Advances in Bioscience and Biotechnology, 2013, 4, 136-142 ABB Published Online January 2013 (
Rho and Ras GTPases in semaphorin-mediated neuronal
Lifei Fan, Morigen
College of Life Sciences, Inner Mongolia University, Hohhot, China
Received 1 November 2012; revised 4 December 2012; accepted 4 January 2013
Neurons are highly polarized cells with a single long
axon and multiple dendrites, all of which are actin-
rich structures. The precise regulation of neuronal
cell morphology is a fundamental aspect of neurobi-
ology. The major role of Rho GTPases, which is con-
served in all eukaryotes, is to regulate the actin and
microtubule cytoskeleton. Therefore the Rho GTPases
are key regulators of neuronal morphology during
development besides their canonical functions in actin
cytoskeletal regulation, cell migration and cell cycle
progression. Semaphorins are a family of secreted or
transmembrane proteins, which function through their
receptor plexins and/or neuropilins to act as the re-
pulsive or attractive guidance cues for axons and den-
drites. It has been demonstrated that the fully activa-
tion of plexins appears to be dependent on the bind-
ing of Rho GTPases to the Rho binding domain (RBD)
and Semaphorin to the extracellular region. Here, we
summarize the functions of the small Rho GTPases in
two well-studied vertebrate Semaphorins, Sema3A
and Sema4D; and the potential roles of the small Rho
GTPases in some poorly-studied vertebrate Sema-
phorins Sema5A, Sema6A and Sema7A. We also sum-
marize the functions of different members of Ras
family, R-Ras, M-Ras and Rap, in Semaphorin sig-
nalling pathways as well.
Keywords: Small Rho GTPase; Semaphorin Signalling;
Neurite Development
The development of a neuron requires a series of steps
that begins with the migration from its birth place, the
initiation and outgrowth of neurite that serve as precur-
sors to axons and dendrites, the polarization, growth,
guidance and branching of axons, the formation of den-
drites and spines, and finally the formation of connec-
tions that allow a neuron to make communication with
appropriate targets [1]. The Rho GTPases have been
found to be involved in several neuronal development
processes, such as neurite outgrowth and differentiation,
axonal initiation, outgrowth, guidance and branching,
and dendritic spine formation and maintenance [2,3].
This part will focus on the role of Rho GTPases, Ras
GTPases, semaphorins, plexins, and their associated ef-
fectors in the regulation of axonal guidance and dendrite
2.1. Semaphorins
Semaphorins were initially identified as an axonal repel-
lent in the central nervous system development [4]. Over
the last few years, it has been shown that, like most
guidance cue families, semaphorins have both repulsive
and attractive functions; moreover, many semaphorins
are bifunctional [5]. Semaphorins can be divided into 8
classes based on their sequence similarity and structural
domains contained. The class 1 and class 2 semaphorins
are found in invertebrates; classes 3 - 7 are vertebrate
semaphorins; and the last class is found in virus. Classes
2 and 3 and the viral semaphorins are secreted; whereas
semaphorins belonged to classes 1, 4, 5, 6 and 7 are all
cell membrane-anchored proteins. All semaphorins are
characterized by the conserved N-terminal sema domain
that is essential for the recognition with another sema
domain on the semaphorin receptor. The semaphorin
domain contains a region that specifies its biological
activity, which consists of a highly conserved 70 amino
acid variant form of the seven-blade beta-propeller fold
[6,7]. At the C terminus of sema domain there is another
conserved domain named as PSI (plexins, semaphorins
and integrins) domain. Different members of semaphorin
family are distinguished by unique additional domains
besides sema domain and PSI domain, such as a signal
immunoglobulin (Ig)-like domain is found in classes 2, 3,
4 and 7 semaphorins, thrombospondin repeats exhibited
in class 5 semaphorins, glyc osyl phosphati dylinositol (GPI)
anchor in class 7 semaphorins and PSD-95/Dlg/ZO-1
(PDZ) binding motif at the C terminus of class 4 sema-
L. F. Fan, Morigen / Advances in Bioscience and Biotechnology 4 (2013) 136-142 137
phorins [8].
