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

Written2008-10John R Basile
Oncology, Diagnostic Sciences University of Maryland, Baltimore Baltimore College of Dental Surgery 650 West Baltimore Street, 7- North Baltimore, Maryland 21201 USA

(Note : for Links provided by Atlas : click)


chromosome 9 open reading frame 164
sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4D
Alias_symbol (synonym)CD100
Other aliasA8
LocusID (NCBI) 10507
Atlas_Id 42255
Location 9q22.2  [Link to chromosome band 9q22]
Location_base_pair Starts at 89377237 and ends at 89479696 bp from pter ( according to hg19-Feb_2009)  [Mapping SEMA4D.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
C5 (9q33.2) / SEMA4D (9q22.2)SEMA4D (9q22.2) / RGS3 (9q32)SEMA4D (9q22.2) / SEMA4D (9q22.2)


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.


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.
  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 (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'.
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).
  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).


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 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-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 (Ch'ng et al., 2007).


Plexins, semaphorins, and scatter factor receptors: a common root for cell guidance signals?
Artigiani S, Comoglio PM, Tamagnone L.
IUBMB Life. 1999 Nov;48(5):477-82. (REVIEW)
PMID 10637762
Semaphorin 4D activates the MAPK pathway downstream of plexin-B1.
Aurandt J, Li W, Guan KL
Biochem J. 2006 Mar 1;394(Pt 2):459-64.
PMID 16187944
The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG.
Aurandt J, Vikis HG, Gutkind JS, Ahn N, Guan KL.
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12085-90. Epub 2002 Aug 26.
PMID 12196628
Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway.
Basile JR, Afkhami T, Gutkind JS.
Mol Cell Biol. 2005 Aug;25(16):6889-98.
PMID 16055703
Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B.
Basile JR, Barac A, Zhu T, Guan KL, Gutkind JS.
Cancer Res. 2004 Aug 1;64(15):5212-24.
PMID 15289326
Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis.
Basile JR, Castilho RM, Williams VP, Gutkind JS.
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9017-22. Epub 2006 Jun 5.
PMID 16754882
Plexin-B1 utilizes RhoA and Rho kinase to promote the integrin-dependent activation of Akt and ERK and endothelial cell motility.
Basile JR, Gavard J, Gutkind JS.
J Biol Chem. 2007a Nov 30;282(48):34888-95. Epub 2007 Sep 12.
PMID 17855350
MT1-MMP controls tumor-induced angiogenesis through the release of semaphorin 4D.
Basile JR, Holmbeck K, Bugge TH, Gutkind JS.
J Biol Chem. 2007b Mar 2;282(9):6899-905. Epub 2007 Jan 4.
PMID 17204469
Semaphorin III is needed for normal patterning and growth of nerves, bones and heart.
Behar O, Golden JA, Mashimo H, Schoen FJ, Fishman MC.
Nature. 1996 Oct 10;383(6600):525-8.
PMID 8849723
Controlling the immune system through semaphorins.
Bismuth G, Boumsell L.
Sci STKE. 2002 Apr 16;2002(128):RE4. (REVIEW)
PMID 11972358
PlexinA2 and semaphorin signaling during cardiac neural crest development.
Brown CB, Feiner L, Lu MM, Li J, Ma X, Webber AL, Jia L, Raper JA, Epstein JA.
Development. 2001 Aug;128(16):3071-80.
PMID 11688557
Control of semaphorin signaling.
Castellani V, Rougon G.
Curr Opin Neurobiol. 2002 Oct;12(5):532-41. (REVIEW)
PMID 12367632
Prognostic significance of CD100 expression in soft tissue sarcoma.
Ch'ng E, Tomita Y, Zhang B, He J, Hoshida Y, Qiu Y, Morii E, Nakamichi I, Hamada K, Ueda T, Aozasa K.
Cancer. 2007 Jul 1;110(1):164-72.
PMID 17520683
Transcription of a novel mouse semaphorin gene, M-semaH, correlates with the metastatic ability of mouse tumor cell lines.
