Genome Biology 2006, 7:211
Protein family review
Umar Yazdani and Jonathan R Terman
Address: Center for Basic Neuroscience, Department of Pharmacology, NA4.301/5323 Harry Hines Blvd, The University of Texas
Southwestern Medical Center, Dallas, TX 75390, USA.
Correspondence: Jonathan R Terman. Email: email@example.com
Semaphorins are secreted, transmembrane, and GPI-linked proteins, defined by cysteine-rich
semaphorin protein domains, that have important roles in a variety of tissues. Humans have 20
semaphorins, Drosophila has five, and two are known from DNA viruses; semaphorins are also
found in nematodes and crustaceans but not in non-animals. They are grouped into eight classes
on the basis of phylogenetic tree analyses and the presence of additional protein motifs. The
expression of semaphorins has been described most fully in the nervous system, but they are also
present in most, or perhaps all, other tissues. Functionally, semaphorins were initially
characterized for their importance in the development of the nervous system and in axonal
guidance. More recently, they have been found to be important for the formation and functioning
of the cardiovascular, endocrine, gastrointestinal, hepatic, immune, musculoskeletal, renal,
reproductive, and respiratory systems. A common theme in the mechanisms of semaphorin
function is that they alter the cytoskeleton and the organization of actin filaments and the
microtubule network. These effects occur primarily through binding of semaphorins to their
receptors, although transmembrane semaphorins also serve as receptors themselves. The best
characterized receptors for mediating semaphorin signaling are members of the neuropilin and
plexin families of transmembrane proteins. Plexins, in particular, are thought to control many of
the functional effects of semaphorins; the molecular mechanisms of semaphorin signaling are still
poorly understood, however. Given the importance of semaphorins in a wide range of functions,
including neural connectivity, angiogenesis, immunoregulation, and cancer, much remains to be
learned about these proteins and their roles in pathology and human disease.
Published: 30 March 2006
Genome Biology 2006, 7:211 (doi:10.1186/gb-2006-7-3-211)
The electronic version of this article is the complete one and can be
found online at http://genomebiology.com/2006/7/3/211
© 2006 BioMed Central Ltd
Gene organization and evolutionary history
Semaphorins are a large and diverse family of widely
expressed secreted and membrane-associated proteins,
which are conserved both structurally and functionally
across divergent animal phyla. This diversity in expression,
structure, and function is highlighted in the manner in
which a number of the semaphorins were originally charac-
terized. The first semaphorin to be discovered, the grasshop-
per transmembrane protein semaphorin-1a (Sema-1a;
originally named Fasciclin IV), was identified in a screen for
molecules with distinctive temporal and spatial distributions
in the developing grasshopper nervous system . In parallel
experiments, a neuronal growth cone collapsing factor asso-
ciated with chicken brain membranes was biochemically
purified and found to be a secreted semaphorin (Sema3A;
originally named Collapsin) . Separate experimentation
and molecular characterization revealed that an antigen first
observed in the 1970s as present in high frequency on
human red blood cells, the John Milton Hagen (JMH)
human blood group antigen, was a glycosylphosphatidyli-
nositol (GPI)-linked semaphorin (Sema7A; also known as
CDw108) [3,4]. And work in the human immune system
showed that an antigen first characterized in 1992 for its
presence on the surface of T lymphocytes was a transmem-
brane semaphorin (Sema4D; originally named CD100) .
Sequences encoding a number of different semaphorins have
since been identified in nematode worms, insects, crus-
taceans, vertebrates, and viruses, but to date they have not
been described in protozoans, plants, or the most primitive
metazoans. Although initially given various and often con-
flicting names, these sequences have now been consolidated
into one family called the semaphorins; the name is derived
from the word ‘semaphore’, meaning to convey information
by a signaling system [6,7]. The semaphorin gene family cur-
rently includes 20 members in mice and humans and five in
Drosophila, and they can be divided into eight classes, 1-7
and V (Figures 1,2) . Vertebrates have members in classes
3-7, whereas classes 1 and 2 are known only in invertebrates
and class V only in viruses.
