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SEMA3F (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3F)

Written2008-03Vincent A Potiron, Harry A Drabkin, Joëlle Roche
Division of Hematology / Oncology, Medical University of South Carolina, P.O. box 250623, 96 Jonathan Lucas Street, Charleston, SC 29425, USA (VAP, HAD); Institut de Physiologie et Biologie Cellulaires, Universite de Poitiers, CNRS UMR 6187, 40 avenue du Recteur Pineau, Poitiers, F-86022, France (VAP, JR)

(Note : for Links provided by Atlas : click)

Identity

Alias_namessema domain
Alias_symbol (synonym)SEMAK
Sema4
Other aliasSEMA-IV
SEMA4
HGNC (Hugo) SEMA3F
LocusID (NCBI) 6405
Atlas_Id 42254
Location 3p21.31  [Link to chromosome band 3p21]
Location_base_pair Starts at 50192478 and ends at 50226508 bp from pter ( according to hg19-Feb_2009)  [Mapping SEMA3F.png]
Fusion genes
(updated 2016)
SEMA3F (3p21.31) / RBM6 (3p21.31)SEMA3F (3p21.31) / SEMA3F (3p21.31)

DNA/RNA

Note History and Nomenclature : the SEMA3F semaphorin gene was independently cloned in 1996 by three groups (Roche et al, 1996; Sekido et al, 1996, Xiang et al, 1996) and was previously named H-SEMA IV. Its current name, SEMA3F, was adopted by the Nomenclature Committee in 1999. SEMA3F was cloned from a recurrent 3p homozygous deletion in small-cell lung cancer cells (SCLC) and is located close to another semaphorin gene called SEMA3B.
Description From the 5' to 3'UTR, SEMA3F encompasses 33,659 bp of DNA on chromosome 3 (3p21.3) between position 50,167,852- 50,201,511 from pter to centromere and is located between the RBM5 and GNAT1 genes in the same orientation.
Transcription The SEMA3F transcript contains 19 exons and is 2.7 Kb in length. Two cDNAs were first cloned from a human brain library and differed in their 5' UTR. One 93 bp alternative exon within the Sema domain has been described. The SEMA3F promoter does not have a TATA box, but a CpG island where several transcriptional start sites are located. Chromatin conformation regulates the expression and inhibitors of histone deacytylases and DNA methylation stimulate SEMA3F transcription (Kusy et al, 2005). SEMA3F is a direct target of p53 (Futamura et al, 2007).