Christensen CR, Klingelhofer J, Tarabykina S, Hulgaard EF, Kramerov D, Lukanidin E.
Cancer Res. 1998 Mar 15;58(6):1238-44.
PMID 9515811
The HGF receptor family: unconventional signal transducers for invasive cell growth.
Comoglio PM, Boccaccio C.
Genes Cells. 1996 Apr;1(4):347-54.
PMID 9135079
Sema4D induces angiogenesis through Met recruitment by Plexin B1.
Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio PM, Bussolino F, Giordano S.
Blood. 2005 Jun 1;105(11):4321-9. Epub 2005 Jan 4.
PMID 15632204
Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho.
Driessens MH, Hu H, Nobes CD, Self A, Jordens I, Goodman CS, Hall A.
Curr Biol. 2001 Mar 6;11(5):339-44..
PMID 11267870
Biological activity of soluble CD100. I. The extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis.
Elhabazi A, Delaire S, Bensussan A, Boumsell L, Bismuth G.
J Immunol. 2001 Apr 1;166(7):4341-7.
PMID 11254687
Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption.
Feiner L, Webber AL, Brown CB, Lu MM, Jia L, Feinstein P, Mombaerts P, Epstein JA, Raper JA.
Development. 2001 Aug;128(16):3061-70.
PMID 11688556
The sema domain.
Gherardi E, Love CA, Esnouf RM, Jones EY.
Curr Opin Struct Biol. 2004 Dec;14(6):669-78. (REVIEW)
PMID 15582390
The semaphorin 4D receptor controls invasive growth by coupling with Met.
Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM.
Nat Cell Biol. 2002 Sep;4(9):720-4.
PMID 12198496
Unified nomenclature for the semaphorins/collapsins. Semaphorin Nomenclature Committee.
Goodman C, Kolodkin A, Luo Y, Puschel A, Raper J
Cell. 1999 May 28;97(5):551-2.
PMID 10367884
CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes.
Granziero L, Circosta P, Scielzo C, Frisaldi E, Stella S, Geuna M, Giordano S, Ghia P, Caligaris-Cappio F.
Blood. 2003 Mar 1;101(5):1962-9. Epub 2002 Oct 24.
PMID 12406905
Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation.
Hall KT, Boumsell L, Schultze JL, Boussiotis VA, Dorfman DM, Cardoso AA, Bensussan A, Nadler LM, Freeman GJ.
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11780-5.
PMID 8876214
Interaction of plexin-B1 with PDZ domain-containing Rho guanine nucleotide exchange factors.
Hirotani M, Ohoka Y, Yamamoto T, Nirasawa H, Furuyama T, Kogo M, Matsuya T, Inagaki S.
Biochem Biophys Res Commun. 2002 Sep 13;297(1):32-7.
PMID 12220504
Repulsive axon guidance molecule Sema3A inhibits branching morphogenesis of fetal mouse lung.
Ito T, Kagoshima M, Sasaki Y, Li C, Udaka N, Kitsukawa T, Fujisawa H, Taniguchi M, Yagi T, Kitamura H, Goshima Y.
Mech Dev. 2000 Oct;97(1-2):35-45.
PMID 11025205
HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages.
Izmailova E, Bertley FM, Huang Q, Makori N, Miller CJ, Young RA, Aldovini A.
Nat Med. 2003 Feb;9(2):191-7. Epub 2003 Jan 21.
PMID 12539042
A functional role for semaphorin 4D/plexin B1 interactions in epithelial branching morphogenesis during organogenesis.
Korostylev A, Worzfeld T, Deng S, Friedel R, Swiercz J, Vodrazka P, Maier V, Hirschberg A, Ohoka Y, Inagaki S, Offermanns S, Kuner R.
Development. 2008 Oct;135(20):3333-43. Epub 2008 Sep 17.
PMID 18799546
Role of neuropilins and semaphorins in angiogenesis and cancer.
Kreuter M, Bielenberg D, Hida Y, Hida K, Klagsbrun M.
Ann Hematol. 2002;81 Suppl 2:S74. (REVIEW)
PMID 12611086
The CD100-CD72 interaction: a novel mechanism of immune regulation.
Kumanogoh A, Kikutani H.
Trends Immunol. 2001 Dec;22(12):670-6.
PMID 11738997
The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D.
Love CA, Harlos K, Mavaddat N, Davis SJ, Stuart DI, Jones EY, Esnouf RM.
Nat Struct Biol. 2003 Oct;10(10):843-8. Epub 2003 Sep 7.
PMID 12958590
Multiple roles for hepatocyte growth factor in sympathetic neuron development.
Maina F, Hilton MC, Andres R, Wyatt S, Klein R, Davies AM.
Neuron. 1998 May;20(5):835-46.
PMID 9620689
Neuronal semaphorins regulate a primary immune response.
