e al., 2012)
Kidins220/ARMS in cell signalling 1847
Jou nal o Cell Science
domain o Kidins220/ARMS and he ansmemb ane domain o
T kA (A e alo e al., 2004) (Fig. 1), whe eas he in e ac ion wi h
p75
NTR
in ol es he las 250 amino acids o Kidins220/ARMS
(Kong e al., 2001) and he p75
NTR
in acellula domain ( esidues
327–342) (Chang e al., 2004). The binding o T k ecep o s and
p75
NTR
o Kidins220/ARMS is di e en ially modula ed by
neu o ophins. Fo ma ion o a Kidins220–T kA complex is
NGF-dependen and pe sis s o up o 25 hou s ollowing
s imula ion wi h NGF (Kong e al., 2001). The assembly o he
e na y complex be ween Kidins220/ARMS, T kA and p75
NTR
is
howe e independen o NGF (Chang e al., 2004). In e es ingly,
inc eased le els o Kidins220/ARMS educe he binding o T kA
o p75
NTR
, sugges ing ha Kidins220/ARMS egula es he
o ma ion o ecep o complexes ha display di e en
neu o ophin-binding a ini ies (Chang e al., 2004). In
addi ion, Kidins220/ARMS selec i ely media es he sus ained
Tunica a
0.1
Common bumblebee
Bu - ailed bumble
Wasp
Ca pen e an
Jumping an
Red bee le
Yellow- e e mosqui o
Mala ia mosqui o
F ui ly
Pea aphid Body louse B.malayi
Eyewo m
Pig oundwo m
C.elegans
C.b iggsae
T ichinella
Sea squi
Hyd a
Pu e ish
Zeb a ish
Tilapia
F og
Chicken
Zeb a inch
Liza d
Rabbi
Ra
Mouse
Human
Monkey
Dog
Elephan
Cnida ia
Nema oda
A h opoda
Cho da a
B. e es is
H. sapiens and M. musculus
D. e io
Ank TMWA WB P o SAM KIM
D. melanogas e
C. elegans
PDZ-binding
mo i
1250500
aa
B
A
Fig. 2. Kidins220/ARMS in e olu ion. (A) Dend og am o Kidins220/ARMS o hologues. The b anch leng hs a e p opo ional o he amoun o in e ed
e olu iona y change be ween sequences. GenBank accession numbe s a e lis ed in Table 2. (B) Schema ic o Kidins220/ARMS domain s uc u e in he indica ed
species. Al e na i e splicing may occu in he C- e minal egion be ween he KIM mo i and he PDZ-binding domain (Iglesias e al., 2000). The shaded g ey box
in he B. e es is sequence indica es a p edic ed N- e minal ex ension. Ank, anky in epea s; WA, Walke A mo i ; WB, Walke B mo i ; TM, ansmemb ane
egions; P o, p oline- ich domain.
Jou nal o Cell Science 125 (8)1848
Jou nal o Cell Science
ac i a ion o MAPK signalling, wi hou a ec ing he as
esponse o neu o ophins o he esponse o o he g ow h
ac o s, such as epide mal g ow h ac o (EGF) (Kong e al.,
2001; A e alo e al., 2004).
