Sema4A induces cell morphological changes through B-type plexin-mediated signaling

Yukawa, Kazunori; Tanaka, Tetsuji; Yoshida, Kenji; Takeuchi, Noriko; Ito, Takuji; Takamatsu, Hyota; Kikutani, Hitoshi; Kumanogoh, Atsushi

doi:10.3892/ijmm_00000334

Cited by 33 publications

(42 citation statements)

References 23 publications

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“…Based on these findings and our data, we can assume that the increased activation of VEGFR-1 induced by the Sema4A/ PlexinD1 pathway and the consequent binding with VEGF-A produced by macrophages or other cell types could be part of the mechanism by which Sema4A exerts its promigratory effect on macrophages. Recently, Sema4A has been reported to bind to all three B-type plexins (PlexinB1, B2, and B3) and plexins found to mediate Sema4A-induced growth cone collapse in mouse hippocampal neurons (22). In this study, we showed that, among the different PlexinBs, macrophages stimulated with poly I:C and LPS displayed increased levels of PlexinB2; however, a functionblocking Ab directed against this receptor did not inhibit the Sema4A-stimulated chemotaxis of macrophages.…”

Section: Discussionmentioning

confidence: 52%

“…Moreover, in the presence of the Rho family GTPase Rnd1, the binding of Sema4A to PlexinB1-B2 and B3 induces COS7 cell contraction through the R-Ras GTPase-activating protein enzymatic activity that characterizes all Plexin cytodomains studied so far (21). Besides acting as a chemorepulsive cue via B-type plexins (21,22), Sema4A has been shown to be constitutively expressed by dendritic cells, where it stimulates T cell activation through Tim-2 receptor, a member of the T cell Ig and mucine domain proteins expressed on activated T cells (19). Moreover, T cells require Sema4A to allow Th cell differentiation.…”

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confidence: 99%

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Semaphorin 4A Exerts a Proangiogenic Effect by Enhancing Vascular Endothelial Growth Factor-A Expression in Macrophages

Meda

Molla

Pizzol

et al. 2012

The Journal of Immunology

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The axon guidance cues semaphorins (Semas) and their receptors plexins have been shown to regulate both physiological and pathological angiogenesis. Sema4A plays an important role in the immune system by inducing T cell activation, but to date, the role of Sema4A in regulating the function of macrophages during the angiogenic and inflammatory processes remains unclear. In this study, we show that macrophage activation by TLR ligands LPS and polyinosinic-polycytidylic acid induced a time-dependent increase of Sema4A and its receptors PlexinB2 and PlexinD1. Moreover, in a thioglycollate-induced peritonitis mouse model, Sema4A was detected in circulating Ly6Chigh inflammatory monocytes and peritoneal macrophages. Acting via PlexinD1, exogenous Sema4A strongly increased macrophage migration. Of note, Sema4A-activated PlexinD1 enhanced the expression of vascular endothelial growth factor-A, but not of inflammatory chemokines. Sema4A-stimulated macrophages were able to activate vascular endothelial growth factor receptor-2 and the PI3K/serine/threonine kinase Akt pathway in endothelial cells and to sustain their migration and in vivo angiogenesis. Remarkably, in an in vivo cardiac ischemia/reperfusion mouse model, Sema4A was highly expressed in macrophages recruited at the injured area. We conclude that Sema4A activates a specialized and restricted genetic program in macrophages able to sustain angiogenesis and participates in their recruitment and activation in inflammatory injuries.

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Section: Discussionmentioning

confidence: 52%

mentioning

confidence: 99%

Semaphorin 4A Exerts a Proangiogenic Effect by Enhancing Vascular Endothelial Growth Factor-A Expression in Macrophages

Meda

Molla

Pizzol

et al. 2012

The Journal of Immunology

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“…*p , 0.05, **p , 0.01, ***p , 0.001. activities of SEMA4A. The binding of SEMA4A to plexin Bs in growth cones of hippocampal neurons induces growth cone collapse (36). SEMA4A associates with TIM2 and is involved in CD4 + T cell activation and differentiation in the immune system (25).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, via plexin D1, SEMA4A inhibits endothelial cell migration and in vivo angiogenesis by suppressing vascular endothelial growth factor-mediated activation of Rac and integrin-dependent cell adhesion (17). In the presence of the Rho family GTPase Rnd1, the binding of SEMA4A to plexin Bs induces cellular contraction through enzymatic activity of R-Ras, a GTPase-activating protein (35,36).…”

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confidence: 99%

mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells

Ito

Nojima

Nishide

et al. 2015

The Journal of Immunology

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Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of mTOR-mediated signals in CD4+ T cell responses, the involvement of mTOR in CD8+ T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8+ T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A−/− CD8+ T cells exhibited impairments in production of IFN-γ and TNF-α and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen-specific effector CD8+ T cell responses were significantly impaired in SEMA4A−/− mice. Furthermore, SEMA4A−/− CD8+ T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8+ T cells. IFN-γ production and mTORC1 activity in SEMA4A−/− CD8+ T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8+ T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8+ T cells, but also reveal a novel link between a semaphorin and mTOR signaling.

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“…23 However, it was also found to produce an opposite effect and enhance angiogenesis by enhancing VEGF expression. 109 Unlike sema3E, sema4A also utilizes type-B plexins, 246,247 neuropilin-1 248 and Tim-2 83 as signal transducing receptors. Sema4A is a well characterized modulator of immune responses 229 and may also affect tumor progression via the immune system.…”

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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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Sema4A induces cell morphological changes through B-type plexin-mediated signaling

Cited by 33 publications

References 23 publications

Semaphorin 4A Exerts a Proangiogenic Effect by Enhancing Vascular Endothelial Growth Factor-A Expression in Macrophages

Semaphorin 4A Exerts a Proangiogenic Effect by Enhancing Vascular Endothelial Growth Factor-A Expression in Macrophages

mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells

The role of the semaphorins in cancer

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