2.2. Semaphorin Receptors
The predominant receptors for semaphorins are plexins,
there are nine members in vertebrates and two in
invertebrates. The vertebrate plexins can be subgrouped
into four; four type A plexins, three type B plexins, one
C type and one D type. Plexin was first identified as a
neuronal cell surface molecule that mediates cell ad-
hesion [9]. Plexins contain a divergent sema domain and
followed by three PSI domains and three IPT domains
(Ig-like, plexin and transcription factors) in their extra-
cellular region. The plexins are distinguished by the
presence of a highly conserved intracellular split GT-
Pase-activating (GAP) cytoplasmic domain [10]. The
unusual thing is the GAP-homology domain is divided
into two separated parts by an unrelated linker region,
which was shown to be able to directly interact with se-
veral small Rho GTPases, such as Rac, Rnd1 and RhoD
[11-13]. The type B plexins contain an additional C-ter-
minal PDZ domain binding site for the interaction with
the PDZ domain containing RhoGEFs [14]; and they also
contain a conserved cleavage site in their extracellular
domain, which can be cleaved by furin-like proprotein
convertases. This post-translational processing greatly
increases the binding and the functional response to their
specific liga n d s emaphorin4 D [15].
Plexins are autoinhibited in the absence of ligand,
binding of semaphorin to the sema domain of plexin
releases the autoinhibition between the sema domain and
the ectodomain and leads to plexin activation [16].
Classes 4 - 7 semaphorins together with Sema3E from
class 3 bind specific plexins directly through sema-sema
domain interaction and activate following signalling
pathways, whereas the other members of class 3 sema-
phorins require neuropilins to serve as binding co-rece-
ptors and the plexins as the signalling-transduction ele-
ments [17].
Neuropilins are transmembrane proteins with short in-
tracellular domains that lack in trinsic enzymatic activity,
and the ectodomain is too short to mediate independent
signal transduction. Thus neuropilins function as co-
receptors to form a transduction complex with other
transmembrane receptors. The neuropilin family contains
two members; neuropilin 1 (NP1) and n euro p ilin 2 (NP2 ).
The two kinds of neuropilins share a similar domain
structure, although the overall homology at the amino-
acid level is only 44% [18]. Neuropilins are found to act
as co-receptors for Semaphorin 3 subfamily, and the
binding ability to different members of Semaphorin 3 is
varied among NP1 and NP2. For example, Sema3A binds
specifically to NP1, whereas Sema3F has high affinity
with NP2 compared with NP1 [18,19].
Most of our understan ding concerning semaphorin signal
transduction in corporation with plexin receptors ori-
ginates from studies of Sema3A and Sema4D in neuronal
cells. The growth cone is a sensitive reg ion located at the
tip of a developing axon, which can sense the extra-
cellular cues. In response to attractive and repulsive sig-
nals, there is continuous reorganization of actin cyto-
skeleton within lamellipodia and filopodia that accounts
for growth cone guidance. Dendrites extend from the cell
body to form a multi-branched tree-like structure, which
receive, process, integrate synaptic inputs from other
neurons [20].
Sema3A, a secreted semaphorin, acts as an attractive
or a repulsive guidance cue for axons by activating a
receptor complex containing NP1 and plexinA1 to work
as the ligand-binding subunit and the signal-transducing
subunit, respectively. In the steady state, plexinA1 is
antoinhibited and is associated with NP1 [16]. FARP2, a
GEF for Rac, is associated with the plexinA1/NP1 com-
plex [21,22]. The binding of Sema3A to plexinA1/NP1
complex not only causes the release of the plexinA1
auto-inhibition but also leads the dissociation of FARP2
from the complex and activation of its Rac-GEF activity.