Moretti S, Procopio A, Boemi M, Catalano A.
Curr Neurovasc Res. 2006 Nov;3(4):295-305. (REVIEW)
PMID 17109625
Semaphorins in cancer.
Neufeld G, Shraga-Heled N, Lange T, Guttmann-Raviv N, Herzog Y, Kessler O.
Front Biosci. 2005 Jan 1;10:751-60. (REVIEW)
PMID 15569615
Context-dependent Taq-polymerase-mediated nucleotide alterations, as revealed by direct sequencing of the ZNF189 gene: implications for mutation detection.
Odeberg J, Ahmadian A, Williams C, Uhlen M, Ponten F, Lundeberg J.
Gene. 1999 Jul 22;235(1-2):103-9.
PMID 10415338
Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons.
Oinuma I, Katoh H, Negishi M.
J Neurosci. 2004 Dec 15;24(50):11473-80.
PMID 15601954
Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF.
Perrot V, Vazquez-Prado J, Gutkind JS.
J Biol Chem. 2002 Nov 8;277(45):43115-20. Epub 2002 Aug 14.
PMID 12183458
Mapping the multiple self-healing squamous epithelioma (MSSE) gene and investigation of xeroderma pigmentosum group A (XPA) and PATCHED (PTCH) as candidate genes.
Richards FM, Goudie DR, Cooper WN, Jene Q, Barroso I, Wicking C, Wainwright BJ, Ferguson-Smith MA.
Hum Genet. 1997 Dec;101(3):317-22.
PMID 9439661
Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin.
Roche J, Boldog F, Robinson M, Robinson L, Varella-Garcia M, Swanton M, Waggoner B, Fishel R, Franklin W, Gemmill R, Drabkin H.
Oncogene. 1996 Mar 21;12(6):1289-97.
PMID 8649831
Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages.
Sierra JR, Corso S, Caione L, Cepero V, Conrotto P, Cignetti A, Piacibello W, Kumanogoh A, Kikutani H, Comoglio PM, Tamagnone L, Giordano S
J Exp Med. 2008 Jul 7;205(7):1673-85. Epub 2008 Jun 16.
PMID 18559453
ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1.
Swiercz JM, Worzfeld T, Offermanns S.
J Biol Chem. 2008 Jan 25;283(4):1893-901. Epub 2007 Nov 19.
PMID 18025083
Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates.
Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H, Chedotal A, Winberg ML, Goodman CS, Poo M, Tessier-Lavigne M, Comoglio PM.
Cell. 1999 Oct 1;99(1):71-80.
PMID 10520995
Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B.
Tomizawa Y, Sekido Y, Kondo M, Gao B, Yokota J, Roche J, Drabkin H, Lerman MI, Gazdar AF, Minna JD.
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13954-9.
PMID 11717452
Semaphorin-plexin signaling guides patterning of the developing vasculature.
Torres-Vazquez J, Gitler AD, Fraser SD, Berk JD, Van NP, Fishman MC, Childs S, Epstein JA, Weinstein BM.
Dev Cell. 2004 Jul;7(1):117-23.
PMID 15239959
Human Semaphorin 3B (SEMA3B) located at chromosome 3p21.3 suppresses tumor formation in an adenocarcinoma cell line.
Tse C, Xiang RH, Bracht T, Naylor SL.
Cancer Res. 2002 Jan 15;62(2):542-6.
PMID 11809707
Met-HGF/SF: tumorigenesis, invasion and metastasis.
Vande Woude GF, Jeffers M, Cortner J, Alvord G, Tsarfaty I, Resau J.
Ciba Found Symp. 1997;212:119-30; discussion 130-2, 148-54. (REVIEW)
PMID 9524767
The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding.
Vikis HG, Li W, Guan KL.
Genes Dev. 2002 Apr 1;16(7):836-45.
PMID 11937491
Functional soluble CD100/Sema4D released from activated lymphocytes: possible role in normal and pathologic immune responses.
Wang X, Kumanogoh A, Watanabe C, Shi W, Yoshida K, Kikutani H.
Blood. 2001 Jun 1;97(11):3498-504.
PMID 11369643
Loss of heterozygosity analysis of keratoacanthoma reveals multiple differences from cutaneous squamous cell carcinoma.
Waring AJ, Takata M, Rehman I, Rees JL.
Br J Cancer. 1996 Mar;73(5):649-53.
PMID 8605102
Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury.
Zhu L, Bergmeier W, Wu J, Jiang H, Stalker TJ, Cieslak M, Fan R, Boumsell L, Kumanogoh A, Kikutani H, Tamagnone L, Wagner DD, Milla ME, Brass LF.
Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1621-6. Epub 2007 Jan 23.
PMID 17244710