Kidins220/ARMS is phospho yla ed on y osine esidues in
esponse o NGF and BDNF, he ime cou se o which ollows
he kine ics o T k au ophospho yla ion and he e o e sugges s
ha his p o ein is a T k ecep o subs a e (Kong e al., 2001). In
addi ion, y osine phospho yla ion o Kidins220/ARMS occu s
simul aneously wi h ha o Shc and PLCc, indica ing ha his
p o ein is amongs he i s o be ac i a ed in esponse o NGF
(A e alo e al., 2004). The adap o p o ein C kL cons i u i ely
binds he second poly-p oline s e ch o Kidins220/ARMS
h ough i s SH3 domain (A e alo e al., 2006). Upon ea ing
cells wi h NGF, Kidins220/ARMS is phospho yla ed a y osine
1096, causing a con o ma ional change in he C kL–Kidins220/
ARMS complex. This allows he ec ui men o downs eam
modula o s o he MAPK pa hway, such as C3G and Rap1
(A e alo e al., 2006), and de e mines i s sus ained ac i a ion,
which occu s mainly a la e endosomes (Hisa a e al., 2007). This
e ec is highly speci ic, as pe u bing Kidins220/ARMS unc ion
by using RNA in e e ence (RNAi) o dominan –nega i e
Kidins220/ARMS cons uc s does no a ec he ansien
MAPK ac i a ion igge ed by EGF and he ini ial s eps o
MAPK signalling, which a e Ras- o Ak -dependen (A e alo
e al., 2004). Impai men o BDNF-induced MAPK ac i a ion has
also been demons a ed in Kidins220/ARMS-de icien neu ons
(Cesca e al., 2012). Among he ansc ip ion ac o s ac i a ed by
he MAPK pa hway, Kidins220/ARMS p omo es nuclea ac o -
kappa B (NF-kB) signalling when cells a e ea ed wi h BDNF,
media ing neu onal su i al (Snide han e al., 2008). In suppo
o hese indings, Kidins220/ARMS
–/–
emb yos show widesp ead
cell dea h in he cen al ne ous sys em (CNS) and pe iphe al
ne ous sys em (PNS) and die a bi h (Cesca e al., 2011; Cesca
e al., 2012). Rema kably, Kidins220/ARMS is one o he ew
p o eins ha is selec i ely equi ed o he sus ained ac i a ion o
MAPK signalling, whe eas mos o he o he ac o s ac in bo h
ansien and sus ained signalling.
Because o he ole Kidins220/ARMS has in su i al pa hways
such as MAPK signalling, i is ecognised as a po en ial
oncogene. Acco dingly, Kidins220/ARMS p e en s s ess-
induced apop osis in melanoma cells and con ibu es o umou
p og ession (Liao e al., 2007; Liao e al., 2011).
In acellula a icking o Kidins220/ARMS
In acellula a ic o Kidins220/ARMS is media ed h ough a
di ec binding o KIM o KLC-1 and KLC-2, and is impo an in
ensu ing a co ec esponse o neu o ophic s imuli in he
neu onal model cell line PC12 (B acale e al., 2007). The KIM
mo i o Kidins220/ARMS does no bea sequence simila i ies
wi h o he KLC-binding p o eins (B acale e al., 2007; Dodding
e al., 2011). Simila ly, he pa o KLC ha in e ac s wi h KIM
has so a no been implica ed in ca go ecogni ion, sugges ing
ha – h ough i s C- e minal egion – KLC ec ui s o he
p o eins, such as 14-3-3 p o ein (Ichimu a e al., 2002) o Jun N-
e minal kinase (JNK)-in e ac ing p o eins (JIPs) (Ve hey e al.,
2001). Fu he mo e, o e exp ession o Kidins220/ARMS does
no in e e e wi h he a icking o o he kinesin-1 ca goes
(B acale e al., 2007; Hammond e al., 2008). The Kidins220/
ARMS–kinesin-1 complex migh , he e o e, cons i u e a modula
sca old o he assembly o la ge p o ein complexes, in which
single componen s associa e wi h KLC as well as wi h he o he
domains o Kidins220/ARMS. Kidins220/ARMS migh link
mo o p o eins o inac i e signalling complexes in o de o
media e hei a ge ing o speci ic domains o he plasma
memb ane. Once hese complexes ha e been deli e ed o hei
inal des ina ion, hey would become ac i a ed upon exposu e o
ophic s imuli.
