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

	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.

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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