Semaphorin genes are dispersed throughout the genome,
typically including several exons per gene, and are known to
be alternatively spliced. There is considerable sequence
diversity within the family: with a few exceptions, individual
members are not more than about 50% identical to each
other at the amino-acid level (see Additional data file 1).
Characteristic structural features
The eight main classes of semaphorins  differ in sequence
and overall structural characteristics, but all members of the
family contain a conserved extracellular domain of about
500 amino acids termed the semaphorin (sema) domain
(Figure 2). This domain shows considerably higher conser-
vation among the different semaphorins and across phyla
than do the full-length proteins (see Additional data file 2).
In addition to several blocks of conserved amino acids, the
sema domain is characterized by highly conserved cysteine
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A phylogenetic tree of semaphorin sequences, showing groupings of related semaphorin genes and their organization into different classes. D, Drosophila;
M, mouse; V, viral; Z, sequence identified only in zebrafish and not in mammals. A Sema5D has also been described, but our analysis indicates that it is a
splice variant of Sema5B. Protein sequences were aligned using ClustalW in Vector NTI software and the tree was generated using the neighbor-joining
method, ignoring positions with gaps.
SE MA VB
SE MA VA
residues that have been found to form intrasubunit disulfide
bonds . Crystal structures have revealed that the sema
domain of both the mouse secreted semaphorin Sema3A and
the human transmembrane semaphorin Sema4D fold in a
variation of the ? propeller topology, a common topology
that occurs in proteins with diverse functions (reviewed in
). Interestingly, these sema domains fold in a manner that
is most similar to the ? propeller topology of integrins and
low-density lipoprotein (LDL) receptors.
The sema domain is also a critical component through which
semaphorins mediate their effects [9-11]. In particular, an
approximately 70-amino-acid region within the sema
domain is important for the effects of Sema3A on repulsive
axon guidance and the collapse of the growing tip or growth
cones of axons, which stops their extension . Structurally,
this portion of the sema domain of Sema3A and Sema4D
appears to correspond to blade three of the seven-bladed ?
propeller topology . Interestingly, a small stretch of
amino acids homologous to tarantula hanatoxin, a K+and
Ca2+ion-channel blocker, is also important for the growth-
cone-collapsing effects of Sema3A .
Immediately to the carboxy-terminal side of the sema
domain, semaphorins contain a plexin-semaphorin-integrin
(PSI) domain (Figure 2). This small stretch of cysteine-rich
residues has also been referred to as a MET-related sequence
(MRS) or a cysteine-rich domain (CRD). With the exception
of some viral semaphorins, all examples of proteins contain-
ing a sema domain have a PSI domain . Crystal-structure
analysis indicates that this domain is highly conserved, but its
three-dimensional position relative to the sema domain can
vary among semaphorins . Semaphorins also have con-
sensus N-linked glycosylation sites and may be alternatively
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Primary structures of members of the semaphorin family. All proteins are shown with their amino termini to the top. Class 1 semaphorins are
invertebrate transmembrane proteins and are structurally very similar to the class 6 semaphorins of vertebrates. Class 2 semaphorins (also from
invertebrates) are secreted; they are structurally similar to vertebrate class 3 semaphorins, which have a stretch of highly basic amino acids in their
carboxy-terminal region. Class 4, 6, and 7 semaphorins have been identified only in vertebrates. Class 4-6 semaphorins are transmembrane proteins.
Class 5 semaphorins are present in both vertebrates (Sema5A, Sema5B) and invertebrates (Sema5c) and contain seven canonical type 1 thrombospondin
repeats (TSRs). Class 6 semaphorins contain variable, alternatively spliced cytoplasmic portions. The lone class 7 sema (Sema7A) contains a membrane-
associated GPI moiety at its carboxy terminus. Class V semaphorins are highly similar to class 7 semaphorins and are found in DNA viruses, including
vaccinia (a close relative to the cowpox virus), human smallpox (variola virus), fowlpox, mousepox (ectromelia virus), and alcelaphine herpesvirus type 1
virus (AHV). Some class V semaphorins (the SemaVA proteins) do not contain an Ig domain, whereas others do (SemaVB proteins). Sema, semaphorin;
PSI, plexin-semaphorin-integrin; Ig, immunoglobulin-like; GPI, glycosylphosphatidylinositol.
spliced (as in Drosophila Sema-1a , and mammalian
Sema3F  and Sema6A ), although little is known
about the significance of these modifications.