Protein

 
  Figure 1 : SEMA3F semaphorin (88 Kd) is secreted and contains the Sema domain, the PSI (plexin-semaphorin-integrin) domain rich in cysteines also referred as the Met related sequence (MRS) domain, an immunoglobulin-like domain and a C-terminal basic region. Its receptor NRP2 (130 Kd) contains the two complement homology (CUB) like domains (a1a2), two coagulation factor V/VIII homology like domains (b1b2), and a meprin (MAM) like domain that may participate to neuropilin dimerization. The cytoplasmic part contains in its C-terminal end the three amino acids SEA. Class-3 semaphorins bind to a1a2 through the Sema domain, Ig-like domain and the C-terminal basic tail, and to b1 through the C-terminal tail. VEGF and heparin bind to b1b2 (review: Geretti et al, 2008). After dimerization NRP2 forms complexes with type-A plexins. Type-A plexins (250 Kd) contain in the extracellular part a Sema domain which functions as an inhibitor of activation in the absence of the ligand. The Sema domain is followed by three PSI domains, then by three IPT (for Ig-like, Plexin , Transcription factors) domains. In the intracellular part, plexins contain the split cytoplasmic SP (Sex-Plexin) domain of about 600 amino acids (also known as the C1 and C2 domains) which functions as a split GTPase activating GAP domain.
Figure 2 : A model representing the signaling events induced by class-3 semaphorins to inhibit integrin activation. See text for sequential events. ECM : extracellular matrix.
Description The SEMA3F protein contains 785 amino acids (88 Kd) for the longest form or 754 amino acids. SEMA3F is a member of class-3 semaphorins. Semaphorins (initially called Fasciclin IV when the first protein was discovered, then Collapsins for their growth cone collapsing activity) belong to a large family of about 30 proteins found in multi-cellular organisms and also in a few viruses. To date, they have not been described in protozoans, plants, and the most primitive metazoans. Their name comes from "semaphore" meaning to convey information by a signaling system. They have been divided into eight classes based on structural features, with classes 3 to 7 represented in vertebrates (for reviews: Yazdani and Terman, 2006; Tran et al, 2007). They can be either transmembranous, GPI-anchored to the plasma membrane, or secreted. The hallmark of semaphorins is the Sema domain in their N-terminal part, that is characterized by approximately 500 amino acids with 14 to 16 cysteines. The extracellular domain is highly conserved among semaphorins and is also shared with receptors of the plexin and Met/Ron families. Another recurrent domain is the PSI domain ("plexin-semaphorin-integrin"). Class-3 semaphorins (A to G) are secreted proteins that contain an immunoglobulin-type domain followed by a C-terminal basic sequence (Figure 1). They can be further processed by furin-like cleavage enzymes with apparent large effects on activity, although this complexity has been often ignored in many biologic reports. For functional activity, semaphorin dimerization through disulfide-bond is necessary. Another possible modification is N-glycosylation.
Expression SEMA3F is expressed in most embryonic and adult human tissues.
Localisation SEMA3F is either secreted or present in the axons (but not in the cellular body of axons), or bound to its receptor at cellular membranes. In normal lung, it is located at the membrane of epithelial cells and type II pneumocytes. It is present at the membrane of lamellipodia of tumor cells in culture.
Function Semaphorins are involved in a variety of functions during development and in adult tissues. They direct tissue morphogenesis, direct axon migration and target connections, and are involved in immune responses, cancer progression, metastasis and angiogenesis. A common theme in the function of semaphorins is that they affect the cytoskeleton and organization of actin filaments in addition to the microtubule network through receptor binding.
Class-3 semaphorins are ligands for Neuropilin-1 (NRP1) and/or Neuropilin-2 (NRP-2). SEMA3F binds with 10 times more affinity to NRP2 than NRP1 (Giger et al, 1998) (Figure 1). Because of their short cytoplasmic sequence, neuropilins associate with plexins for signal transduction (Tamagnone et al, 1999) and plexins A1 and A3 are co-receptors for SEMA3F (Figure 1). Except SEMA3E, all class-3 semaphorins, require NRP. Plexin stimulation by class-3 semaphorins involves small GTPases. The Rac guanine nucleotide exchange factor (GEF) FARP2 is associated with plexins (Figure 2, step"0") and, upon semaphorin binding to NRP, it is released from sequestration (step "1"). As a consequence, FARP2 exerts its GEF activity leading to a rapid increase of active Rac1 -GTP (step "2") that favors the binding of active GTPase Rnd1 to plexin (steps "3-4"). As a consequence, R-Ras is inactivated by the GAP activity of plexins (step "5"), leading to integrin inhibition. Also, free FARP2 competes with talin for binding to PIPKIγ661 (step "6"), impairing talin binding to beta-integrin, which is necessary for focal adhesion (for reviews see Yazdani and Terman, 2006; Serini et al, 2008). Activation of type-A plexins by SEMA3s induces phosphorylation of CRMP2 (Collapsin Response Mediator Protein) which hinders its tubulin binding activity. Semaphorin signaling involves cyclic nucleotides, nitric oxyde, and NRP endocytosis.
The function of the cytoplasmic domain of NRP is not clear as it has no apparent kinase motif. However, the NRP-interacting protein (NIP) containing a PDZ domain often involved in protein-protein interactions, binds to the last terminal three amino acids (SEA) of NRPs.
Neuropilins were independently identified as co-receptors for vascular endothelial growth factor (VEGF) and the semaphorin/neuropilin system is an important regulator of cardiovascular development and angiogenesis (review: Geretti et al, 2008). Class-3 semaphorins, and particularly SEMA3A, have been described as competitors for VEGF165 binding to NRPs. During vascular development, SEMA3s repulse vessels between somites in which they are expressed. However, Sema3A and Sema3F-induced ERK1 / ERK2 inhibition is unrelated to the ability of VEGF to induce phosphorylation of VEGFR2, suggesting that while antagonistic the semaphorin effects may not be directly competitive in terms of binding. A major consequence of SEMA3s in angiogenesis may derive from their ability to inhibit integrin activation.
NRP2, the receptor of SEMA3F, can form complexes with VEGFR-1, VEGFR-2, and VEGFR-3; the latter binds VEGF-C and VEGF-D (review: Bielenberg and Klagsbrun, 2007). NRP2 is expressed in both venous and lymphatic endothelial cells, suggesting that SEMA3F may be involved in lymphangiogenesis.
Interestingly, other ligands for NRPs have been described including placenta growth factor (PlGF-2), fibroblast growth factor, galectin, and hepatocyte growth factor (HGF). In addition, NRP1 interacts with c-Met (Matsushita et al, 2007). The adhesion molecules L1-CAM and Nr-CAM also associate with NRPs (Castellani et al, 2002). This variety of partners suggests that NRPs are part of a signalosome complex (Sulpice et al, 2008).
SEMA3F is involved in brain and lung development. In mouse lung explants grown ex vivo, Sema3A inhibits branching whereas Sema3C and Sema3F promote it. In lung epithelium, Sema3C and Sema3F may induce formation of the terminal buds. The development of other organs involving branching may also be affected by SEMA3F, but this has not yet been documented. Indeed, SEMA3A is involved in ureteric bud branching morphogenesis. Because of its localization in 3p21.3, a region of loss of heterozygosity (LOH) in lung tumors, SEMA3F was suspected in 1996 to be a tumor suppressor gene, which was later demonstrated.
Homology SEMA3F shares 42 to 52% amino acid identity with other class-3 human semaphorins with the maximum identity with SEMA3C (52%). SEMA3F has 96.3% identity with its murine homolog Sema3F. Such a high degree of amino acid conservation is indicative of a restricted evolutionary freedom, emphasizing the apparent fundamental biological importance of these proteins.

