A SEMA3E mutant resistant to cleavage by furins (UNCL-SEMA3E) inhibits choroidal neovascularization

Toledano, Shira; Han, Lu; Palacio, Agustina; Kigel, Boaz; Kessler, Ofra; Allon, Gilad; Barak, Yoreh; Neufeld, Gera; Schaal, Shlomit

doi:10.1016/j.exer.2016.10.004

Cited by 6 publications

(2 citation statements)

References 37 publications

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“…In the case of sema3A, it seems that the inhibition is not due to competition with factors such as VEGF-A for binding to neuropilin-1 but is due to the activation of intracellular signaling cascades that inhibit the propagation of signaling cascades activated by pro-angiogenic factors such as VEGF-A (Figure 3) [47]. Similarly, sema3E which does not bind to neuropilins or tyrosine-kinase coupled VEGF receptors [18] nevertheless inhibits VEGF-A-induced activation of ERK [93] and VEGF-A-induced angiogenesis [94,95]. Finally, structural studies indicate that VEGF-A and sema3A bind to non-overlapping sites on neuropilin-1, arguing against a competition-based anti-angiogenic mechanism [46,96].…”

Section: Class-3 Semaphorins As Regulators Of Tumor Progressionmentioning

confidence: 99%

Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression

Toledano

Nir-Zvi

Engelman

et al. 2019

IJMS

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Semaphorins are the products of a large gene family containing 28 genes of which 21 are found in vertebrates. Class-3 semaphorins constitute a subfamily of seven vertebrate semaphorins which differ from the other vertebrate semaphorins in that they are the only secreted semaphorins and are distinguished from other semaphorins by the presence of a basic domain at their C termini. Class-3 semaphorins were initially characterized as axon guidance factors, but have subsequently been found to regulate immune responses, angiogenesis, lymphangiogenesis, and a variety of additional physiological and developmental functions. Most class-3 semaphorins transduce their signals by binding to receptors belonging to the neuropilin family which subsequently associate with receptors of the plexin family to form functional class-3 semaphorin receptors. Recent evidence suggests that class-3 semaphorins also fulfill important regulatory roles in multiple forms of cancer. Several class-3 semaphorins function as endogenous inhibitors of tumor angiogenesis. Others were found to inhibit tumor metastasis by inhibition of tumor lymphangiogenesis, by direct effects on the behavior of tumor cells, or by modulation of immune responses. Notably, some semaphorins such as sema3C and sema3E have also been found to potentiate tumor progression using various mechanisms. This review focuses on the roles of the different class-3 semaphorins in tumor progression.

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Section: Class-3 Semaphorins As Regulators Of Tumor Progressionmentioning

confidence: 99%

Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression

Toledano

Nir-Zvi

Engelman

et al. 2019

IJMS

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“…Furin-like proteinases were shown to cleave Sema3 at different sites and thereby regulate their function ( 9 ). This statement was proven by several scientific studies, in one of which, for example, it was demonstrated that furin-like proteinases proteolytically activate the predominant form (p61) of Sema3E and promote tumor cell motility ( 10 ), whereas in other studies, the uncleavable form of Sema3E acts as anti-angiogenic and anti-metastatic factor ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

Importance of the putative furin recognition site 742RNRR745 for antiangiogenic Sema3C activity in vitro

Valiulytė

Preitakaite

Tamašauskas

et al. 2018

Braz J Med Biol Res

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Angiogenesis is one of the key processes in the growth and development of tumors. Class-3 semaphorins (Sema3) are characterized as axon guidance factors involved in tumor angiogenesis by interacting with the vascular endothelial growth factor signaling pathway. Sema3 proteins convey their regulatory signals by binding to neuropilins and plexins receptors, which are located on the effector cell. These processes are regulated by furin endoproteinases that cleave RXRR motifs within the Sema, plexin-semaphorins-integrin, and C-terminal basic domains of Sema3 protein. Several studies have shown that the furin-mediated processing of the basic domain of Sema3F and Sema3A is critical for association with receptors. It is unclear, however, if this mechanism can also be applied to other Sema3 proteins, including the main subject of this study, Sema3C. To address this question, we generated a variant of the full-length human Sema3C carrying point mutation R745A at the basic domain at the hypothetical furin recognition site 742RNRR745, which would disable the processing of Sema3C at this specific location. The effects produced by this mutation were tested in an in vitro angiogenesis assay together with the wild-type Sema3C, Sema3A, and Sema3F proteins. Our results showed that the inhibitory effect of Sema3C on microcapillary formation by human umbilical vein endothelial cells could be abrogated upon mutation at the Sema3C basic domain within putative furin cleavage site 742RNRR745, indicating that this site was essential for the Sema3 biological activity.

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Class-3 semaphorins: Potent multifunctional modulators for angiogenesis-associated diseases

Jiao

Liu

Tan

et al. 2021

Biomedicine & Pharmacotherapy

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A SEMA3E mutant resistant to cleavage by furins (UNCL-SEMA3E) inhibits choroidal neovascularization

Cited by 6 publications

References 37 publications

Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression

Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression

Importance of the putative furin recognition site 742RNRR745 for antiangiogenic Sema3C activity in vitro

Class-3 semaphorins: Potent multifunctional modulators for angiogenesis-associated diseases

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