In contrast to these defining characteristics, individual sem-
aphorins have a number of distinguishing features. Sema-
phorins vary in their membrane anchorage, and include
secreted, transmembrane, and GPI-linked family members
(Figure 2). They may also contain additional sequence
motifs, including a single C2-class immunoglobulin-like (Ig)
domain, a stretch of highly basic amino acids, and/or seven
canonical type 1 thrombospondin repeats (TSRs; Figure 2).
These additional domains are responsible for at least some
of their functional effects; for example, the Ig domain and
basic tail of chicken Sema3A potentiate the effect of its sema
domain in growth-cone collapse , and the throm-
bospondin repeats of mammalian Sema5A are important in
regulating the effect of Sema5A on axon guidance [11,16].
Localization and function
As a group, semaphorins are expressed in most tissues and
this expression varies considerably with age. The expression
patterns of the individual semaphorins are best character-
ized in the nervous system, particularly during development,
where most, or perhaps all, semaphorins are widely
expressed in the nervous system by neuronal and non-
neuronal cells (reviewed in ; see Table 1 for details of the
expression and functions of all members of the family and
associated references). Semaphorins are also widely
expressed in many organ systems and their derivatives,
including the cardiovascular, endocrine, gastrointestinal,
hepatic, immune, musculoskeletal, renal, reproductive, and
No particular pattern of expression appears to define each of
the different classes of semaphorins, but many are dynami-
cally expressed in particular areas during development, and
this expression often decreases with maturity. In the nervous
system, for example, semaphorin expression is often associ-
ated with growing axons as they form axonal tracts, but this
expression often decreases following the formation of the
tracts. Interestingly, changes in the adult expression levels of
semaphorins have been described following injury in neu-
ronal and non-neuronal tissues, during tumorigenesis, and
in association with other pathological conditions.
The diverse expression patterns of the different semaphorins
suggest that they are important in a variety of functions
during development and into adulthood. Indeed, genetic
analyses in both invertebrates and vertebrates indicate that
semaphorins are often required for viability and reveal, in
combination with additional functional assays, distinct roles
in various physiological and pathological processes in most
or perhaps all tissues. These studies reveal that semaphorins
function to direct tissue morphogenesis through their effects
on cellular processes such as adhesion, aggregation, fusion,
migration, patterning, process formation, proliferation, via-
bility, and cytoskeletal organization.
Semaphorins are best known for their roles in nervous
system development, and a number of approaches in vivo
and in vitro indicate that semaphorins can enable axons to
find and connect with one another and their other targets
(reviewed in ). An important way in which semaphorins
guide these growing axons is by repelling them or preventing
them from entering certain regions. For example, characteri-
zation of their normal expression patterns, the defects
observed in particular semaphorin mutants, and assays in
vivo and in vitro have revealed that at least some sema-
phorins form molecular boundaries to prevent axons and
cells from entering inappropriate areas. Semaphorins also
have roles in physiological and pathological processes in the
adult. In the nervous system, altered semaphorin function
has been linked to epilepsy, retinal degeneration,
Alzheimer’s disease, motor neuron degeneration, schizo-
phrenia, and Parkinson’s disease [19-22].
Semaphorins may also limit the ability of axons to regrow
after injury and prevent abnormal sprouting of axons
involved in pain or autonomic function [23-26]. In the
immune system, semaphorins are critical for various phases
of the immune response (Table 2; reviewed in ). Sema-
phorins are also involved in cancer progression, by affecting
chemotaxis, viability, tumorigenesis, metastasis, and angio-
genesis (reviewed in ). More recently, semaphorins
have also been implicated in vascular health and heart
disease (reviewed in ).
The molecular mechanisms by which semaphorins mediate
their functional effects are far from clear. Semaphorin-
mediated axon repulsion is a result of the modification of
the axonal cytoskeleton at the growing tips or growth cones
of axons. The control of axon outgrowth or growth-cone
motility depends critically upon the dynamics of F-actin
polymerization and depolymerization, coupled with the reg-
ulation of F-actin translocation and microtubule dynamics.
