Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival

Toyofuku, Toshihiko; Nojima, Satoshi; Ishikawa, Takako; Takamatsu, Hyota; Tsujimura, Tohru; Matsuda, Junko; Seki, Takaharu; Kumanogoh, Atsushi

doi:10.1101/gad.184481.111

Cited by 39 publications

(39 citation statements)

References 52 publications

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“…1). Some membrane anchored semaphorins may themselves be able to function as signal transducing proteins [6][7][8][9] although more proof for that may still be required. The active forms of several class-3 and class-6 semaphorins are homodimers, 5,[10][11][12] suggesting that all active semaphorins are homodimeric.…”

Section: The Semaphorin Familymentioning

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: The Semaphorin Familymentioning

confidence: 99%

The role of the semaphorins in cancer

Neufeld

Mumblat

Smolkin

et al. 2016

Cell Adhesion & Migration

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“…Similarly, total levels of prosaposin mRNA and protein are increased following nerve injury in motoneurons, beginning on the third day following injury and continuing to change until post-injury day 21 (Chen et al, 2008; Unuma et al, 2005). Furthermore, prosaposin expression and release are greatly upregulated in animal models of focal cerebral ischemia (Costain et al, 2010; Hiraiwa et al, 2003; Yokota et al, 2001), and prosaposin release from the retinal pigment epithelial cells in the eye can be elevated by cell stress induced by either light or hydrogen peroxide (Toyofuku et al, 2012). …”

Section: Prosaposin Releasementioning

confidence: 99%

The protective role of prosaposin and its receptors in the nervous system

et al. 2014

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Prosaposin (also known as SGP-1) is an intriguing multifunctional protein that plays roles both intracellularly, as a regulator of lysosomal enzyme function, and extracellularly, as a secreted factor with neuroprotective and glioprotective effects. Following secretion, prosaposin can undergo endocytosis via an interaction with the low-density lipoprotein-related receptor 1 (LRP1). The ability of secreted prosaposin to promote protective effects in the nervous system is known to involve activation of G proteins, and the orphan G protein-coupled receptors GPR37 and GPR37L1 have recently been shown to mediate signaling induced by both prosaposin and a fragment of prosaposin known as prosaptide. In this review, we describe recent advances in our understanding of prosaposin, its receptors and their importance in the nervous system.

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“…S1, http://www.iovs.org/ lookup/suppl/doi:10.1167/iovs.11-9378/-/DCSupplemental) suggest that SEMA4A mutants may cause the loss of function by their accumulation in ER, which leads to the susceptibility to ER stress in vivo. Knockout of SEMA4A leads to protein accumulation in ER of ARPE-19 cells, 25 therefore, SEMA4A may be important in maintaining the ER environment. Although SEMA4A mutants could exert the abnormality in tunicamycintreated condition (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…4B, 5), endogenous SEMA4A may counteract the abnormal function of SEMA4A mutants. SEMA4A responds to oxidative stress in retina 25 ; therefore, SEMA4A mutants may also lead to the susceptibility to oxidative stress in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, SEMA4A has been reported to bind prosaponin and rab11/FIP2, which are associated with endosomal sorting between the cell surface and endoplasmic reticulum and important in oxidative stress. 25 These interacting proteins may be associated with vulnerabilities to light, ER, and oxidative stress. Although the observed effect on cell dysfunction could be due to a general effect of SEMA4A accumulation in the ER, other factor(s) such as melanin (which is synthesized in the RPE and important to reduce light-induced toxicity) and its synthase (also found in the ER) may be involved in converting light stress to ER stress, and may be altered by the F350C mutation.…”

Section: Discussionmentioning

confidence: 99%

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SEMA4A Mutations Lead to Susceptibility to Light Irradiation, Oxidative Stress, and ER Stress in Retinal Pigment Epithelial Cells

Tsuruma

Nishimura

Kishi

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. RP is a retinal degeneration disorder that is caused by mutations of various genes, including semaphorin-4A (SEM-A4A). A number of retinal diseases, including RP, are associated with light exposure, oxidative stress, and endoplasmic reticulum (ER) stress. In this study, we investigated whether mutant SEMA4A causes retinal dysfunction via light exposure, oxidative stress, and ER stress.METHODS. Mutant SEMA4A (D345H or F350C) was overexpressed in a human retinal epithelium cell line ARPE19. Intracellular localization of mutant SEMA4A was investigated using confocal laser scanning microscopy. The ARPE-19 cells were also irradiated with white light, and expression of 78 kDa glucose-regulated protein (GRP78), a marker of ER stress, and phagocytosis were measured. The cells were treated with an ER stress inducer, tunicamycin, or an oxidative stressor, H 2 O 2 , and cell death was measured. Human SEMA4A mutants were expressed in zebrafish embryos with tunicamycin and mRNA of DNA damage-inducible transcript 3 (ddit3) was measured as an ER stress marker.RESULTS. Mutant SEMA4A was localized in the ER, whereas wild type (WT) SEMA4A was observed in cell membranes. The expression of GRP78 was increased by mutant SEMA4A following light irradiation, and phagocytosis was suppressed in mutant SEMA4A-transfected cells. Mutant SEMA4A induced susceptibility to ER stress and oxidative stress. In zebrafish, human mutant SEMA4A increased ddit3 mRNA compared with WT under the ER stress condition. CONCLUSIONS.Our results suggest that mutations in SEMA4A may cause susceptibility to light exposure, oxidative stress, and ER stress, which may be involved in the progression and pathology of RP. (Invest Ophthalmol Vis Sci. 2012;53:6729-6737)

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Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival

Cited by 39 publications

References 52 publications

The role of the semaphorins in cancer

The role of the semaphorins in cancer

The protective role of prosaposin and its receptors in the nervous system

SEMA4A Mutations Lead to Susceptibility to Light Irradiation, Oxidative Stress, and ER Stress in Retinal Pigment Epithelial Cells

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