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

2008-03-01   Vincent A Potiron , Harry A Drabkin , Joëlle Roche 





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.


From the 5 to 3UTR, 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.


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).


Atlas Image
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.


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.


SEMA3F is expressed in most embryonic and adult human tissues.


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.


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.


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.



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

Entity name
Lung Cancer
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).
Atlas Image
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 name
Ovarian cancer
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 name
Other cancers
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 name
Neurological and other pathologies
In the nervous system, altered semaphorin function has been linked to epilepsy, retinal degeneration, Alzheimers disease, motor neuron degeneration, schizophrenia, and Parkinsons 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.


Pubmed IDLast YearTitleAuthors
177685982007Targeting endothelial and tumor cells with semaphorins.Bielenberg DR et al
107024102000Semaphorin SEMA3F localization in malignant human lung and cell lines: A suggested role in cell adhesion and cell migration.Brambilla E et al
124566422002Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A.Castellani V et al
167317412006The role of neuropilins in cancer.Ellis LM et al
173080832007Possible role of semaphorin 3F, a candidate tumor suppressor gene at 3p21.3, in p53-regulated tumor angiogenesis suppression.Futamura M et al
182835472008Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis.Geretti E et al
98564631998Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity.Giger RJ et al
163568252006The neuropilins and their role in tumorigenesis and tumor progression.Guttmann-Raviv N et al
148718322004Semaphorin-3F is an inhibitor of tumor angiogenesis.Kessler O et al
159670982005Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells.Kusy S et al
160059892005Promoter characterization of Semaphorin SEMA3F, a tumor suppressor gene.Kusy S et al
128456302003Expression of VEGF, semaphorin SEMA3F, and their common receptors neuropilins NP1 and NP2 in preinvasive bronchial lesions, lung tumours, and cell lines.Lantuéjoul S et al
179749732007Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1.Matsushita A et al
126596732003Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading.Nasarre P et al
158020232005Semaphorin SEMA3F has a repulsing activity on breast cancer cells and inhibits E-cadherin-mediated cell adhesion.Nasarre P et al
155696152005Semaphorins in cancer.Neufeld G et al
170104102006Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas.Osada R et al
178757112007Semaphorin SEMA3F affects multiple signaling pathways in lung cancer cells.Potiron VA et al
86498311996Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin.Roche J et al
158147922005Secreted semaphorins modulate synaptic transmission in the adult hippocampus.Sahay A et al
86330261996Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns.Sekido Y et al
103678841999Unified nomenclature for the semaphorins/collapsins. Semaphorin Nomenclature Committee.
182855122008Besides adhesion: new perspectives of integrin functions in angiogenesis.Serini G et al
175034122007Neuropilins in physiological and pathological angiogenesis.Staton CA et al
180656942008Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity.Sulpice E et al
105209951999Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates.Tamagnone L et al
175397532007Semaphorin regulation of cellular morphology.Tran TS et al
178553782007Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis?Williams A et al
119806612002Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice.Xiang R et al
87861191996Isolation of the human semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer.Xiang RH et al
165845332006The semaphorins.Yazdani U et al

Other Information

Locus ID:

NCBI: 6405
MIM: 601124
HGNC: 10728
Ensembl: ENSG00000001617


dbSNP: 6405
ClinVar: 6405
TCGA: ENSG00000001617


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Axon guidanceKEGGko04360
Axon guidanceKEGGhsa04360

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
155208582004Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype.94
175696712007Semaphorin-3A and semaphorin-3F work together to repel endothelial cells and to inhibit their survival by induction of apoptosis.75
186605022008ABL2/ARG tyrosine kinase mediates SEMA3F-induced RhoA inactivation and cytoskeleton collapse in human glioma cells.54
188187662008Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells.49
126596732003Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading.39
223504132012RORα suppresses breast tumor invasion by inducing SEMA3F expression.39
173080832007Possible role of semaphorin 3F, a candidate tumor suppressor gene at 3p21.3, in p53-regulated tumor angiogenesis suppression.36
176934322007Interactions of the G quartet forming semaphorin 3F RNA with the RGG box domain of the fragile X protein family.34
191772002009ZEB-1, a repressor of the semaphorin 3F tumor suppressor gene in lung cancer cells.32
203888052010Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F.32


Vincent A Potiron ; Harry A Drabkin ; Joëlle Roche

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

Atlas Genet Cytogenet Oncol Haematol. 2008-03-01

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