Following exposure to secreted Sema3A, growth cones
undergo a rapid collapse that is accompanied by the depoly-
merization of F-actin, a decreased ability to polymerize new
F-actin, attenuated microtubule dynamics, and collapsed
microtubule arrays (reviewed in ). The molecular mech-
anisms underlying these phenomena are poorly understood
but may also be responsible for many of the functional
effects that semaphorins have in non-neuronal tissues. For
example, the cytoskeleton is required for cells to move,
polarize, change shape, engulf particles, and interact with
other cells; even the most divergent family member, the viral
semaphorin SemaVA, induces actin cytoskeletal rearrange-
ment in dendritic cells of the immune system and alters the
ability of these cells to adhere and migrate .
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Expression and function of semaphorins
SemaphorinSpecies Expression (with representative references)Functions (with representative references)
Sema-1a Insects and worms Epidermis , neurons [1,6,13,50] Cell migration , digestion/defecation , fecundity
, morphogenesis , neural connectivity [1,13]
Sema-1b Insects and worms Glia , oocytes  Cell migration , morphogenesis , neural
Sema-2a Insects and worms Epidermis , epithelium , gonads ,
muscles , neurons 
Cell migration , morphogenesis , neural
Sema3A Vertebrates Adipose tissue [56,57], bone , cartilage ,
cancer cells , connective tissue , endothelial
cells , epithelium , glia , gut , heart
[2,58], kidney , limb , lung , meningeal
cells , muscle [2,57], neurons [2,58], pituitary
, placenta , scar tissue , teeth ,
umbilical cord , uterus 
Bone formation , cancer-cell chemotaxis ,
cartilage formation , cell death , cell adhesion
and aggregation [61,116], cell migration and patterning
[117-119], cell proliferation , cytoskeletal organization
, heart formation , lung formation , neural
connectivity [2,113,122], vasculogenesis [61,123]
Sema3B Vertebrates Cancer cells , endothelial cells , glia ,
mammary gland , muscle , neurons ,
Cell death , cytoskeletal organization , neural
connectivity , tumor suppression 
Sema3C VertebratesCancer cells , connective tissue , endothelial
cells , fibroblasts , glia , lung [60,73],
macrophages , mammary gland , neurons
, skeleton , teeth 
Cardiovascular development , cell survival ,
cytoskeletal organization , heart formation , lung
formation , neural connectivity [9,128]
Sema3D Vertebrates Bone , cartilage , endothelial cells ,
epidermis , fibroblasts , glia , heart ,
meninges , muscle , neurons 
Neural connectivity 
Sema3E VertebratesCancer cells , ear , endothelial cells ,
lung , nervous tissue [25,74,80], skeleton ,
Cell growth , cell migration , cytoskeletal
organization , neural connectivity [80,129], tumor
metastasis , vascular patterning 
Sema3F Vertebrates Cancer cells , dermis , ependyma ,
epithelium , eye , gonads , gut ,
heart , kidney , lung [81,82], muscle ,
neurons , pancreas , prostate , skin ,
spleen , submandibular gland , teeth ,
thymus , thyroid gland 
Angiogenesis , cell attachment , cell migration
[133,134], cell proliferation , cytoskeletal
organization [14,135], lung formation , neural
connectivity [82,136], tumor metastasis , tumor
suppression , synaptic transmission 
Sema3G VertebratesHeart , kidney , lung , meninges ,
neurons , placenta 
Cell migration , neural connectivity 
Sema4A Vertebrates Epithelial cells , glia , immune cells [84,85],
mammary gland , neurons , teeth 
Cell survival , cytoskeletal organization ,
lymphocyte activation and immune responses [84,85],
neural connectivity , retina and visual system 
Sema4B VertebratesGlia , immune cells , neurons [60,87],
Sema4C VertebratesBone , ear , glia , immune cells ,
kidney , lung , muscle , neurons [88,90],
regenerating muscle , teeth , pituitary 
Sema4DVertebrates Glia , gonads , gut , immune cells [86,91], Angiogenesis [140,141], cell aggregation and adhesion
kidney , heart , lung , lymph node ,
mammary gland , muscle , neurons ,
placenta , prostate , spleen , teeth ,
[91,142], cell death , cell differentiation , cell
migration [35,140,141], cell proliferation , cell
survival [91,145], cytoskeletal organization [143,146],
invasive/cancerous growth , immune responses
[91,144], neural connectivity [24,145,146]
Sema4E ZebrafishEpithelium , nervous system Neural connectivity 
Sema4FVertebratesGlia , immune cells , lung , mammary
gland , neurons [94,95], teeth 
Cytoskeletal organization , neural connectivity 
Post-translational processing underlies at least some of the
functional effects of semaphorins. Several secreted and
transmembrane semaphorins undergo proteolytic process-
ing, and this is important in semaphorin-mediated repulsive
axon guidance, growth-cone collapse, cell migration, inva-
sive growth, and metastasis (for example, see [32-35]). For
example, mouse Sema3A, Sema3B, and Sema3C are synthe-
sized as inactive precursors and become repulsive for axons
upon proteolytic cleavage .