The a icking o Kidins220/ARMS o he plasma memb ane
elies on PKD ac i i y (Sanchez-Ruiloba e al., 2006). PKD is a
se ine/ h eonine kinase in ol ed in se e al cellula p ocesses,
such as cell p oli e a ion and Golgi-complex a icking (Van
Lin e al., 2002). Kidins220/ARMS cons i u i ely in e ac s wi h
PKD and is phospho yla ed by his kinase on se ine 919 upon
s imula ion wi h pho bol es e (Iglesias e al., 2000). Kidins220/
ARMS associa es wi h memb ane mic odomains a he leading
edge o mo ile imma u e dend i ic cells (Riol-Blanco e al.,
2004), o PC12 cells and o p ima y co ical neu ons (Cab e a-
Poch e al., 2004). This lipid-mic odomain-associa ed pool o
Kidins220/ARMS colocalises wi h PKD. In addi ion, Kidins220/
ARMS and PKD a e bo h p esen in he ans-Golgi ne wo k
(TGN). The exp ession o a kinase-dead o m o PKD al e s he
dis ibu ion o Kidins220/ARMS, causing i s accumula ion in
in acellula s uc u es ha con ain TGN ma ke s. PKD ac i i y
con ols Kidins220/ARMS a icking o he plasma memb ane
h ough he phospho yla ion-dependen ec ui men o PDZ
p o eins a he TGN (Sanchez-Ruiloba e al., 2006). The e o e,
Table 2. Kidins220/ARMS o hologues and hei GenBank
accession numbe s
O ganism Common name
GenBank accession
numbe
Acy hosiphon pisum Pea aphid XP_001943427
Anolis ca olinensis Liza d XP_003215436
Anopheles gambiae Mala ia mosqui o XP_320386
Asca is suum Pig oundwo m ADY40531
Bombus impa iens Common bumblebee XP_003493060
Bombus e es is Bu - ailed bumble XP_003400873
B ugia malayi Round wo m XP_001895979
Caeno habdi is b iggsae Wo m XP_002633264
Caeno habdi is elegans Wo m CAA92996
Campono us lo idanus Ca pen e an EFN63057
Canis lupus amilia is Dog XP_532865
Culex quinque ascia us Yellow- e e mosqui o XP_001843847
Danio e io Zeb a ish NP_956276
D osophila melanogas e F ui ly NP_611574
Gallus gallus Chicken XP_419939
Ha pegna hos sal a o Jumping an EFN89445
Homo sapiens Human NP_065789
Hyd a magnipapilla a Hyd a XP_002154747
Loa loa Eye wo m XP_003141375
Loxodon a a icana Elephan XP_003411847
Macaca mula a Monkey XP_001083478
Mus musculus Mouse NP_001074847
Nasonia i ipennis Wasp XP_003426415
Oikopleu a dioica Sea squi CBY24367
O eoch omis nilo icus Tilapia XP_003446685
O yc olagus cuniculus Rabbi XP_002722525
Pediculus humanus co po is Body louse XP_00242719
Ra us no egicus Ra NP_446247
Taeniopygia gu a a Zeb a inch XP_002197621
Te aodon nig o i idis Pu e ish CAG10502
T ibolium cas aneum Red bee le XP_001811729
T ichinella spi alis Po k wo m XP_003380555
Xenopus opicalis F og NP_001120159
Kidins220/ARMS in cell signalling 1849
Jou nal o Cell Science

he in e ac ion wi h PKD could egula e he o ma ion o
signalling pla o ms ha con ain Kidins220/ARMS and one o
mo e memb ane ecep o s.
Kidins220/ARMS egula es cy oskele al emodelling and
neu onal di e en ia ion
The unc ion o neu ons g ea ly depends on hei highly pola ised
mo phology, which is es ablished du ing de elopmen (da Sil a
and Do i, 2002). Neu o ophins and o he g ow h ac o s induce
ea angemen s o he cy oskele on a g ow h cones and changes
in gene exp ession (Hube e al., 2003), which need o be highly
coo dina ed. Kidins220/ARMS is ideally sui ed o ul il his ole,
because i is implica ed in neu o ophin signalling and in e ac s
wi h cy oskele al componen s (Higue o e al., 2010; Neub and
e al., 2010; Pa k e al., 2010). Neu i e ou g ow h equi es he
o ma ion o F-ac in (Hube e al., 2003), and Kidins220/ARMS
colocalises wi h F-ac in in NGF-di e en ia ed PC12 cells
(Neub and e al., 2010; Pa k e al., 2010) and hippocampal
neu ons (Higue o e al., 2010). In e es ingly, he amoun o F-
ac in a g ow h cones co ela es wi h he amoun o Kidins220/
ARMS p esen a hese si es (Higue o e al., 2010), indica ing he
impo ance o Kidins220/ARMS in cy oskele al emodelling in
de eloping neu ons.
