Semaphorin signaling: progress made and promises ahead

Zhou, Yun; Gunput, Rou-Afza F.; Pasterkamp, R. Jeroen

doi:10.1016/j.tibs.2008.01.006

Cited by 273 publications

(274 citation statements)

References 74 publications

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“…Therefore, there could be a shared mechanism between GBM dispersal and radial migration of cortical neurons. In other studies, the bifunctional nature of Sema3A in the nervous system has been attributed to the differential availability of intracellular signaling effectors, such as cyclic nucleotides (cGMP) (Zhou et al, 2008). It was shown that elevating intracellular cGMP levels could switch a neuronal Sema3A response from repulsive to attractive (Song et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

et al. 2009

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Glioblastoma multiforme (GBM) is the most malignant glioma type with diffuse borders due to extensive tumor cell infiltration. Therefore, understanding the mechanism of GBM cell dispersal is critical for developing effective therapies to limit infiltration. We identified neuropilin-1 as a mediator of cancer cell invasion by a functional proteomic screen and showed its role in GBM cells. Neuropilin-1 is a receptor for semaphorin3A (Sema3A), a secreted chemorepellent that facilitates axon guidance during neural development. Although neuropilin-1 expression in GBMs was previously shown, its role as a Sema3A receptor remained elusive. Using fluorophore-assisted light inactivation and RNA interference , we showed that neuropilin-1 is required for GBM cell migration. We also showed that GBM cells secrete Sema3A endogenously, and RNA interferencemediated downregulation of Sema3A inhibits migration and alters cell morphology that is dependent on Rac1 activity. Sema3A depletion also reduces dispersal, which is recovered by supplying Sema3A exogenously. Extracellular application of Sema3A decreases cell-substrate adhesion in a neuropilin-1-dependent manner. Using immunohistochemistry, we showed that Sema3A is overexpressed in a subset of human GBMs compared with the non-neoplastic brain. Together, these findings implicate Sema3A as an autocrine signal for neuropilin-1 to promote GBM dispersal by modulating substrate adhesion and suggest that targeting Sema3A-neuropilin-1 signaling may limit GBM infiltration.

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Section: Discussionmentioning

confidence: 99%

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

et al. 2009

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“…In the nervous system, semaphorin-plexin signaling has been shown to mediate diverse neural functions by regulating GTPase activities and cytoplasmic/receptor-type protein kinases. 11,31,32 These plexin-mediated signals are involved in integrin-mediated attachment, 15,33,34 actomyosin contraction [35][36][37][38] and microtubule destabilization. [39][40][41] In addition, plexins can associate with different coreceptors in distinct tissues to allow semaphorins to exert pleiotropic functions.…”

Section: Semaphorins and Their Receptorsmentioning

confidence: 99%

“…29,46,47 Plexin-B1 and CD72 were identified as the Sema4D receptors in the nervous and immune systems. 11,48 CD72 negatively regulates B cells by recruiting the tyrosine phosphatase Src homology phosphatase-1 (SHP1) to its immunoreceptor tyrosine-based inhibitory motifs (ITIM). 49,50 Ligation of Sema4D to CD72 causes SHP1 to dissociate from CD72, resulting in B-cell and DC activation.…”

Section: Semaphorins and Their Receptorsmentioning

confidence: 99%

“…They were initially identified as repulsive axon guidance molecules that were required to direct neuronal axons to their appropriate targets. 9 More than 20 types of semaphorins have been identified, 10 and they have diverse functions in many physiological process, 11 including cardiogenesis, 12,13 angiogenesis, 14,15 vasculogenesis, 16 tumor metastasis, [17][18][19] osteoclastogenesis 20 and immune regulation. 21,22 In this review, we focus on two functional aspects of semaphorins, their roles in immune cell-cell interactions and immune cell trafficking.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of immune cell responses by semaphorins and their receptors

2010

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Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several members of semaphorins, so-called 'immune semaphorins', are crucially involved in various phases of immune responses. These semaphorins regulate both immune cell interactions and immune cell trafficking during physiological and pathological immune responses. Here, we review the following two functional aspects of semaphorins and their receptors in immune responses: their functions in cell-cell interactions and their involvement in immune cell trafficking.

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“…Although semaphorins were initially identified as axonal guidance cues during neuronal development (9,10), accumulating evidence now indicates that several semaphorins play a crucial role in physiologic and pathologic immune responses (11). The expression of Sema4D is abundantly observed in T cells, but only weakly detected in naive B cells, macrophages, and dendritic cells (DCs); however, its expression is significantly upregulated on cellular activation (12,13).…”

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confidence: 99%

Roles of Sema4D–Plexin-B1 Interactions in the Central Nervous System for Pathogenesis of Experimental Autoimmune Encephalomyelitis

Okuno

Nakatsuji

Moriya

et al. 2009

The Journal of Immunology

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Although semaphorins were originally identified as axonal guidance molecules during neuronal development, it is emerging that several semaphorins play crucial roles in various phases of immune responses. Sema4D/CD100, a class IV semaphorin, has been shown to be involved in the nervous and immune systems through its receptors plexin-B1 and CD72, respectively. However, the involvement of Sema4D in neuroinflammation still remains unclear. We found that Sema4D promoted inducible NO synthase expression by primary mouse microglia, the effects of which were abolished in plexin-B1–deficient but not in CD72-deficient microglia. In addition, during the development of experimental autoimmune encephalomyelitis (EAE), which was induced by immunization with myelin oligodendrocyte glycoprotein-derived peptides, we observed that the expression of Sema4D and plexin-B1 was induced in infiltrating mononuclear cells and microglia, respectively. Consistent with these expression profiles, when myelin oligodendrocyte glycoprotein-specific T cells derived from wild-type mice were adoptively transferred into plexin-B1–deficient mice or bone marrow chimera mice with plexin-B1–deficient CNS resident cells, the development of EAE was considerably attenuated. Furthermore, blocking Abs against Sema4D significantly inhibited neuroinflammation during EAE development. Collectively, our findings demonstrate the role of Sema4D–plexin-B1 interactions in the activation of microglia and provide their pathologic significance in neuroinflammation.

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Semaphorin signaling: progress made and promises ahead

Cited by 273 publications

References 74 publications

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

Regulation of immune cell responses by semaphorins and their receptors

Roles of Sema4D–Plexin-B1 Interactions in the Central Nervous System for Pathogenesis of Experimental Autoimmune Encephalomyelitis

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