GTP-bound form of Rac is sequestered by plexinA1 and
in turn causes the recruitment of another Rho GTPase
Rnd1 to the linker region of intracellular domain of
plexinA1. Binding of Rnd1 to the linker region disrupts
an inhibitory interaction between the N-terminal and
C-terminal parts of the split GAP domain [23]; then the
intrinsic R-Ras GAP activity of the sp lit GAP domain of
plexinA1 is activated, followed by the downregulation of
R-Ras activity, the inactivation of integrin, the turnover
of focal adhesion and the detachment of cells from the
ECM [22]. GTP-bound Rac can activate PAK to initiate
actin polymerization, so the sequestration of RacGTP
inhibits PAK activation, which therefore inhibits actin
polymerization. In another aspect, the FERM domain of
FARP2 sequesters an isoform of type-I phosphatidy-
linositol phosph ate kinase, PIPKIγ661, inhibitin g its inte-
raction with focal adhesion protein talin and suppressing
focal adhesion. The Sema3A/plexinA1 signalling path-
way influences focal adhesion property in three ways;
sequestration of Rac, downregulation of R-Ras and se-
questration of PIPKIγ66, all of which lead to suppression
of integrin functions and inhibit cell adhesion to the
extracellular matrix, and ultimately cause the axonal
repulsion [22]. Interestingly, the interaction between
Rnd1 and plexinA1 can be inhibited by RhoD, which
binds to the same linker region as Rnd1 does on ple-
xinA1 [11,24] (Figure 1).
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L. F. Fan, Morigen / Advances in Bioscience and Biotechnology 4 (2013) 136-142
Figure 1. Semaphorin intracellular signalling events. The main
signal transduction pathways by which Sema3A and Sema4D
active plexinA1 or plexinB1. Plexin-mediated effects on actin
cytoskeletal remodelling are regulated by Rho GTPases; Rac1,
Rnd1 and RhoD. Semaphorin signalling results in growth cone
repulsion in the nervous system development due to the activa-
tion of the R-Ras GAP activity of the intracellular domain of
plexinA1 and plexinB1, and in turn inhibits the integrin func-
tion through suppressing PI3K signalling pathway. Semaphorin
signalling results in dendrite repellence in the nervous system
development due to the activation of the M-Ras GAP activity
of the intracellular domain of plexinB1, and in turn suppresses
ERK activation. PleixnB1 induces axonal growth cone collapse
and dendrite repellence through its Ras-GAP activity for R-Ras
and M-Ras, respectively (Figure adapted from [5]).
Sema4D, also known as CD100, is a transmembrane
semaphorin that works through plexinB1 as its receptor.
It has been shown that a 120-residue cytoplasmic inde-
pendent folding domain of plexin-B1 that directly binds
three Rho family GTPases, Rac1, Rnd1, and RhoD; and
the Cdc42/Rac interactive bind ing-lik e motif of plexinB1
is not involved in th is interaction [11]. In the resting state,
plexinB1 are dimerized and inactive, the binding of Se-
ma4D to the receptor causes the conformational change
and leads to the recruitment of Rac1 and Rnd1 to the
plexinB1. The dimeric structures are altered and the
plexinB1 is activated. The intrinsic R-Ras GAP activity
of the split GAP domain of plex inB1 is also activated by
the binding of Rac1 and Rnd1 to the liker region, which
leads to the inhibition of R-Ras activity and focal adhe-
sion turnover [10]. The binding of RhoD to the Rho
GTPase interacting region inhibits Rnd1 activity. Com-
pared to other semaphorins, type B semaphorins have a
C-terminal PDZ binding domain that can directly interact
with PDZ-RhoGEF/LARG, a Rho GEF, to induce RhoA
and ROCK activation [14]. Surprisingly, the cell con-
traction triggered by Sema4D and plexinB1 signalling
pathway is both Rac1 and RhoA dependent, but how
Sema4D induces Rac1 activation is still unclear [12]
(Figure 1).