Pa k and colleagues ecen ly cha ac e ised an in e ac ion
be ween Kidins220/ARMS and sep in 5 (Pa k e al., 2010), a
p o ein in ol ed in cy oskele al o ganisa ion and memb ane
ubula ion (Tanaka-Takiguchi e al., 2009). Independen ly, we
epo ed ha Kidins220/ARMS binds and ac i a es T io
(Neub and e al., 2010), a RhoGEF ha p omo es neu i e
ou g ow h h ough cy oskele al emodelling (Dickson, 2001;
Es ach e al., 2002; Go ek e al., 2005). In NGF-s imula ed
PC12 cells, his cha ac e is ic o T io has been linked o i s i s
GEF domain, which ac i a es he small GTPases Rac1 and RhoG
(Ba eman and Van Vac o , 2001; Es ach e al., 2002). This
ac i i y o he GEF domain is egula ed by he lanking SH3 and
spec in domains o T io. C ucially, Kidins220/ARMS binds o
he la e egion h ough i s N- e minal anky in epea s
(Neub and e al., 2010). This in e ac ion is impo an o he
unc ion o T io, as o e exp ession o his domain causes
widesp ead ac i a ion o Rac1. Because a localised ac i a ion
o Rac1 a neu i e ips is necessa y o neu i e ex ension (Aoki
e al., 2004), he o e exp ession o he anky in epea s inhibi s
neu i e ou g ow h in PC12 cells and hippocampal neu ons
(Neub and e al., 2010).
In addi ion o he ac in cy oskele on, Kidins220/ARMS
in e ac s wi h mic o ubules by binding ubulin, he
mic o ubule-associa ed p o eins 1a, 1b and 2 (MAP1a, MAP1b
and MAP2, espec i ely), and he s a hmin amily membe s
SCG10 and SCLIP (also known as STMN2 and STMN3,
espec i ely) (Higue o e al., 2010). These ac o s ha e a well-
es ablished ole in neu onal mo phogenesis (Poulain and Sobel,
2009) and hei abili y o modula e mic o ubule dynamics is
phospho yla ion dependen (Owen and Go don-Weeks, 2003). In
his con ex , Higue o and colleagues ound a educ ion in he
phospho yla ion o s a hmin and MAP1b in Kidins220/ARMS
knockdown neu ons (Higue o e al., 2010). In e es ingly,
down egula ion o Kidins220/ARMS in young hippocampal
neu ons a ou s he o ma ion o mul iple axon-like p ocesses,
whe eas i s knockdown in cells a la e s ages o di e en ia ion
leads o an abe an dend i ic a bou (Higue o e al., 2010). These
esul s ha e been con i med in Kidins220/ARMS
2/2
neu ons, in
which longe axons and a simpli ied dend i ic ne wo k we e
de ec ed when compa ed wi h wild- ype cells (Cesca e al., 2012).
In summa y, Kidins220/ARMS con ols axonal and dend i ic
ma u a ion by di ec ly modula ing cy oskele al dynamics and, in
pa allel, by inducing changes in sus ained MAPK-dependen
gene exp ession.
E ec s o Kidins220/ARMS on neu onal ac i i y
Neu o ophins a e equi ed o synap ogenesis and neu onal
ma u a ion (Ma inez e al., 1998; Poo, 2001). In e es ingly, he
exp ession le els o Kidins220/ARMS a e highly egula ed
du ing hese p ocesses (Co es e al., 2007; Higue o e al.,
2010). In hippocampal neu ons, Kidins220/ARMS is mo e
abundan du ing ea ly s ages o di e en ia ion compa ed wi h
la e s ages, when mo e synapses a e p esen and neu onal
ac i i y is highe (Co es e al., 2007; Higue o e al., 2010).
These indings suppo ecen esul s sugges ing ha
Kidins220/ARMS exp ession nega i ely egula es he
memb ane le els o he GluA1 subuni o he a-amino-3-
hyd oxy-5-me hyl-4-isoxazolep opionic acid (AMPA) glu ama e
ecep o (A e alo e al., 2010). Du ing neu onal de elopmen ,
his ecep o is a ge ed o he cell su ace o c ea e a ma u e
glu ama e gic synapse (Hall and Ghosh, 2008). In he adul b ain,
GluA2 is he main AMPA ecep o subuni , and he inco po a ion
o he GluA1 subuni esul s in he o ma ion o Ca
2+
-pe meable
AMPA ecep o s ha lack GluA2 (Bassani e al., 2009), which
a e c ucial in es ablishing and main aining synap ic plas ici y
(Man, 2011). Down egula ion o Kidins220/ARMS by using
RNAi o in Kidins220/ARMS
+/2
mice leads o an inc ease o
GluA1 a he plasma memb ane, which can be also de ec ed as a
ise in AMPA- ecep o -media ed cu en s (A e alo e al., 2010).