Mutations

Note SEMA3F is located in a region of loss of heterozygosity in lung and breast cancers. No inactivating mutations have been described in lung cancers although there are several polymorphisms and expression levels are often affected.

Implicated in

Note
  
Entity Lung Cancer
Disease The first evidence implicating SEMA3F in lung cancer was its location in 3p21.3. This hypothesis was supported by transfection of an 80 Kb genomic clone containing SEMA3F into a mouse tumor cell line that inhibited tumorigenesis in vivo. While SEMA3F is expressed in the normal human lung, the protein is lost or delocalized in the cytoplasm of tumor cells. Moreover, its loss correlates inversely with the grade and stage of lung cancer, and also with the expression of VEGF165 (Brambilla et al, 2000; Lantuejoul et al, 2003).
In vivo, SEMA3F potently inhibits tumorigenesis in a xenograft cancer model induced by lung cancer cells (Kusy et al, 2005; Futamura et al, 2007; Potiron et al, 2007). One observation was that tumors formed by SEMA3F-expressing cells display reduced vascularization. Consistent with the inhibition of integrin activation by plexin signaling (review: Serini et al, 2008), reduced b3 integrin activation was found in SEMA3F-transfected H157 lung cancer cells, along with reduced adhesion to fibronectin and vitronectin (Potiron et al, 2007, Kusy et al, 2005). Additional signaling changes induced by SEMA3F in lung cancer cells included loss of activated ERK1/2, AKT and STAT3, with downstream inhibition of HIF1a translation and VEGF165 mRNA expression. SEMA3F inhibited the activity of integrin-linked kinase (ILK) although this appeared to account only for the loss of phospho-ERK1/2 (Potiron et al, 2007) (Figure 3).
 
Figure 3 : A hypothetic model representing the antitumoral activity of SEMA3F. In lung cancer cells, SEMA3F would inhibit integrin activation. Therefore STAT3, AKT, or ERK1/2 would be inactivated. As a consequence, the cell phenotype would change and VEGF expression would be reduced leading to less tumor angiogenesis (Potiron et al, 2007).
  
  
Entity Ovarian cancer
Disease In ovarian cancer, an elevated VEGF/SEMA ratio is a poor prognostic feature (Osada et al, 2006) but no specific SEMA3F detection was performed in this study.
  
  
Entity Other cancers
Note SEMA3F could be involved in other cancers. In xenograft models induced by ovarian cancer cells and murine fibrosarcoma cells, SEMA3F showed reduced tumorigenicity or even inhibit tumor formation in nude mice (Xiang et al, 2002). In addition, with melanoma (Bielenberg et al, 2004) and transformed HEK293 cells (Kessler et al, 2004), tumors formed by SEMA3F-expressing cells display reduced vascularization. In vitro, secretion of SEMA3F by transfected tumors repels endothelial cells (ECs) (Bielenberg et al, 2004). SEMA3F also inhibits VEGF165 and basic-FGF-induced ERK1/2 activation and EC proliferation (Kessler et al, 2004). Similarly, SEMA3F repels breast cancer cells (Nasarre et al, 2005) and has an antagonistic effect on breast cancer cell spreading by VEGF165 (Nasarre et al, 2003). Reduced b1 integrin or b3 integrin activation was found in melanoma cells (Bielenberg et al, 2004). Thus, SEMA3F has emerged as a potent tumor suppressor and antagonist of VEGF-driven tumor neovascularization (reviews: Neufeld et al, 2005; Bielenberg and Klagsbrun, 2007).
SEMA3F antitumor activity can be impaired by abnormal expression of NRPs that are frequently overexpressed and often associated with poor prognosis and advance disease. Recent excellent reviews cover NRP involvement in cancers (Ellis, 2006; Guttman-Raviv et al, 2006; Bielenberg and Klagsbrun, 2007; Staton et al, 2007; Geretti et al, 2008).
The semaphorin pathway could be a target for cancer treatment. Inhibiting strategies include VEGF or NRP-blocking antibodies, NRP blocking peptides and NRP soluble forms. On the other hand, injection of the extracellular domain of SEMA6A has been developed with success in mice to reduce tumors and their vascularization.
  