Oligomerization is another modification that is important
for semaphorin function. The secreted vertebrate sema-
phorin Sema3A is a dimer [9,36,37], and dimerization is
important for its activity in repulsive axon guidance and
growth-cone collapse [36,37]. Cysteine residues in the
carboxy terminus are important for this dimerization,
although weak dimerization also occurs between sema
domains . Transmembrane semaphorins also form
disulfide-linked dimers and depend on oligomerization for
at least some of their functional effects [5,11,16,36,38-40].
Semaphorin receptors and signaling
Semaphorins exert the majority of their effects by serving as
ligands and binding to other proteins through their extracel-
lular domains. All classes of semaphorins except class 2 have
been found to bind directly to members of the plexin (Plex)
family of transmembrane receptors (reviewed in ; see
Table 2 for a summary of the receptors and signaling pro-
teins associated with semaphorins and Figure 3 for the
primary structure of known semaphorin receptors). Interest-
ingly, plexins also contain sema domains, albeit highly diver-
gent, that are important for binding to semaphorins .
Several other proteins have also been identified that bind to
the extracellular portions of semaphorins (Figure 3). In par-
ticular, members of the neuropilin (Npn) family of trans-
membrane proteins are receptors for class 3 semaphorins
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Table 1 (continued)
SemaphorinSpecies Expression (with representative references) Functions (with representative references)
Sema4G Vertebrates Ear , epithelium , glia , gut , hair
follicles , kidney , liver , neurons ,
pituitary , teeth 
Sema5A Vertebrates Cancer cells , glia , heart , kidney ,
liver , lung , muscle , neurons , spleen neural connectivity [11,16,25], vasculature patterning 
, teeth 
Cell morphology , cytoskeletal organization ,
Sema5B Vertebrates Bone , cancer cells , glia , neurons ,
Sema5c Insects Cardiac cells , epidermis [97,99], gut ,
muscle [55,99], oocytes 
Tumor metastasis , tumor suppression 
Sema6A Vertebrates Cancer cells , bone , glia , gut ,
immune cells , kidney , lung , muscle
, neurons , meninges , teeth 
Angiogenesis , cell migration , cytoskeletal
organization , neural connectivity [40,49,151]
Sema6B Vertebrates Bone , cancer cells , glia , heart ,
liver , lung , muscle , nervous tissue
[39,103], teeth 
Neural connectivity 
Sema6C VertebratesBone , dermis , glia , heart ,
kidney , liver , muscle , neurons
, placenta , teeth 
Cytoskeletal organization [104,105], neural connectivity
Sema6D VertebratesGut , heart , kidney , liver ,
lung , muscle , neurons , placenta
, uterus 
Cell migration , cytoskeletal organization , heart
formation [48,152], morphogenesis , neural
Sema7A VertebratesAdrenal gland , bone , cancer cells ,
erythrocytes , fibroblasts , glia , gonads
, gut , heart , kidney , lung , neural connectivity 
lymph nodes , immune cells , muscle ,
neurons , placenta , spleen , teeth ,
Cell fusion , cell migration [108,153], immune
responses , stimulating cytokine production ,
SemaVADNA virusesNot applicableCell adhesion , cell migration , cell retraction