This paper should be referenced as such :
Basile, JR
SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM), short cytoplasmic domain, (semaphorin) 4D)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(9):660-665.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  t(9;9)(q22;q32) SEMA4D/RGS3
t(9;9)(q22;q33) C5/SEMA4D

External links

HGNC (Hugo)SEMA4D   10732
Entrez_Gene (NCBI)SEMA4D  10507  semaphorin 4D
AliasesC9orf164; CD100; COLL4; M-sema-G; 
SEMAJ; coll-4
GeneCards (Weizmann)SEMA4D
Ensembl hg19 (Hinxton)ENSG00000187764 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000187764 [Gene_View]  ENSG00000187764 [Sequence]  chr9:89377237-89479696 [Contig_View]  SEMA4D [Vega]
ICGC DataPortalENSG00000187764
Genatlas (Paris)SEMA4D
SOURCE (Princeton)SEMA4D
Genetics Home Reference (NIH)SEMA4D
Genomic and cartography
GoldenPath hg38 (UCSC)SEMA4D  -     chr9:89377237-89479696 -  9q22.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SEMA4D  -     9q22.2   [Description]    (hg19-Feb_2009)
EnsemblSEMA4D - 9q22.2 [CytoView hg19]  SEMA4D - 9q22.2 [CytoView hg38]
Mapping of homologs : NCBISEMA4D [Mapview hg19]  SEMA4D [Mapview hg38]
Gene and transcription
Genbank (Entrez)AB210030 AI055975 AJ420442 AK090804 AK091601
RefSeq transcript (Entrez)NM_001142287 NM_006378 NM_182635
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SEMA4D
Cluster EST : UnigeneHs.494406 [ NCBI ]
CGAP (NCI)Hs.494406
Alternative Splicing GalleryENSG00000187764
Gene ExpressionSEMA4D [ NCBI-GEO ]   SEMA4D [ EBI - ARRAY_EXPRESS ]   SEMA4D [ SEEK ]   SEMA4D [ MEM ]
Gene Expression Viewer (FireBrowse)SEMA4D [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)10507
GTEX Portal (Tissue expression)SEMA4D
Human Protein AtlasENSG00000187764-SEMA4D [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92854   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ92854  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ92854
Splice isoforms : SwissVarQ92854
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)    SEMA (PS51004)   
Domains : Interpro (EBI)Ig-like_dom    Ig-like_fold    Ig_sub    Ig_sub2    Immunoglobulin    Plexin_repeat    PSI    Semap_dom    Semaphorin    WD40/YVTN_repeat-like_dom   
Domain families : Pfam (Sanger)ig (PF00047)    PSI (PF01437)    Sema (PF01403)   
Domain families : Pfam (NCBI)pfam00047    pfam01437    pfam01403   
Domain families : Smart (EMBL)IG (SM00409)  IGc2 (SM00408)  PSI (SM00423)  Sema (SM00630)  
Conserved Domain (NCBI)SEMA4D
DMDM Disease mutations10507
Blocks (Seattle)SEMA4D
PDB (SRS)1OLZ    3OL2   
PDB (PDBSum)1OLZ    3OL2   
PDB (IMB)1OLZ    3OL2   
PDB (RSDB)1OLZ    3OL2   
Structural Biology KnowledgeBase1OLZ    3OL2   
SCOP (Structural Classification of Proteins)1OLZ    3OL2   
CATH (Classification of proteins structures)1OLZ    3OL2   
Human Protein Atlas [tissue]ENSG00000187764-SEMA4D [tissue]
Peptide AtlasQ92854
IPIIPI00023807   IPI00915390   IPI00167427   IPI00910938   IPI00926816   IPI00926930   IPI00925498   IPI01010225   
Protein Interaction databases
IntAct (EBI)Q92854
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription by RNA polymerase II  positive regulation of protein phosphorylation  receptor activity  transmembrane signaling receptor activity  receptor binding  protein binding  extracellular space  extracellular space  plasma membrane  integral component of plasma membrane  immune response  cell adhesion  negative regulation of cell adhesion  regulation of cell shape  negative regulation of alkaline phosphatase activity  positive regulation of phosphatidylinositol 3-kinase signaling  semaphorin receptor binding  semaphorin receptor binding  positive regulation of cell migration  positive regulation of cell migration  regulation of cell projection organization  neuropilin binding  negative regulation of apoptotic process  positive regulation of GTPase activity  positive regulation of GTPase activity  ossification involved in bone maturation  negative regulation of osteoblast differentiation  positive regulation of collateral sprouting  regulation of dendrite morphogenesis  positive regulation of peptidyl-tyrosine phosphorylation  negative regulation of peptidyl-tyrosine phosphorylation  negative chemotaxis  leukocyte aggregation  semaphorin-plexin signaling pathway  semaphorin-plexin signaling pathway  semaphorin-plexin signaling pathway involved in bone trabecula morphogenesis  