Sema5A is a transmembrane semaphorin, and the unique
feature of class 5 semaphorins is that they contain seven
thrombospondin repeats in their extracellular region. It
has been shown that Sema5A interacts specifically with
plexinB3, and the thrombospondin repeats may play
indispensable roles in this interaction, as truncated form
of Sema5A comprising the sema domain but lacking
thrombospondin repeats interacts weakly with plexinB3
[25]. Sema5B is the highly homologous Semaphorin
with Sema5A; however, it does not interact with ple-
xinB3. On the other hand, Sema5A does not interact with
either plexinA1, plexinB1 or plexinB2 [25]. Recently, It
has been shown that Sema5A inhibits human glioma cell
motility through the complex formed by its receptor
plexinB3, RhoGDIα and Rac1 [26]. The cytoplasmic
domain of plexinB3 interacts with RhoGDIα directly;
after Sema5A binding to plexinB3, both RhoGDIα and
active Rac1 are recruited to plexinB3 in a noncompe-
titive manner, providing a docking site for their inter-
action. The interaction between RhoGDIα and plexinB3
is transient, after a short time, RhoGDIα dissociates from
plexinB3 together with active Rac1; therefore Rac1 is
extracted from cell membrane by RhoGDIα and the Rac1
signal is silenced. It was also demonstrated that the en-
hanced interaction between RhoGDIα and Rac1 under
Sema5A stimulation is dependent on plexinB3 [26]. This
is another example of how Semaphorin and their plexin
receptors regulate actin cytoskeleton through Rho GT-
Pases and their regulators. Intriguingly , sm all R ho GTPases
such as RhoA and Cdc42 can not bind to plexinB3; it
will be of great interest to investigate whether Rnd1,
RhoD or other small Rho GTPases could be able to in-
teract with plexinB3, and the contribution of the splited
Ras GAP domain of plexinB3 on the downstream sig-
Sema6A, a transmembrane semaphorin, was first iden-
tified as a repulsive axon guidance cue [27]. It has been
shown recently to pro mote the dendritic growth of lateral
motor column (LMC) neurons through Sema6A-plex-
inA4-FARP1 signalling pathway [28]. In fact, Sema3A
can also repel growth cone while under other conditions
stimulates the dendrite outgrowth [29]. FARP1, also
named as CDEP, is comprised of an N-terminal FERM
domain, a central DH domain, and the C-terminal PH1,
PH2 domains. The DH-PH1 domain is conserved in
all eukaryotic GEFs, and the PH domain is responsible
for binding to the membrane or cytoskeleton [30,31]. Al-
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L. F. Fan, Morigen / Advances in Bioscience and Biotechnology 4 (2013) 136-142 139
though FARP1 shares similar domain structures with
FARP2, they two have distinct functions in triggering the
exchange of GDP to GTP; FARP2 is a specific Rac1
GEF [21], while FARP1 is a GEF for Rho [31]. FARP2
has been shown to be involved in cell-cell junction for-
mation downstream of nectins and in axonal repulsion
downstream of semaphorin 3A [22]. To date very little is
known about FARP1; it is upregulated in differentiating
chondrocytes, and is expressed in liver, spleen, brain,
heart and intestine [31]. It is found that FARP1, a spe-
cific effector for Sema6A-plexinA4 signalling pathway
in the developing vertebrate spinal cord, is necessary and
sufficient to promote LMC motor neuron dendrite gro wth
without affecting axons, and the Rho GEF activity of
FARP1 is indispensable for this function [28]. In the
silent state, the FERM and PH domains of FARP1 bind
to the intracellular domain of plexinA4 independently of
neuropilins. The binding of Sema6A to plexinA4 relea-
ses the autoinhibition of plexinA4 and activates the Rho
GEF activity of FARP1. It is shown that plexinA4-de-
pendent regulation of LMC motor neuron dendrite length
requires ligand activation, and FARP1 is not dissociated
from plexinA4 in the presence of Sema6A binding.
Sema6A binding does not affect the binding affinity be-
tween plexinA4 and FARP1, but stimulates the Rho GEF
activity of FARP1 towards downstream Rho GTPases.
FARP1 Rho-GEF activity is critical for mediating the
Sema6A-plexinA4-dependent growth of LMC motor neu -
ron dendrites, but how it modifies the downstream effec-
tors is still unclear [28]. As a Rho GEF, FARP1 might
regulate downstream signalling pathways by modulating
the activity of small Rho GTPase proteins. Rho GTPases
signalling pathways are regulators of actin and micro-
tubule cytoskeletons, which are the fundamental struc-
tures of dendrites. Thus, it is presumed that FARP1 mo-
dulates cytoskeletal structures by regulating Rho GT-
Pases, and in turn promotes LMC motor dendrite growth.