, cytoskeletal organization , immunomodulation
, proinflammatory responses , inducing
cytokine production , regulating phagocytosis 
SemaVBDNA viruses Not applicableCell aggregation 
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Receptors and signaling proteins associated with semaphorins
Binding receptors (with
Signaling proteins (with
‘Reverse’ signaling (with
Sema-1a PlexA [158,159] OTK , Gyc76c , MICAL , Nervy ,
PKA , Rac 
Sema-1b PlexA --
Sema3A Npn-1 [160,161],
PlexA1, A2, A3, A4 [165,173,174], PlexD1 , VEGF receptor ,
L1CAM , integrins , ?2-chimaerin , Cdc42 ,
Cdk5 , cGKI/PKG [181,182], Calcium channels , cofilin ,
CRAM , CRMP , FARP2 , Fes , Fyn , Go/Gi ,
guanylate cyclase , GSK-3 , LIM kinase , 12/15-lipoxygenase
, MAP kinases , MLCK , nNOS , PI 3-kinase ,
PIPKI?661 , PKA , PTEN , Rac , Rap1 , Rho ,
Rnd , ROCK , R-Ras 
Sema3BNpn-1 , Npn-2  NrCAM , FAK , MAP kinases , Src -
Sema3CNpn-1 , Npn-2  PlexD1 , MLCK , ROCK -
Sema3D Npn-1 --
Sema3E Npn-1 , PlexD1 Ca2+channels , MAP kinases , PKC , Ras -
Sema3F Npn-2 , Npn-1  PlexA3, A4 [173,174], NrCAM , E-cadherin ,
Beta-catenin , PI 3-kinase , MAP kinases 
Sema4A Tim-2  ROCK -
Sema4B-- PSD-95 
Sema4C-- PSD-95 , GIPC ,
Sema4D PlexB1 , PlexB2 , Met , Ron , ErbB2 , PlexC1 , integrin , AKT ,
CD72  Gab1 , LARG , 12/15-lipoxygenase , p190RhoGAP ,
PDZ-RhoGEF , PI 3-kinase , Pyk2 , Ras [46,203], Rho ,
Rnd , Src , MAP kinases , Raf 
CD45 , serine kinase
Sema5APlexB3 , HSPG ,
CSPG , Syn-3 
Sema6APlexA4 -EVL 
Sema6BPlexA4 - Src 
Sema6DPlexA1  OTK , VEGF receptor 2 Abl 
Sema7APlexC1  Integrins , Arg , FAK , MAP kinases  Kinase activity 
SemaVA PlexC1 Integrins , cofilin , FAK -
SemaVB PlexC1 --
A hyphen indicates not known. Abbreviations:Abl, Abelson tyrosine kinase; AKT, AKT serine/threonine kinase; Arg, Abl-related tyrosine kinase; CAM, cell
adhesion molecule; CD45, CD45 phosphatase; Cdk5, cyclin-dependent kinase 5; CRAM, CRMP-associated molecule; CRMP, collapsing response mediator
protein; cGKI, cGMP dependent protein kinase I; CSPG, chondroitin sulfate proteoglycan; ErbB2, receptor tyrosine kinase; ena, enabled; EVL, ena/VASP-
like protein; FAK, focal adhesion tyrosine kinase; FARP2, FERM domain-containing GEF; Fes, feline sarcoma tyrosine kinase; Fyn, Fyn tyrosine kinase; Gab1,
GRB2 associated binding protein 1; GIPC, GAIP interacting protein carboxy terminus; GSK-3, glycogen synthase kinase-3; Gyc76c, receptor guanylate
cyclase 76c; HSPG, heparin sulfate proteoglycan; LARG, leukemia-associated RhoGEF; Met, receptor tyrosine kinase; MICAL, molecule interacting with
CasL; MLCK, myosin light chain kinase; nNOS, neuronal nitric oxide synthase; Npn, neuropilin; OTK, off-track receptor tyrosine kinase; PI 3-kinase,
phosphatidylinositol 3-kinase; PIPKI?661, PIP kinase type I; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; Plex, plexin; Pyk2, Pyk2
tyrosine kinase; PSD-95, post-synaptic density protein; PTEN, PTEN phosphatase; ROCK, Rho-associated kinase; Ron, receptor tyrosine kinase; Src, Src
tyrosine kinase; Syn-3, syndecan-3; Tim, T-cell immunoglobulin domain and mucin domain; VEGF, vascular endothelial growth factor.