In pa allel, educed le els o Kidins220/ARMS de e mine an
inc ease in phospho yla ion o GluA1 a Se ine 831, which is
associa ed wi h an enhanced ecep o conduc ance (Benke e al.,
1998; De kach e al., 1999). In e es ingly, GluA1 bu no GluA2
co-immunop ecipi a es wi h Kidins220/ARMS (A e alo e al.,
2010). These esul s sugges ha , du ing de elopmen , in egions
cha ac e ised by high le els o Kidins220/ARMS, GluA1-
con aining AMPA ecep o s a e e ained in acellula ly h ough
an in e ac ion wi h Kidins220/ARMS. When neu ons ma u e and
synapses a e o med, Kidins220/ARMS le els dec ease, allowing
o he su ace exp ession o GluA1 and he es ablishmen o
synap ic s eng h. The GluA1-speci ic in e ac ion o Kidins220/
ARMS he e o e sugges s ha his p o ein indi ec ly modula es
Ca
2+
homeos asis a he ne e e minal, and has a ole in synap ic
plas ici y.
Kidins220/ARMS le els co ela e wi h he ac i i y o he
neu onal ne wo k. In ma u e neu onal cul u es, Kidins220/ARMS
also associa es wi h NMDA ecep o s (Lopez-Menendez e al.,
2009). Upon o e s imula ion o he NMDA ecep o , o example
du ing exci o oxici y o when neu ons a e depola ised, ac i i y-
dependen Ca
2+
in lux h ough NMDA ecep o s leads o a
dec ease in Kidins220/ARMS le els owing o ansc ip ional
down egula ion (Lopez-Menendez e al., 2009) and p o ein
clea age by calpain (Lopez-Menendez e al., 2009; Wu e al.,
2010). Because Kidins220/ARMS knockdown causes a dec ease
in he amoun o phospho yla ed MAPK (Lopez-Menendez e al.,
2009), a educ ion in he exp ession o Kidins220/ARMS migh
con ibu e o neu onal dea h h ough a dec ease in MAPK
signalling. Acco dingly, in an animal model o ce eb al ischemia,
Kidins220/ARMS le els co ela e wi h he ex en o neu onal cell
Jou nal o Cell Science 125 (8)1850
Jou nal o Cell Science
dea h, which was a ibu ed o exci o oxic NMDA- ecep o
ac i a ion (Lopez-Menendez e al., 2009). Al oge he , hese
indings indica e ha he amoun o Kidins220/ARMS is igh ly
con olled and has a undamen al ole in neu onal su i al, bo h
unde basal and exci o oxic condi ions. In addi ion o si es o
calpain clea age (Lopez-Menendez e al., 2009; Wu e al., 2010),
si es o caspase-3-dependen clea age (Ju e al., 2007) and o
ubiqui yla ion (Kim e al., 2011) a e p esen in he Kidins220/
ARMS sequence. Fu he s udies a e he e o e needed o a be e
unde s anding o he molecula mechanisms ha egula e he
u no e o Kidins220/ARMS.