Sema7A is a membrane-anchored semaphorin, acting
as both an immune and a neural Semaphorin through its
receptor plexinC1 and β1-integrins [32-34]. In both the
central and peripheral nervous system, Sema7A act as
contractive guidance cue to enhance axon growth and it
is also required for axon tract formation during embry-
onic development [32]. Sema7A activates plexinC1 by
dimerization and in turn activates mitogen-activated pro-
tein kinase (MAPK), Lim Kinase II (a protein that phos-
phorylates cofilin), then inactivates cofilin (an actin-
binding protein involved in cell migration) [32,33].
Sema7A also activates β1-integrins, and in turn activates
focal adhesion kinase (FAK), followed by a secondary
MAPK activation [35]. It is known that LIMK is acti-
vated by p21-activated kinase 1(PAK1), which is in turn
activated by Rac1. Thus it is highly possible th at Rac1 is
downstream of plexinC1 and/or β1-integrins activation
via Sema7A binding. It is great interesting to determine
whether small Rho GTPases can interact with the intra-
cellular domain of plexinC1 and have an influence on
Sema7A-induced axon grow th.
The activation of plexinA1 and plexinB1 by Sema3A
and Sema4D respectively leads to the activation of
R-Ras GAP activity of intracellular domain of plexinA1
and plexinB1 [10,22]. R-Ras activates the Phosphoi-
nositide 3-kinase (PI3K) and generates Phosphatidy-li-
nositol (3,4,5)-trisphosphate (PtdIns (3,4,5) P3) second
messenger, which alters the conformation and locali-
zation of AKT and leads its activation, promoting cell
adhesion and migration through integrin activation [36]
(Figure 1). In addition, the intracellular domain of ple-
xins is highly conserved in all plexin family members.
Thus it is possible that the intersection between plexin
and Ras signalling is a common feature of plexin signal-
ling. The Ras GTPases family is comprised of a large
number of small GTPases, among them R-Ras, TC21
and M-Ras are homologues [37]. However, it has been
shown that the downstream signalling pathway after M-
Ras activation is different from the one downstream of
R-Ras. M-Ras activation leads to ERK activation through
binding to B-Raf, which is similar to the downstream
signalling pathway of classical Ras [36] (Figure 1).
Interestingly, Sema4D-plexinB1 singlling pathway has
been identified as the first example to active the GAP
activity of plexinB1 for both R-Ras and M-Ras [38].
However, the functions of R-Ras and M-Ras in neuronal
development are quite different: R-Ras activity is incr-
eased in the stage when axons are elongated and spe-
cified, while M-Ras activity is enhanced during the pe-
riod of dendritic development [39]. The suppression of
M-Ras activity via plexinB1 Ras GAP domain is corre-
lated with reduced dentritic grow th and branching. Thus,
pleixnB1 induces axonal growth cone collapse and den-
drites repellence through its Ras-GAP activity for R-Ras
and M-Ras, respectively [38]. It was reported that ple-
xins fail to function as GAPs for R-Ras unless there is a
sequential interaction of the cytoplasmic domain of ple-
xins with two different Rho GTPases; Rac1 and Rnd1
[10,22]. The fully activation of plexins appears to be
dependent on the binding of a Rho GTPase to the Rho
binding domain (RBD) and Semaphorin to the extra-
cellular region as well [10,22]. Intriguingly, there are
further evidences for the role of Rho GTPases in Sema-
phorin-plexin signalling pathways which are contrary to
the former research. It was demonstrated that purified
cytoplasmic region of Plexins exhibit GAP activity for
Rap1B and Rap2A but not for R-ras or M-Ras. It was
shown that the Rho GTPases do not induce the dime-
rization of plexins and do not stimulate the RapGAP ac-
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L. F. Fan, Morigen / Advances in Bioscience and Biotechnology 4 (2013) 136-142
tivity of plexinscyto in solution either (Rap is another
member of the Ras GTPases family) [40,41]. The roles
of Rho GTPases in Semaphorin-plexin signalling path-
ways may be involved in sequestering Rho GTPases
from their downstream effectors, or destablizing the in-
active dimmer of plexin formed on the cell surface, or
helping reconstruct the spatial structure of the plexin
cytoplasmic region which is helpfu l for plexin activation
PC12 is a cell line derived from a pheochromocytoma of
the rat adrenal medulla; they stop dividing and begin to
differentiation and neurite outgrowth after stimulation
with nerve growth factor (NGF). Thus they have been
used as a model system for neuronal differentiation.