Ontology : EGO-EBInegative regulation of transcription by RNA polymerase II  positive regulation of protein phosphorylation  receptor activity  transmembrane signaling receptor activity  receptor binding  protein binding  extracellular space  extracellular space  plasma membrane  integral component of plasma membrane  immune response  cell adhesion  negative regulation of cell adhesion  regulation of cell shape  negative regulation of alkaline phosphatase activity  positive regulation of phosphatidylinositol 3-kinase signaling  semaphorin receptor binding  semaphorin receptor binding  positive regulation of cell migration  positive regulation of cell migration  regulation of cell projection organization  neuropilin binding  negative regulation of apoptotic process  positive regulation of GTPase activity  positive regulation of GTPase activity  ossification involved in bone maturation  negative regulation of osteoblast differentiation  positive regulation of collateral sprouting  regulation of dendrite morphogenesis  positive regulation of peptidyl-tyrosine phosphorylation  negative regulation of peptidyl-tyrosine phosphorylation  negative chemotaxis  leukocyte aggregation  semaphorin-plexin signaling pathway  semaphorin-plexin signaling pathway  semaphorin-plexin signaling pathway involved in bone trabecula morphogenesis  
Pathways : KEGGAxon guidance   
REACTOMEQ92854 [protein]
REACTOME PathwaysR-HSA-416700 [pathway]   
NDEx NetworkSEMA4D
Atlas of Cancer Signalling NetworkSEMA4D
Wikipedia pathwaysSEMA4D
Orthology - Evolution
GeneTree (enSembl)ENSG00000187764
Phylogenetic Trees/Animal Genes : TreeFamSEMA4D
Homologs : HomoloGeneSEMA4D
Homology/Alignments : Family Browser (UCSC)SEMA4D
Gene fusions - Rearrangements
Fusion : MitelmanC5/SEMA4D [9q33.2/9q22.2]  [t(9;9)(q22;q33)]  
Fusion : MitelmanSEMA4D/RGS3 [9q22.2/9q32]  [t(9;9)(q22;q32)]  
Fusion PortalC5 9q33.2 SEMA4D 9q22.2 PRAD
Fusion PortalSEMA4D 9q22.2 RGS3 9q32 PRAD
Fusion : QuiverSEMA4D
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSEMA4D [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SEMA4D
Exome Variant ServerSEMA4D
ExAC (Exome Aggregation Consortium)ENSG00000187764
GNOMAD BrowserENSG00000187764
Genetic variants : HAPMAP10507
Genomic Variants (DGV)SEMA4D [DGVbeta]
DECIPHERSEMA4D [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSEMA4D 
ICGC Data PortalSEMA4D 
TCGA Data PortalSEMA4D 
Broad Tumor PortalSEMA4D
OASIS PortalSEMA4D [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSEMA4D  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSEMA4D
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch SEMA4D
DgiDB (Drug Gene Interaction Database)SEMA4D
DoCM (Curated mutations)SEMA4D (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SEMA4D (select a term)
NCG5 (London)SEMA4D
Cancer3DSEMA4D(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry SEMA4D
NextProtQ92854 [Medical]
Target ValidationSEMA4D
Huge Navigator SEMA4D [HugePedia]
snp3D : Map Gene to Disease10507
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD10507
Chemical/Pharm GKB GenePA35654
Clinical trialSEMA4D
canSAR (ICR)SEMA4D (select the gene name)
PubMed86 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Mon Jul 16 10:00:17 CEST 2018

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