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Gene Section
Review
SEMA4D (sema domain, immunoglobulin domain
(Ig), transmembrane domain (TM) and short
cytoplasmic domain, (semaphorin) 4D)
John R Basile
Oncology and Diagnostic Sciences University of Maryland, Baltimore Baltimore College of Dental Surgery
650 West Baltimore Street, 7- North Baltimore, Maryland 21201 USA (JRB)
Published in Atlas Database: October 2008
Online updated version : http://AtlasGeneticsOncology.org/Genes/SEMA4DID42255ch9q22.html
DOI: 10.4267/2042/44561
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: A8, BB18, CD100, GR3, M-sema-G,
OTTHUMP00000021622, SEMAJ, coll-4
HGNC (Hugo): SEMA4D
Location: 9q22.2
Note
Sema4D is 862 amino acids with a predicted mass of
96.15 kd. Experimentally, Sema4D runs at about 150
kd on a Western blot.
DNA/RNA
Note
Semaphorin 4D (Sema4D) was originally identified by
Hall., et al. (1996) as a cell surface protein important in
B and T lymphocyte activation. Its expression is
upregulated in lymphocytes in an immune response
(Kumanogoh et al., 2000; Wang et al., 2001). Sema 4D
is also expressed in other tissues where it is involved in
many motility responses (for review: Artigiani et al.,
1999), including regulation of axonal growth cone
guidance (Swiercz et al., 2002), regulation of cell-cell
contacts and branching morphogenesis in epithelium
(Giordano et al., 2002), promotion of angiogenesis
(Basile et al., 2004; Conrotto et al., 2005; Basile et al.,
2006), and growth and metastasis of tumors (for
review: Neufeld et al., 2005).
Fig. 1: Sema4D is composed of a Sema domain, a Cystine Rich
domain, an Immunoglobulin-like domain, a transmembrane
segment and a short cytoplasmic tail.
Description
Description
The gene for Sema4D is located at 9q22.2-q31, a locus
that includes PTCH and the xeroderma pigmentosum
gene XPA. Sema 4D corresponds to open reading
frame 164 and spans the positions 91,181,972 to
91,260,688 on the minus strand.
The semaphorins have been shown to exert control over
the proliferation and activation of lymphocytes (Hall et
al., 1996; Kumanogoh et al., 2001; Wang et al., 2001)
(for review: Bismuth et al., 2002), promote tumor
growth and metastasis (Christensen et al., 1998) (for
review: Kreuter et al., 2002) and regulate development
of the lungs (Ito et al., 2000) and the heart and
Transcription
The mRNA is 4,675 bp in length.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9)
660
SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM)
and short cytoplasmic domain, (semaphorin) 4D)
vasculature (Behar et al., 1996; Brown et al., 2001;
Feiner et al., 2001; Torres-Vazquez et al., 2004). There
are more than 20 known semaphorins grouped into
eight classes: classes 1 and 2 are invertebrate
semaphorins, classes 3 to 7 are found in vertebrates,
and an eighth class, class V, has been identified in
some non-neurotropic DNA viruses (for review:
Semaphorin Nomenclature Committee, 1999).
Sema4D is composed of a Sema domain, a Cystine
Rich domain (also called the Plexin Repeat Domain or
the Met Related Sequence), an Immunoglobulin-like
domain, and a short cytoplasmic tail (Fig. 1). The Sema
domain, a seven-bladed beta-propeller similar in
topology to integrins (Love et al., 2003), occurs in the
semaphorins and their receptors, the plexins, as well as
in the hepatocyte growth factor (HGF) receptor family
members Met and RON (for review: Gherardi et al.,
2004). The Cystine Rich domain has an unknown
function but is found in several different receptors.
Three copies of this repeat are found in Plexin-B1, the
receptor for Sema4D (Tamagnone et al., 1999), while
the Met receptor contains one copy. Immunoglobulin
domain family members include components of
immunoglobulins and cell surface glycoproteins such
as the T-cell receptors CD2, CD4, and CD8. The
function of the Sema4D intracellular domain is not
known, but it has been associated with a serine kinase
activity, suggesting that bi-directional signaling may
take place (Elhabazi et al., 1997).
Sema4D is processed into a slightly smaller form that is
shed by some cell types. Elhabazi et al. (2001)
observed the release of soluble Sema4D from T
lymphocytes upon the cleavage of the membrane bound
protein at a cysteine residue located immediately
adjacent to the transmembrane domain. Zhu, et al.
(2007) have demonstrated that platelets express
Sema4D, Plexin-B1, and CD72, and that Sema4D is
gradually shed from the surface following platelet
activation by ADAM17 (also called tumor-necrosis
factor-alpha (TNF-a) converting enzyme, or TACE) in
a process that promotes formation of a thrombus. Head
and neck squamous cell carcinoma cells secrete a
soluble form of Sema4D that promotes tumor-induced
angiogenesis, in this case cleaved by the membrane
type 1-matrix metalloproteinase (MT1-MMP, also
called MMP14) (Basile et al, 2006). Upregulation of
the MMPs occurs in cancer cells and has, in fact, been
linked to the acquisition of an aggressive, more
vascular and more invasive phenotype.