Binding of NGF to its tyrosine kinase receptor Trk leads
to neuronal differentiation through Ras-MAPK signalling
pathway [42]. The three well-studied Rho GTPases
RhoA, Rac1 and Cdc42 are all involved in neuronal dif-
ferentiation in PC12 cells. Overexpression of Rho in
PC12 cells induces neurite retraction and cell round-
ing through its downsteam effector ROCK, while neurite
outgrowth promoted by Cdc42 and Rac is mediated
through MRCKα [43]. The less-studied Rho GTPases,
such as Rnd1, Rnd2, Rnd3 and RhoG, also have func-
tions in regulating neuronal d ifferentiation in PC12 cells.
Overexpression of Rnd1 in PC12 cells induces neurite
outgrowth in a Rac-dependent manner, and the down-
regulation of RhoA activity mediated by direct interac-
tion between Rnd1 and FRS2β is also involved in this
process [44,45]. Rnd2 induces neurites formation in
PC12 cells through its downstream effector Rapostlin in
a GTP dependent manner [46-48]. Rnd3 stimulates neu-
rite outgrowth in PC12 cells through inhibiting the ac-
tivity of RhoA/ROCK1 signalling [49]. Overexpression
of wild-type RhoG in PC12 cells induces neurite out-
growth in the absence of NGF, and it was shown that
RhoG is acting as a key regulator in NGF-induced neu-
rite outgrowth downstream of Ras and upstream of Rac
and Cdc42 [50].
Given that multiple members of Rho GTPases have im-
portant roles in neuronal development, it will be of great
interest to define the functions of the poorly-understood
members of the family in neuronal differentiation. The
Rif GTPase is a relatively recent addition to the Rho
family; it is found only in chordates and displays a rela-
tively low homology to other family member s. Activated
Rif was found to be an alternative trigger for the forma-
tion of actin stress fibers in epithelial cells through ef-
fector mDia1 [51,52]. Unlike the classical stress fiber
inducer RhoA, Rif does not raise ROCK activity in cells,
instead Rif appears to regulate the localizatio n of myosin
light chain phosphorylation [51,52]. Activated Rif also
triggers the formation of filopodia through its effector
mDia2, and this signalling pathway is totally independ-
ent of the classical filopodia-formation pathway induced
by Cdc42 and its effector WASP/ARP2/3 [53]. Intrigu-
ingly, recent work has shown that Cdc42 and Rif work
together in the formation of dendritic spines, which de-
velop from dendritic filopodia [54]. Rif is quite d istantly
related with the other Rho GTPases family members, but
on the same branch as human RhoD that is shown to
have important functions on inhibiting Semaphorin-ple-
xin signalling by binding to the intracellular domain of
plexins [24]. Investigation of the roles of the poorly-
defined Rho GTPases, such as Rif, in axonal and den-
dritic development will shed light on the fine-tune regu-
lation of neuronal differentiation system.
Semaphorin-plexin signalling is essential for neuronal
development regulation, and the disorder of the pathways
has been implicated in neurological diseases and cancer
[55]. The RBDs of plexins binds to a group of Rho fam-
ily GTPases, such as Rac1, Rnd1 and RhoD, facilitating
the normal transduction of the signals from Semaphorin-
plexin to the downstream effectors [10,12,22,24,56]. It is
high possible that other Rho GTPases also have the af-
finity to the RBD of plexins, and on the contrary, there
should be other plexins existing to interact with Rho
GTPases besides the plexins listed here. Modulating the
activities of certain Rho family members and/or their
GEFs, GAPs and DGIs may be developed as novel stra-
tegies in neurological diseases and cancer therapies.
This work was supported by the Program of Higher-level talents of
Inner Mongolia University ( SPH-IMU 30105-125128).
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