  
Entity Neurological and other pathologies
Note In the nervous system, altered semaphorin function has been linked to epilepsy, retinal degeneration, Alzheimer's disease, motor neuron degeneration, schizophrenia, and Parkinson's disease. They can limit the ability of axons to regrow after injury. When SEMA3F is knocked down in mice, the three month old animals are prone to seizures defined as an epileptogenic EEG change accompanied by a behavioral change (Sahay et al, 2005). SEMA3F in addition to SEMA3A would be a key player in myelin repair in multiple sclerosis (Williams et al, 2007).
Semaphorins could be involved in the "Cri du Chat" syndrome (CdCS) that results from deletions on 5p where SEMA5A (previously described as SEMAF) has been mapped to the critical region. In addition, semaphorins could play a role in a chronic inflammation disease like rheumatoid arthritis.
  

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Citation

This paper should be referenced as such :
Potiron, VA ; Drabkin, HA ; Roche, J
SEMA3F (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3F)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(1):62-67.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/SEMA3FID42254ch3p21.html


External links

Nomenclature
HGNC (Hugo)SEMA3F   10728
Cards
AtlasSEMA3FID42254ch3p21
Entrez_Gene (NCBI)SEMA3F  6405  semaphorin 3F
AliasesSEMA-IV; SEMA4; SEMAK
GeneCards (Weizmann)SEMA3F
Ensembl hg19 (Hinxton)ENSG00000001617 [Gene_View]  chr3:50192478-50226508 [Contig_View]  SEMA3F [Vega]
Ensembl hg38 (Hinxton)ENSG00000001617 [Gene_View]  chr3:50192478-50226508 [Contig_View]  SEMA3F [Vega]
ICGC DataPortalENSG00000001617
TCGA cBioPortalSEMA3F
AceView (NCBI)SEMA3F
Genatlas (Paris)SEMA3F
WikiGenes6405
SOURCE (Princeton)SEMA3F
Genetics Home Reference (NIH)SEMA3F
Genomic and cartography
GoldenPath hg19 (UCSC)SEMA3F  -     chr3:50192478-50226508 +  3p21.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)SEMA3F  -     3p21.3   [Description]    (hg38-Dec_2013)
EnsemblSEMA3F - 3p21.3 [CytoView hg19]  SEMA3F - 3p21.3 [CytoView hg38]
Mapping of homologs : NCBISEMA3F [Mapview hg19]  SEMA3F [Mapview hg38]
OMIM601124   
Gene and transcription
Genbank (Entrez)AA378582 AB209259 BC042914 BF058597 BQ949723
RefSeq transcript (Entrez)NM_001318798 NM_001318800 NM_004186
RefSeq genomic (Entrez)NC_000003 NC_018914 NT_022517 NW_004929309
Consensus coding sequences : CCDS (NCBI)SEMA3F
Cluster EST : UnigeneHs.32981 [ NCBI ]
CGAP (NCI)Hs.32981
Alternative Splicing GalleryENSG00000001617
Gene ExpressionSEMA3F [ NCBI-GEO ]   SEMA3F [ EBI - ARRAY_EXPRESS ]   SEMA3F [ SEEK ]   SEMA3F [ MEM ]
Gene Expression Viewer (FireBrowse)SEMA3F [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6405
GTEX Portal (Tissue expression)SEMA3F
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13275   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ13275  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ13275
Splice isoforms : SwissVarQ13275
PhosPhoSitePlusQ13275
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)    SEMA (PS51004)   
Domains : Interpro (EBI)Ig-like_dom    Ig-like_fold    Ig_sub    Plexin-like_fold    Semap_dom    Semaphorin    WD40/YVTN_repeat-like_dom   
Domain families : Pfam (Sanger)Sema (PF01403)   
Domain families : Pfam (NCBI)pfam01403   
Domain families : Smart (EMBL)IG (SM00409)  PSI (SM00423)  Sema (SM00630)  
Conserved Domain (NCBI)SEMA3F
DMDM Disease mutations6405
Blocks (Seattle)SEMA3F
SuperfamilyQ13275
Human Protein AtlasENSG00000001617
Peptide AtlasQ13275
HPRD03079
IPIIPI00298003   IPI00556643   IPI00927913   IPI00927665   IPI00927097   IPI00926865   IPI00926618   
Protein Interaction databases
DIP (DOE-UCLA)Q13275
IntAct (EBI)Q13275
FunCoupENSG00000001617
BioGRIDSEMA3F
STRING (EMBL)SEMA3F
ZODIACSEMA3F
Ontologies - Pathways
