SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4D)

2008-10-01   John R Basile  

Oncology, Diagnostic Sciences University of Maryland, Baltimore Baltimore College of Dental Surgery 650 West Baltimore Street, 7- North Baltimore, Maryland 21201 USA

Identity

HGNC
LOCATION
9q22.2
LOCUSID
ALIAS
A8,BB18,C9orf164,CD100,COLL4,GR3,M-sema-G,SEMAJ,coll-4
FUSION GENES

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).

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.

Transcription

The mRNA is 4,675 bp in length.

Proteins

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.
Atlas Image
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

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 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).

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 (Chng 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.
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 nucleotide-exchange factors) LARG (leukemia-associated RhoGEF) and PRG (PDZ-RhoGEF) bind to the PDZ-binding 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 epithelial-mesenchymal 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 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).
Atlas Image
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.

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), there is no definitive evidence that Sema4D can serve as an oncogene or tumor suppressor.

Implicated in

Entity name
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 (Chng et al., 2007). Sema4D is also overexpressed by many different aggressive carcinomas, and its activity on Plexin-B1-expressing 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 (Chng et al., 2007).

Article Bibliography

Pubmed IDLast YearTitleAuthors
106377621999Plexins, semaphorins, and scatter factor receptors: a common root for cell guidance signals?Artigiani S et al
161879442006Semaphorin 4D activates the MAPK pathway downstream of plexin-B1.Aurandt J et al
121966282002The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG.Aurandt J et al
160557032005Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway.Basile JR et al
152893262004Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B.Basile JR et al
167548822006Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis.Basile JR et al
178553502007Plexin-B1 utilizes RhoA and Rho kinase to promote the integrin-dependent activation of Akt and ERK and endothelial cell motility.Basile JR et al
172044692007MT1-MMP controls tumor-induced angiogenesis through the release of semaphorin 4D.Basile JR et al
88497231996Semaphorin III is needed for normal patterning and growth of nerves, bones and heart.Behar O et al
119723582002Controlling the immune system through semaphorins.Bismuth G et al
116885572001PlexinA2 and semaphorin signaling during cardiac neural crest development.Brown CB et al
123676322002Control of semaphorin signaling.Castellani V et al
175206832007Prognostic significance of CD100 expression in soft tissue sarcoma.Ch'ng E et al
95158111998Transcription of a novel mouse semaphorin gene, M-semaH, correlates with the metastatic ability of mouse tumor cell lines.Christensen CR et al
91350791996The HGF receptor family: unconventional signal transducers for invasive cell growth.Comoglio PM et al
156322042005Sema4D induces angiogenesis through Met recruitment by Plexin B1.Conrotto P et al
112678702001Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho.Driessens MH et al
112546872001Biological activity of soluble CD100. I. The extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis.Elhabazi A et al
116885562001Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption.Feiner L et al
155823902004The sema domain.Gherardi E et al
121984962002The semaphorin 4D receptor controls invasive growth by coupling with Met.Giordano S et al
103678841999Unified nomenclature for the semaphorins/collapsins. Semaphorin Nomenclature Committee.
124069052003CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes.Granziero L et al
88762141996Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation.Hall KT et al
122205042002Interaction of plexin-B1 with PDZ domain-containing Rho guanine nucleotide exchange factors.Hirotani M et al
110252052000Repulsive axon guidance molecule Sema3A inhibits branching morphogenesis of fetal mouse lung.Ito T et al
125390422003HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages.Izmailova E et al
187995462008A functional role for semaphorin 4D/plexin B1 interactions in epithelial branching morphogenesis during organogenesis.Korostylev A et al
126110862002Role of neuropilins and semaphorins in angiogenesis and cancer.Kreuter M et al
117389972001The CD100-CD72 interaction: a novel mechanism of immune regulation.Kumanogoh A et al
129585902003The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D.Love CA et al
96206891998Multiple roles for hepatocyte growth factor in sympathetic neuron development.Maina F et al
171096252006Neuronal semaphorins regulate a primary immune response.Moretti S et al
155696152005Semaphorins in cancer.Neufeld G et al
104153381999Context-dependent Taq-polymerase-mediated nucleotide alterations, as revealed by direct sequencing of the ZNF189 gene: implications for mutation detection.Odeberg J et al
156019542004Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons.Oinuma I et al
121834582002Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF.Perrot V et al
94396611997Mapping the multiple self-healing squamous epithelioma (MSSE) gene and investigation of xeroderma pigmentosum group A (XPA) and PATCHED (PTCH) as candidate genes.Richards FM et al
86498311996Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin.Roche J et al
185594532008Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages.Sierra JR et al
180250832008ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1.Swiercz JM et al
105209951999Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates.Tamagnone L et al
117174522001Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B.Tomizawa Y et al
152399592004Semaphorin-plexin signaling guides patterning of the developing vasculature.Torres-Vázquez J et al
118097072002Human Semaphorin 3B (SEMA3B) located at chromosome 3p21.3 suppresses tumor formation in an adenocarcinoma cell line.Tse C et al
95247671997Met-HGF/SF: tumorigenesis, invasion and metastasis.Vande Woude GF et al
119374912002The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding.Vikis HG et al
113696432001Functional soluble CD100/Sema4D released from activated lymphocytes: possible role in normal and pathologic immune responses.Wang X et al
86051021996Loss of heterozygosity analysis of keratoacanthoma reveals multiple differences from cutaneous squamous cell carcinoma.Waring AJ et al
172447102007Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury.Zhu L et al