. Both the basic tail and the sema domain of Sema3A are
important for binding to Npn-1, although binding to the
sema domain is weaker. Neuropilins, however, only have
short cytoplasmic tails that are not required for the effects of
semaphorins on axon guidance . Interestingly, neuro-
pilins also bind plexins, such that class 3 semaphorins,
which bind to neuropilins, signal their effects through the
cytoplasmic domain of plexins.
The signal transduction cascades used by semaphorins are
poorly understood. No canonical signal transduction path-
ways seem to mediate the effects of semaphorins, making the
identification of semaphorin signaling intermediates difficult.
Over the past few years, however, a number of proteins have
been identified and linked with semaphorin signaling, includ-
ing G proteins, kinases, regulators of cyclic nucleotide levels,
oxidation-reduction enzymes, and regulators of the actin
cytoskeleton (Table 2). These intermediates suggest that novel
signaling cascades implement semaphorin function (reviewed
in [21,41-44]), although a complete signaling pathway through
which these proteins direct semaphorin function has not yet
been characterized. Furthermore, semaphorin signaling inter-
mediates have been identified using several different func-
tional assays, complicating a precise determination of the
roles of these proteins in the different semaphorin functions.
At the moment, the best characterized semaphorin signaling
cascades are those used for axon guidance and cell migration.
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Semaphorin receptors. Members of the plexin protein family are organized into four classes (A, B, C, and D); plexins are known to bind to semaphorins
from all classes except class 2, whose receptors are unknown. Class 3 semaphorins bind both members of the neuropilin protein family. Sema4A binds
Tim-2, a member of the T cell, immunoglobulin and mucin (Tim) domain protein family expressed on activated T cells . Sema 4D binds CD72, a
member of the C-type lectin family, and uses it for its effects in lymphoid tissues . Sema, semaphorin; PSI, plexin-semaphorin-integrin; IPT,
immunoglobulin-like fold shared by plexins and transcription factors; GAP, GTPase-activating protein; MAM, Meprin, A5, Mu; PMR, polymorphic region;
ITIM, immunoreceptor tyrosine-based inhibitory motif; IgV, immunoglobulin variable region.
Class 3 Semaphorin classes
1, 3, 4, 5, 6, 7, V
Sema 4D Sema 4A
Coagulation factor domain
α helical domain
GAP homology domain
Semaphorin-mediated repulsive axon-guidance signaling
depends on the large cytoplasmic domains of plexins, at least
some of which have GTPase-activating protein (GAP) activ-
ity: these domains show sequence similarity to a group of
Ras-family-specific GAPs, and mammalian PlexA1 and
PlexB1 have GAP activity towards R-Ras [45,46]. The cyto-
plasmic domains of plexins also bind other small GTPases as
well as binding regulators of GTPase activity, including
guanine-nucleotide exchange factors (GEFs) and GAPs .
The functional implications of these interactions are best
understood for mammalian Sema4D and mammalian PlexB1:
activation of PlexB1 by Sema4D enhances the activity of
RhoGEFs, activating the small GTPase RhoA, and leads to
cytoskeletal rearrangement and repulsive axon guidance.
There may be variation, however, in the signaling cascades
activated by the different semaphorins. Repulsive axon guid-
ance signaling by invertebrate Sema-1a or vertebrate Sema3A
through class A plexins, for example, uses many proteins not
currently characterized as important for repulsive axon guid-
ance by Sema4D and PlexB1 [18,21,41,42].