Ligation of plexins by semaphorins initiates a signaling
cascade that involves the G-protein-mediated pathways.
For example, Plexin-A1 and Plexin-B1 are known to
act as R-Ras GAPs (GTPase-activating proteins) when
bound by their respective semaphorins (Oinuma et al.,
2004). There is also data to suggest that Plexin-B1 may
compete for Rac binding with PAK (p21-activated
kinase) (Vikis et al., 2002). Therefore, in addition to
inhibiting Ras signaling through its Ras GAP activity,
Plexin-B1 may sequester Rac and inhibit PAK
activation. The Rho specific GEFs (guanine nucleotideexchange factors) LARG (leukemia-associated
RhoGEF) and PRG (PDZ-RhoGEF) bind to the PDZbinding motif at the C-terminus of Plexin-B1 and
mediate activation of the small GTPase RhoA, and
subsequently its downstream effector Rho Kinase
(ROK), in response to Sema4D ligation (Driessens et
al., 2001; Aurandt et al., 2002; Hirotani et al., 2002;
Perrot et al., 2002; Swiercz et al., 2002; Basile et al.,
2004; Basile et al., 2007a). Indeed, Sema4D-Plexin-B1
binding contributes to coordination of epithelialmesenchymal interactions during organogenesis via
modulation of RhoA signaling (Korostylev et al.,
2008).
Plexin-B1-mediated
signaling
begins
with
phosphorylation of a tyrosine residue in the
intracellular Sex-Plex domain upon Sema4D binding
(for review: Castellani et al., 2002). However, it was
not known how Plexin-B1 or its downstream target
proteins are phosphorylated, since Plexin-B1 is devoid
of intrinsic tyrosine kinase activity. A search for the
kinase associated with Plexin-B1 revealed that in
MLP29 liver progenitor cells, Plexin-B1 interacted
with the extracellular domain of the scatter factor
receptor tyrosine kinase c-Met (Giordano et al., 2002).
In fact, this Plexin-B1/ c-Met interaction may be
responsible for a pro-migratory, angiogenic response
observed in Sema4D treated endothelial cells (Conrotto
et al., 2005) (Fig. 2A). Sema4D-mediated activation of
Expression
Sema4D is expressed in many tissues including skeletal
muscle, blood and bone marrow, lymphoid tissues such
as the spleen and thymus, the testes, kidney, small
intestine, prostate, heart, placenta, lung, pancreas and
the peripheral and central nervous system, as well as in
many carcinomas (Basile et al., 2006) and sarcomas
(Ch'ng et al., 2007).
Localisation
Sema4D is a transmembrane protein bound to the cell
surface, though it is sometimes found in a smaller,
secreted form (Elhabazi et al., 2001; Basile et al.,
2007b; Zhu et al., 2007).
Function
Sema4D is expressed on the surface of T, B and
dendritic cells and modulates their function through
either Plexin-B1 or CD72, a lower affinity receptor for
Sema4D found in lymphoid tissues. (Kumanogoh et al.,
2000) (for review: Moretti et al., 2006). There is
evidence that the HIV-1 Tat protein upregulates the
expression of Sema4D in immature dendritic cells, an
effect that likely facilitates the expansion of HIV-1
infection (Izmailova et al., 2003). Sema4D also induces
collapse of axonal growth cones during neural
development and remodeling by binding and activating
Plexin-B1 (Oinuma et al., 2004), which is why when
many of the semaphorins were first characterized they
were referred to as 'collapsins'.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9)
Basile JR
661
SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM)
and short cytoplasmic domain, (semaphorin) 4D)
Plexin-B1 also may promote cell migration by
stimulating an intracellular kinase cascade that begins
with the recruitment of PDZ RhoGEF and LARG to the
C-terminal PDZ binding motif of Plexin-B1. This
induces activation of RhoA and ROK and the
subsequent phosphorylation and activation of the
cytoplasmic tyrosine kinase PYK2, which then
phosphorylates Plexin-B1 in the intracellular Sex-Plex
domain in a step necessary for a cellular response
(Basile et al., 2005) (Fig. 2B). In this model, signaling
proceeds through Src, Akt and ERK and results in
reorganization of the cytoskeleton (Basile et al., 2005;
Aurandt et al., 2006; Basile et al., 2007a)(Fig. 2B).
Interestingly, a recent study has shown that inhibition
of migration may be elicited by Sema4D under certain
conditions where Plexin-B1 preferentially associates
with the receptor tyrosine kinase ErbB-2 instead of Met
(Swiercz et al., 2008) (Fig. 2C).
Basile JR
Homology
Sema4D exhibits homology with the semaphorins and
c-Met and the Met-like protein tyrosine kinase RON,
receptors collectively known as the scatter factor
receptors (for review: Comoglio et al., 1996). The
scatter factor receptors participate in branching
morphogenesis, axonal guidance in neuronal tissues,
and normal and aberrant proliferation and enhanced
cell motility in many different cell types (for review:
Vande Woude et al., 1997; Maina et al., 1998).