QuickGOQ13275
Ontology : AmiGOneural crest cell migration  extracellular space  axon guidance  facial nerve structural organization  trigeminal nerve structural organization  nerve development  branchiomotor neuron axon guidance  semaphorin receptor binding  positive regulation of cell migration  ventral trunk neural crest cell migration  neuropilin binding  chemorepellent activity  negative regulation of axon extension involved in axon guidance  axon extension involved in axon guidance  negative chemotaxis  sympathetic ganglion development  semaphorin-plexin signaling pathway  sympathetic neuron projection extension  sympathetic neuron projection guidance  neural crest cell migration involved in autonomic nervous system development  semaphorin-plexin signaling pathway involved in neuron projection guidance  semaphorin-plexin signaling pathway involved in axon guidance  
Ontology : EGO-EBIneural crest cell migration  extracellular space  axon guidance  facial nerve structural organization  trigeminal nerve structural organization  nerve development  branchiomotor neuron axon guidance  semaphorin receptor binding  positive regulation of cell migration  ventral trunk neural crest cell migration  neuropilin binding  chemorepellent activity  negative regulation of axon extension involved in axon guidance  axon extension involved in axon guidance  negative chemotaxis  sympathetic ganglion development  semaphorin-plexin signaling pathway  sympathetic neuron projection extension  sympathetic neuron projection guidance  neural crest cell migration involved in autonomic nervous system development  semaphorin-plexin signaling pathway involved in neuron projection guidance  semaphorin-plexin signaling pathway involved in axon guidance  
Pathways : KEGGAxon guidance   
NDEx NetworkSEMA3F
Atlas of Cancer Signalling NetworkSEMA3F
Wikipedia pathwaysSEMA3F
Orthology - Evolution
OrthoDB6405
GeneTree (enSembl)ENSG00000001617
Phylogenetic Trees/Animal Genes : TreeFamSEMA3F
HOVERGENQ13275
HOGENOMQ13275
Homologs : HomoloGeneSEMA3F
Homology/Alignments : Family Browser (UCSC)SEMA3F
Gene fusions - Rearrangements
Fusion : MitelmanSEMA3F/RBM6 [3p21.31/3p21.31]  
Fusion: TCGASEMA3F 3p21.31 RBM6 3p21.31 LUAD LUSC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSEMA3F [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SEMA3F
dbVarSEMA3F
ClinVarSEMA3F
1000_GenomesSEMA3F 
Exome Variant ServerSEMA3F
ExAC (Exome Aggregation Consortium)SEMA3F (select the gene name)
Genetic variants : HAPMAP6405
Genomic Variants (DGV)SEMA3F [DGVbeta]
DECIPHER (Syndromes)3:50192478-50226508  ENSG00000001617
CONAN: Copy Number AnalysisSEMA3F 
Mutations
ICGC Data PortalSEMA3F 
TCGA Data PortalSEMA3F 
Broad Tumor PortalSEMA3F
OASIS PortalSEMA3F [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSEMA3F  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSEMA3F
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 SEMA3F
DgiDB (Drug Gene Interaction Database)SEMA3F
DoCM (Curated mutations)SEMA3F (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SEMA3F (select a term)
intoGenSEMA3F
NCG5 (London)SEMA3F
Cancer3DSEMA3F(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601124   
Orphanet
MedgenSEMA3F
Genetic Testing Registry SEMA3F
NextProtQ13275 [Medical]
TSGene6405
GENETestsSEMA3F
Huge Navigator SEMA3F [HugePedia]
snp3D : Map Gene to Disease6405
BioCentury BCIQSEMA3F
ClinGenSEMA3F
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6405
Chemical/Pharm GKB GenePA35650
Clinical trialSEMA3F
Miscellaneous
canSAR (ICR)SEMA3F (select the gene name)
Probes
Litterature
PubMed53 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSEMA3F
EVEXSEMA3F
GoPubMedSEMA3F
iHOPSEMA3F
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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