The Cleavage of Semaphorin 3C Induced by ADAMTS1 Promotes Cell Migration

Esselens, Cary; Malapeira, Jordi; Colomé, Núria; Casal, Carmen; Rodrı́guez-Manzaneque, Juan Carlos; Canals, Françesc; Arribas, Joaquı́n

doi:10.1074/jbc.m109.055129

Cited by 96 publications

(91 citation statements)

References 50 publications

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“…61,116 Like the other class-3 semaphorins, sema3C too is cleaved in conserved sites by furin like pro-protein convertases as well as by ADAMTS1. 170 The major cleavage product generated by furin like pro-protein convertases (p65-Sema3C) is inactive as an inducers of cell contraction but is still able to support survival of tumor cells in cell culture 61 suggesting that it may perhaps contribute to tumor progression when generated in the tumor microenvironment which is usually enriched with these furins. 171 Likewise, the sema3C cleavage products generated by cleavage with ADAMTS1 promotes the migration of breast cancer cells.…”

Section: Semaphorins As Regulators Of Tumor Progressionmentioning

confidence: 99%

The role of the semaphorins in cancer

Neufeld

Mumblat

Smolkin

et al. 2016

Cell Adhesion & Migration

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The semaphorins were initially characterized as axon guidance factors, but have subsequently been implicated also in the regulation of immune responses, angiogenesis, organ formation, and a variety of additional physiological and developmental functions. The semaphorin family contains more then 20 genes divided into 7 subfamilies, all of which contain the signature sema domain. The semaphorins transduce signals by binding to receptors belonging to the neuropilin or plexin families. Additional receptors which form complexes with these primary semaphorin receptors are also frequently involved in semaphorin signaling. Recent evidence suggests that semaphorins also fulfill important roles in the etiology of multiple forms of cancer. Some semaphorins have been found to function as bona-fide tumor suppressors and to inhibit tumor progression by various mechanisms while other semaphorins function as inducers and promoters of tumor progression. The semaphorin familyThe semaphorin family members are divided into 8 subclasses of which subclasses 1 and 2 contain invertebrate semaphorins while subclasses 3-7 contain the 22 vertebrate semaphorins. The 8th subclass contains viral semaphorins. In early publications, semaphorins were assigned confusing names. This situation was rectified by the adoption of a unified nomenclature in which sema is followed by the subclass number and by alphabetic designation within the subclass.1 Semaphorins are characterized by the presence of a »500 amino-acids long sema domain located close to their N-termini which is also present in semaphorin receptors of the plexin family, and by a plexin-semaphorin-integrin (PSI) domain located downstream to the sema domain. The sema domain is essential for semaphorin activity and plays a role in the determination of the receptor binding specificity.2 The sema domains of several different semaphorins were characterized by X-ray crystallography revealing a b propeller topology.3-5 Different semaphorin subclasses are characterized by class specific structural motifs. Thus, the vertebrate semaphorins belonging to classes 3, 4 and 7 contain immunoglobulin like domains, class-5 semaphorins contain thrombospondin repeats and class-3 semaphorins contain a basic domain. Class-3 semaphorins are the only vertebrate semaphorins produced as secreted proteins while other vertebrate semaphorins are membrane anchored or trans-membrane proteins that can be further processed into soluble forms by proteolytic cleavage (Fig.

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Section: Semaphorins As Regulators Of Tumor Progressionmentioning

confidence: 99%

The role of the semaphorins in cancer

Neufeld

Mumblat

Smolkin

et al. 2016

Cell Adhesion & Migration

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“…2A; ref. 34). These observations suggest that sema3C is a heparainbinding protein and that binding to heparin or heparan sulfates may be important to its activity.…”