Bo h exci a o y and inhibi o y ci cui s a e in luenced
by Kidins220/ARMS. A dec ease o Kidins220/ARMS in
hippocampal neu ons esul s in a lesse elease o c-aminobu y ic
acid (GABA), whe eas o e exp ession o Kidins220/ARMS has
he opposi e e ec , p obably because o a mechanism ha occu s
a he p esynap ic e minal (Su achan e al., 2010). Ou ecen
wo k, using cul u ed neu ons om Kidins220/ARMS
2/2
mouse
emb yos, indica es ha Kidins220/ARMS egula es he eco e y
o synap ic s eng h a inhibi o y GABAe gic synapses, whe eas
inhibi o y basal ansmission is no a ec ed (Scholz-S a ke e al.,
2012). These indings a e in line wi h p e ious da a ha show a
ecip ocal ela ionship be ween neu onal ac i i y and he le el o
Kidins220/ARMS (Co es e al., 2007). In e es ingly, incuba ion o
hippocampal neu ons wi h ei he BDNF o he neu onal-ac i i y-
modula ing e odo oxin causes an inc ease o Kidins220/ARMS
exp ession, bu combina ion o hese ea men s does no ha e an
addi i e e ec (Co es e al., 2007). This obse a ion sugges s ha
neu o ophin- o ac i i y-dependen changes con ol Kidins220/
ARMS le els by ac ing on he same pa hway. The in ol emen o
Kidins220/ARMS in neu o ophin-dependen synap ic plas ici y is
u he con i med by he inding ha BDNF-induced po en ia ion
o exci a o y pos synap ic cu en s is impai ed in Kidins220/
ARMS
2/2
neu ons (Cesca e al., 2012). Al oge he , hese esul s
sugges ha Kidins220/ARMS unc ions as a neu onal ma u a ion
and ac i i y senso .
Mos o hese da a we e ini ially ob ained by acu e down- o
up egula ion o Kidins220/ARMS, and ha e subsequen ly been
con i med using Kidins220/ARMS
+/2
mice, which exp ess 30–
40% less p o ein han wild- ype animals. In his mouse s ain,
bo h basal synap ic neu o ansmission and long- e m po en ia ion
(LTP) a e inc eased (Wu e al., 2009; Wu e al., 2010). In
addi ion, hey show de ec s in spa ial memo y o ma ion
(Du y e al., 2011), a p ocess in which a co ec balance
be ween LTP and long- e m dep ession (LTD) is pa amoun
(Kemp and Manahan-Vaughan, 2007; Ge e al., 2010). Because
homozygous Kidins220/ARMS
2/2
emb yos die a bi h, u u e
analysis o condi ional Kidins220/ARMS
2/2
mouse lines will
help o u he ou unde s anding on he ole o his p o ein in
synap ic plas ici y and highe b ain unc ions.
Neu onal ac i i y also media es s uc u al modi ica ions ha
a e impo an o de elopmen o he CNS and o synap ic
plas ici y. BDNF is an impo an ac i i y-dependen ac o ,
which induces dend i ic g ow h and con ols dend i ic spine
mo phogenesis (Cohen-Co y and F ase , 1995; McAllis e e al.,
1995; Ho ch and Ka z, 2002; Liu e al., 2007). Kidins220/
ARMS
2/2
emb yos and adul Kidins220/ARMS
+/2
mice display
de ec s in dend i ic g ow h and b anching (Wu e al., 2009; Cesca
e al., 2012), indica ing ha Kidins220/ARMS is impo an
in BDNF-induced dend i ic de elopmen . Dend i ic b anching
co ela es wi h he s abilisa ion o he synapse, which can be
assessed by measu ing dend i ic spine u no e . Indeed, spine
s abili y is educed in Kidins220/ARMS
+/2
mice (Wu e al.,
2009), sugges ing a ole o Kidins220/ARMS in cy oskele al
emodelling e en s ha unde ly he homeos a ic con ol o hese
pos synap ic s uc u es. In suppo o his idea, Kidins220/ARMS
in e ac s wi h kali in (Neub and e al., 2010), a RhoGEF ha
con ols he signalling e en s downs eam o EphB, NMDA and
AMPA ecep o s, which modula e he o ma ion o dend i ic
spines (Penzes and Jones, 2008).
Kidins220/ARMS a he c oss oad o se e al signalling
s eams
Kidins220/ARMS is no only in ol ed in T k, NMDA and
AMPA ecep o signalling, bu i is also a downs eam a ge o
eph ins (Kong e al., 2001; Luo e al., 2005) and in e ac s wi h
VEGFR (Cesca e al., 2012). Th ough i s in e ac ion wi h
VEGFR, Kidins220/ARMS migh ha e a ole in ascula
de elopmen , connec ing neu o ophins wi h VEGF signalling.