Other Information

Locus ID:

NCBI: 10507
MIM: 601866
HGNC: 10732
Ensembl: ENSG00000187764

Variants:

dbSNP: 10507
ClinVar: 10507
TCGA: ENSG00000187764
COSMIC: SEMA4D

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000187764ENST00000339861Q92854
ENSG00000187764ENST00000356444Q92854
ENSG00000187764ENST00000418828C9JD54
ENSG00000187764ENST00000420101A0A0C4DG45
ENSG00000187764ENST00000420681C9JFP1
ENSG00000187764ENST00000420987Q92854
ENSG00000187764ENST00000422704Q92854
ENSG00000187764ENST00000429836E9PFD9
ENSG00000187764ENST00000433650C9JYS7
ENSG00000187764ENST00000438547Q92854
ENSG00000187764ENST00000450295Q92854
ENSG00000187764ENST00000455551Q92854
ENSG00000187764ENST00000537934E9PFD9
ENSG00000187764ENST00000540475F5H044

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Axon guidanceKEGGko04360
Axon guidanceKEGGhsa04360
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Semaphorin interactionsREACTOMER-HSA-373755
Sema4D in semaphorin signalingREACTOMER-HSA-400685
Sema4D mediated inhibition of cell attachment and migrationREACTOMER-HSA-416550
Sema4D induced cell migration and growth-cone collapseREACTOMER-HSA-416572
Other semaphorin interactionsREACTOMER-HSA-416700

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
378467332024Comparative evaluation of semaphorin-4D, peptidylarginine deiminase-2, and matrix metalloproteinase-8 levels of gingival crevicular fluid in periodontally healthy and Stage III periodontitis smoker and non-smoker patients before and after non-surgical periodontal therapy.0
380978642024Sema4D as a biomarker for Predicting rheumatoid arthritis disease activity.0
378467332024Comparative evaluation of semaphorin-4D, peptidylarginine deiminase-2, and matrix metalloproteinase-8 levels of gingival crevicular fluid in periodontally healthy and Stage III periodontitis smoker and non-smoker patients before and after non-surgical periodontal therapy.0
380978642024Sema4D as a biomarker for Predicting rheumatoid arthritis disease activity.0
362574022023The Potential Immunomodulatory Roles of Semaphorin 4D in Human Periapical Lesions.0
373950112023Protection of Barrier Function in Cultured Human Corneal Epithelial Cells by Semaphorin 4D.1
362574022023The Potential Immunomodulatory Roles of Semaphorin 4D in Human Periapical Lesions.0
373950112023Protection of Barrier Function in Cultured Human Corneal Epithelial Cells by Semaphorin 4D.1
354018782022Soluble Sema4D Level Is Positively Correlated with Sema4D Expression in PBMCs and Peripheral Blast Number in Acute Leukemia.1
354018782022Soluble Sema4D Level Is Positively Correlated with Sema4D Expression in PBMCs and Peripheral Blast Number in Acute Leukemia.1
329483332021Signaling from membrane semaphorin 4D in T lymphocytes.2
335932752021CD100 modulates cytotoxicity of CD8(+) T cells in patients with acute myocardial infarction.1
336274832021A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis.2
336498512021Semaphorin 4D is a potential biomarker in pediatric leukemia and promotes leukemogenesis by activating PI3K/AKT and ERK signaling pathways.5
337769912021Soluble Sema4D in Plasma of Head and Neck Squamous Cell Carcinoma Patients Is Associated With Underlying Non-Inflamed Tumor Profile.8

Citation

John R Basile

SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4D)

Atlas Genet Cytogenet Oncol Haematol. 2008-10-01

Online version: http://atlasgeneticsoncology.org/gene/42255/haematological-explorer/favicon/humanGenome