Section: Generation Of An Active Point Mutated Sema3c (Fr-sema3c) Thamentioning

confidence: 99%

Full-Length Semaphorin-3C Is an Inhibitor of Tumor Lymphangiogenesis and Metastasis

et al. 2015

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Semaphorins play important regulatory roles in diverse processes such as axon guidance, angiogenesis, and immune responses. We find that semaphorin-3C (sema3C) induces the collapse of the cytoskeleton of lymphatic endothelial cells (LEC) in a neuropilin-2-, plexin-D1-, and plexin-A1-dependent manner, while most other semaphorins, including antiangiogenic semaphorins such as sema3A do not. Sema3C is cleaved, like other class-3 semaphorins, by furin-like pro-protein convertases (FPPC). Cleaved sema3C (p65-Sema3C) was unable to induce the collapse of the cytoskeleton of LEC. FPPC are strongly upregulated in tumor cells. In order to examine the effects of full-length sema3C on tumor progression, we therefore generated an active point mutated furin cleavage-resistant sema3C (FR-sema3C). FR-sema3C inhibited potently proliferation of LEC and to a lesser extent proliferation of human umbilical vein-derived endothelial cells. FR-sema3C also inhibited VEGF-C-induced phosphorylation of VEGFR-3, ERK1/2, and AKT. Expression of recombinant FR-sema3C in metastatic, triple-negative LM2-4 breast cancer cells did not affect their migration or proliferation in vitro. However, tumors derived from FR-sema3C-expressing LM2-4 cells implanted in mammary fat pads developed at a slower rate, contained a lower concentration of blood vessels and lymph vessels, and metastasized much less effectively to lymph nodes. Interestingly, p65-Sema3C, but not FR-sema3C, rendered A549 lung cancer cells resistant to serum deprivation, suggesting that previously reported protumorigenic activities of sema3C may be due to p65-Sema3C produced by tumor cells. Our observations suggest that FR-sema3C may be further developed into a novel antitumorigenic drug. Cancer Res; 75(11); 2177-86. Ó2015 AACR.

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“…It was reported that CD36 has been subjected to positive selection for malaria or some unknown selection pressures (Aitman et al 2000;Omi et al 2002Omi et al , 2003Fry et al 2009). SEMA3C, induced by ADAMTS1, promotes the migration of cancer cells (Esselens et al 2010). The 6p21-22 region, harboring human major histocompatibility complex (MHC), also showed an overrepresentation of African ancestry in this study (although <3 SD) and has been reported under selection in various studies (Garrigan and Hedrick 2003;Tang et al 2007).…”

Section: Natural Selection In African Americansmentioning

confidence: 99%

Genome-wide detection of natural selection in African Americans pre- and post-admixture

Jin¹,

Xu²,

Wang³

et al. 2011

Genome Res.

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It is particularly meaningful to investigate natural selection in African Americans (AfA) due to the high mortality their African ancestry has experienced in history. In this study, we examined 491,526 autosomal single nucleotide polymorphisms (SNPs) genotyped in 5210 individuals and conducted a genome-wide search for selection signals in 1890 AfA. Several genomic regions showing an excess of African or European ancestry, which were considered the footprints of selection since population admixture, were detected based on a commonly used approach. However, we also developed a new strategy to detect natural selection both pre-and post-admixture by reconstructing an ancestral African population (AAF) from inferred African components of ancestry in AfA and comparing it with indigenous African populations (IAF). Interestingly, many selection-candidate genes identified by the new approach were associated with AfA-specific highrisk diseases such as prostate cancer and hypertension, suggesting an important role these disease-related genes might have played in adapting to a new environment. CD36 and HBB, whose mutations confer a degree of protection against malaria, were also located in the highly differentiated regions between AAF and IAF. Further analysis showed that the frequencies of alleles protecting against malaria in AAF were lower than those in IAF, which is consistent with the relaxed selection pressure of malaria in the New World. There is no overlap between the top candidate genes detected by the two approaches, indicating the different environmental pressures AfA experienced pre-and post-population admixture. We suggest that the new approach is reasonably powerful and can also be applied to other admixed populations such as Latinos and Uyghurs.

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The Cleavage of Semaphorin 3C Induced by ADAMTS1 Promotes Cell Migration

Cited by 96 publications

References 50 publications

The role of the semaphorins in cancer

The role of the semaphorins in cancer

Full-Length Semaphorin-3C Is an Inhibitor of Tumor Lymphangiogenesis and Metastasis

Genome-wide detection of natural selection in African Americans pre- and post-admixture

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