Indeed, Kidins220/ARMS
2/2
emb yos e eal an abno mal
ascula pa e n in he b ain (Cesca e al., 2012), simila o ha
obse ed in mice lacking neu opilin-1, a co- ecep o o
VEGFR (Gu e al., 2003). Addi ionally, Kidins220/ARMS is
phospho yla ed when cells ha exp ess EphB2 a e s imula ed
wi h eph in-B2 (Kong e al., 2001). Kidins220/ARMS also
enhances EphA4 signalling, which is igge ed by eph in-A1
du ing he o ma ion o he neu omuscula junc ion h ough i s
binding o a-syn ophin. Mo eo e , Kidins220/ARMS co-
immunop ecipi a es wi h and is phospho yla ed by he EphA4
ecep o (Luo e al., 2005).
T kB, EphA4, EphB1, EphB2, EphB3, NMDA and AMPA
ecep o s a e all implica ed in synap ogenesis and dend i ic spine
ma u a ion (Cons an ine-Pa on and Cline, 1998; Poo, 2001;
Klein, 2009; Lai and Ip, 2009; McKinney, 2010). In e es ingly,
hese ecep o s display a subs an ial c oss alk among each o he ;
he NMDA ecep o is phospho yla ed upon BDNF s imula ion
(Lin e al., 1998) and he EphB ex acellula domain in e ac s
di ec ly wi h he NMDA ecep o (Dal a e al., 2000; Hende son
e al., 2001). In addi ion, eph in-B-media ed ac i a ion o EphB
leads o NMDA- ecep o -dependen Ca
2+
in lux (Takasu e al.,
2002), which migh in luence he le el o Kidins220/ARMS
p o ein syn hesis and i s downs eam signalling. Al oge he , hese
da a sugges ha Kidins220/ARMS con ols synap ic o ma ion
and s abili y by ac ing as a common downs eam a ge o T kB,
NMDA, AMPA and EphB ecep o s. Fig. 3 summa ises he
p esen knowledge ega ding he unc ion o Kidins220/ARMS a
synapses, bo h in he p esynap ic compa men and in dend i ic
spines. Fu u e s udies aimed a inc easing ou unde s anding o
hese in e ac ions a e likely o e eal new aspec s o he
molecula mechanisms unde lying synapse o ma ion.
Fu u e pe spec i es
Kidins220/ARMS o ches a es di e en unc ions in he ne ous
sys em as well as in o he issues. In addi ion o he neu onal
pheno ypes obse ed in he CNS and PNS, Kidins220/ARMS
2/2
emb yos show ca diac mal o ma ions and se e e de ec s in
ascula de elopmen (Cesca e al., 2011; Cesca e al., 2012).
Se e al epo s also indica e a ole o Kidins220/ARMS in he
immune sys em (Riol-Blanco e al., 2004; Ni e al., 2010; Jean-
Mai e e al., 2011; Ni e al., 2011). Wi h ull and condi ional
knockou mouse lines o hand, i will now be possible o ca y ou
a unc ional analysis o his e sa ile p o ein in issues o he han
Kidins220/ARMS in cell signalling 1851
Jou nal o Cell Science
he ne ous sys em. These ools will also allow he di e en ia ion
o cell-au onomous and non-au onomous oles o Kidins220/
ARMS in i o. Fo example, ex ensi e cell dea h was epo ed in
b ains o Kidins220/ARMS
2/2
emb yos, leading o abno mal
en icle enla gemen (Cesca e al., 2011; Cesca e al., 2012).
Abla ion o Kidins220/ARMS only in he ne ous sys em,
howe e , does no yield he high le el o cell dea h obse ed in
Kidins220/ARMS
2/2
emb yos (Cesca e al., 2012). Because he
apop o ic egions in Kidins220/ARMS
2/2
b ains co espond o
some o he a eas ha display abno mal ascula pa e ning,
de ec i e ascula isa ion migh con ibu e, a leas in pa , o he
ins ances o neu onal dea h obse ed in hese a eas.