Mutations
Note
There are no known somatic or germline mutations for
Sema4D. Unlike other semaphorins such as Sema3F,
whose loss is implicated in lung carcinomas and thus
may act as a tumor suppressor (Roche et al., 1996;
Tomizawa et al., 2001; Tse et al., 2002),
Fig. 2: Binding of Sema4D to Plexin-B1 via their Sema domains stimulates the tyrosine kinase activity of Met (A) or ErbB-2 (C), resulting
in tyrosine phosphorylation of Plexin-B1 in the Sex-Plex domain and initiation of a pro- or anti- migratory response, respectively. Sema4D
may also activate an intracellular tyrosine kinase cascade via PDZ RhoGEF or LARG, culminating in a RhoA and ROK-dependent
activation of the non-receptor tyrosine kinase PYK2 (B). In turn, PYK2 tyrosine-phosphorylates Plexin-B1 and activates Src, Akt and ERK
to elicit a pro-migratory response.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9)
662
SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM)
and short cytoplasmic domain, (semaphorin) 4D)
Basile JR
there is no definitive evidence that Sema4D can serve
as an oncogene or tumor suppressor.
Human CD100, a novel leukocyte semaphorin that promotes
B-cell aggregation and differentiation. Proc Natl Acad Sci U S
A. 1996 Oct 15;93(21):11780-5
Implicated in
Roche J, Boldog F, Robinson M, Robinson L, Varella-Garcia
M, Swanton M, Waggoner B, Fishel R, Franklin W, Gemmill R,
Drabkin H. Distinct 3p21.3 deletions in lung cancer and
identification of a new human semaphorin. Oncogene. 1996
Mar 21;12(6):1289-97
Various tumors
Note
Acting through Plexin-B1, Sema4D has been shown to
promote angiogenesis (Basile et al., 2004; Conrotto et
al., 2005; Basile et al., 2006) and also enhance invasive
growth and proliferation of tumor cells, while
simultaneously offering protection against apoptosis
(Granziero et al., 2003; Conrotto et al., 2004; Conrotto
et al., 2005). A recent publication shows a correlation
between high levels of Sema4D expression in sarcomas
and a higher mitotic count, cellularity, and Ki-67
labeling index, when compared to tumors with lower
levels of Sema4D expression (Ch'ng et al., 2007).
Sema4D is also overexpressed by many different
aggressive carcinomas, and its activity on Plexin-B1expressing endothelial cells promotes enhanced growth
and vascularity of tumor xenografts in nude mice in
vivo (Basile et al., 2006). Expression of Sema4D by
tumor-associated macrophages may also enhance
tumor-induced angiogenesis and vessel maturation
(Sierra et al., 2008).
Disease
There are no known diseases directly related to
Sema4D overexpression or mutation. However, in
chronic lymphocytic leukemia, there is evidence that
Sema4D positive leukemic cells may interact with
Plexin-B1-expressing bone marrow stromal cells,
follicular dendritic cells, and activated T lymphocytes,
resulting in enhanced proliferation and survival of the
malignant cells (Granziero et al., 2003).
Deletion of the Sema4D locus, which also includes
PTCH and XPA, has been observed in the self-healing
squamous epithelioma, also known as the
keratoacanthoma, and in many squamous cell
carcinomas (Waring et al., 1996; Richards et al., 1997;
Odeberg et al., 1999), two lesions with a great degree
of histological similarity.
Prognosis
Higher expression levels of Sema4D are prognostic of
poorer overall survival in certain sarcomas (Ch'ng et
al., 2007).
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differences from cutaneous squamous cell carcinoma. Br J
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Elhabazi A, Lang V, Hérold C, Freeman GJ, Bensussan A,
Boumsell L, Bismuth G. The human semaphorin-like leukocyte
cell surface molecule CD100 associates with a serine kinase
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Richards FM, Goudie DR, Cooper WN, Jene Q, Barroso I,
Wicking C, Wainwright BJ, Ferguson-Smith MA. Mapping the
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Christensen CR, Klingelhöfer J, Tarabykina S, Hulgaard EF,
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Maina F, Hilton MC, Andres R, Wyatt S, Klein R, Davies AM.
Multiple roles for hepatocyte growth factor in sympathetic
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Chedotal A, Winberg ML, Goodman CS, Poo M, TessierLavigne M, Comoglio PM. Plexins are a large family of
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Fujisawa H, Taniguchi M, Yagi T, Kitamura H, Goshima Y.
Repulsive axon guidance molecule Sema3A inhibits branching
morphogenesis of fetal mouse lung. Mech Dev. 2000 Oct;97(12):35-45
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Vodrazka P, Maier V, Hirschberg A, Ohoka Y, Inagaki S,
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Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9)
Basile JR
Basile JR. SEMA4D (sema domain, immunoglobulin domain
(Ig), transmembrane domain (TM) and short cytoplasmic
domain, (semaphorin) 4D). Atlas Genet Cytogenet Oncol
Haematol. 2009; 13(9):660-665.
665