Specific signaling proteins may also be required for the dis-
tinct functions of semaphorins. For example, Sema4D,
together with PlexB1, limits cell migration or axon out-
growth by signaling through signaling proteins including the
epidermal growth factor receptor ErbB2, Rho kinase, 12-15
lipoxygenase, and PlexC1; whereas Sema4D signaling
through PlexB2 and the hepatocyte growth factor receptor
Met, the receptor tyrosine kinase Ron, p190RhoGap, the
tyrosine kinases Pyk2, Src, and Akt, and phosphatidylinosi-
tol 3-kinase enables cell migration or axon outgrowth
(reviewed in [41,47]).
Importantly, recent work has also begun to identify mecha-
nisms by which semaphorin signaling and its functional
effects can be modulated. Neurotrophins, growth factors,
chemokines, cell adhesion molecules, and integrins have all
been shown to modulate semaphorin signaling, and some of
these effects seem to occur through cyclic nucleotides, nitric
oxide, and semaphorin receptor endocytosis [21,41,42].
Interestingly, semaphorins can also serve as cell-surface
receptors for plexins and perhaps other proteins, and
mediate some of their functional effects through ‘reverse sig-
naling’  (Table 2). In particular, transmembrane sema-
phorins can function as receptors essential for generating
proper neuronal connectivity [49,50] and cardiac develop-
ment , and these effects have been linked to the associa-
tion of their cytoplasmic portions with signaling and
anchoring proteins (Table 2).
Despite considerable progress in our characterization of
members of the semaphorin family, much remains to be
learned about their functions and molecular mechanisms of
action. Several semaphorins have yet to be functionally
characterized, and many have undergone only a cursory
examination. A number of questions remain, including the
purpose of having so many related semaphorins and the under-
lying logic to their complex expression patterns and physiologi-
cal roles. The degree of interaction among semaphorins is also
poorly understood. Do they regulate each other’s signaling cas-
cades? Do they physically associate? What special attributes
and abilities do the secreted, transmembrane, and GPI-linked
forms of semaphorins functionally provide?
Understanding the signaling cascades that underlie the dif-
ferent functional effects of semaphorins will provide insights
into these important proteins. Are there differences in the
signaling cascades activated by the different semaphorins?
How much do their signaling cascades vary in order to
mediate their different cellular effects? How do semaphorins
exert their dramatic effects on the cytoskeleton?
A more detailed understanding of the role of semaphorins in
the normal functioning adult is important. In the nervous
system, the role of semaphorins in forming neural connec-
tions is well established, but the role of semaphorins in
neural connectivity as it pertains to thought, emotion,
memory, and behavior is unknown. The role of semaphorins
in human disease and pathology is also poorly understood.
Mutations in semaphorins are associated with patients with
cancer , retinal degeneration , decreased bone
mineral density , rheumatoid arthritis , and
CHARGE syndrome (a disorder characterized by cranial
nerve dysfunction, cardiac anomalies, and growth retarda-
tion) . Further characterization of the semaphorins and
a better understanding of their signaling mechanisms will
undoubtedly uncover additional roles for semaphorins and
semaphorin signaling in human disease.
Given the role of semaphorins in a wide range of tissues and
functions including neurobiology, vasculobiology, cancer
biology, and immunobiology, further characterizing the
semaphorins and their signaling cascades will reveal funda-
mental mechanisms of how these systems work and strate-
gies for preventing and treating pathologies associated with
Additional data files
The following additional data files are available: tables of the
protein sequence identities between different semaphorins
over the whole sequence (Additional data file 1) and the
sema domain (Additional data file 2).
We thank R. Giger, M. Henkemeyer, and A. Kolodkin for helpful com-
ments on the manuscript, and Zhiyu Huang for helpful discussions. This
work was supported by grants from the NIH/NIMH (MH069787), The
Whitehall Foundation, and The March of Dimes Basil O’Connor Starter
Scholar Research Award to J.R.T. J.R.T. is the Rita C. and William P.
Clements, Jr Scholar in Medical Research.
http://genomebiology.com/2006/7/3/211 Genome Biology 2006,Volume 7, Issue 3, Article 211 Yazdani and Terman 211.9
Genome Biology 2006, 7:211
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