Like neu o ophins and hei ecep o s, Kidins220/ARMS is
in ol ed in egula ing he equilib ium be ween cell dea h and cell
su i al by a ec ing signalling pa hways ha ac as p incipal
egula o s o his p ocess, such as he ERK pa hway (Ma in and
Cla k, 2007). Indeed, T k ecep o s we e o iginally iden i ied as
oncogenes (Ma in-Zanca e al., 1986). I is he e o e no
su p ising ha Kidins220/ARMS was sugges ed o ha e a ole
as an oncogene and ha i is o e exp essed in melanoma, a skin
cance o neu al c es o igin (Liao e al., 2007; Liao e al. 2011)
and possibly in o he ypes o cance . Unde s anding how o
con ol he ac i i y o Kidins220/ARMS du ing umou
p og ession, o example by speci ically a ge ing i s NTPase
domain, ep esen s a possible a enue o he apeu ic in e en ion
and an a ac i e means o s udy he balance be ween dea h and
su i al signals. The in ol emen o Kidins220/ARMS in he
ascula de elopmen wi hin speci ic a eas o he b ain is also
e y appealing, bo h in he con ex o cance he apy and
ollowing ischemic insul s, whe eby a boos in neo ascula isa ion
T kB
EphB
NMDAR
AMPAR
T io o kali in
Rac1
MAPK
Gene
exp ession
T kB
Modula ion o usion and ecycling
o
elease p obabili y o SVs
Ac in
Ac in
Kidins220/ARMS
Endosome
?
P esynap ic
e minal
Dend i ic
spine
?
?
?
Synap ic esicle
BDNF
Exci a o y
synapse
Inhibi o y
synapse
Key
Fig. 3. Role o Kidins220/ARMS a synapses. A exci a o y
synapses, Kidins220/ARMS media es BDNF-induced
po en ia ion, whe eas a inhibi o y synapses, i is in ol ed in
neu o ophin-independen sho - e m plas ici y. In bo h cases,
he obse ed cellula pheno ypes can be explained by
al e a ions o synap ic esicle usion and ecycling, o
changes in he elease p obabil y. The p ecise molecula
mechanisms a he basis o his egula ion a e p esen ly
unclea ( ed ques ion ma ks). In dend i ic spines, du ing
synapse o ma ion, NMDA, T k and Eph ecep o s unde go
subs an ial c oss alk wi h each o he ( ed a ows), wi h
Kidins220/ARMS as a possible common downs eam a ge .
Kidins220/ARMS signals o he ac in cy oskele on ia Rac1
h ough i s in e ac ion wi h T io o kali in. In pa allel,
Kidins220/ARMS ac i a es neu onal su i al and
di e en ia ion by he sus ained MAPK pa hway, which
mainly akes place on endosomal compa men s. Kidins220/
ARMS also egula es he a ge ing o he GluA1 subuni o
he AMPA ecep o o he cell su ace. Howe e , when and
how Kidins220/ARMS is in e nalised is p esen ly unknown.
Kidins220/ARMS migh signal o T io (o kali in) and MAPK
om an AMPA- ecep o -con aining endocy ic compa men
(dashed a ows), bu his hypo hesis equi es u he
in es iga ion (indica ed by ed ques ion ma ks). AMPAR,
AMPA ecep o ; NMDAR, NMDA ecep o .
Jou nal o Cell Science 125 (8)1852
Jou nal o Cell Science
migh be bene icial. Fu u e esea ch in hese a eas can e eal
exci ing new di ec ions o a be e unde s anding o signal
in eg a ion a cellula and issue le els, and migh o e new
ansla ional oppo uni ies in impo an ields o medicine.
Acknowledgemen s
We hank P. Chak a a y o help wi h he bioin o ma ics analyses,
and C.L. Thomas, A. Yabe, N. Schmieg and J. Scholz-S a ke o
c i ical eading o he manusc ip .
Funding
This s udy was suppo ed by esea ch g an s om: Cance Resea ch
UK ( o G.S.); he I alian Ins i u e o Technology ( o F.C. and F.B.);
he I alian Minis y o Uni e si y and Resea ch [2008T4ZCNL g an
numbe 2008T4ZCNL o F.B.]; he Compagnia di San Paolo, To ino
( o F.B.); Tele hon-I aly [g an numbe GGP09134 o F.B.] and he
Spanish Minis y o Science and Inno a ion [g an numbe JCI-2008-
01843 o V.N.].
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