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).

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.