Identification of an S100A8 Receptor Neuroplastin-β and its Heterodimer Formation with EMMPRIN

Sakaguchi, Masakiyo; Yamamoto, Mami; Miyai, Masahiro; Maeda, Takeyasu; Hiruma, Junichiro; Murata, Hitoshi; Kinoshita, Rie; Ruma, I Made Winarsa; Putranto, Endy Widya; Inoue, Yusuke; Morizane, Shin; Huh, Nam; Tsuboi, Ryoji; Hibino, Toshihiko

doi:10.1016/j.jid.2016.06.617

Cited by 51 publications

(51 citation statements)

References 35 publications

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“…Besides classical S100A8/A9 receptors, toll-like receptor 4 (TLR4) 4,5 and receptor for advanced glycation end products (RAGE), 5,6 we have reported the presence of the important novel receptors including extracellular matrix metalloproteinase inducer (EMMPRIN), neuroplastin (NPTN)α and β, melanoma cell adhesion molecule (MCAM) and activated leukocyte cell adhesion molecule (ALCAM). [7][8][9][10][11][12] Among these receptors, we found that lung cancer cell lines highly express NPTNβ compared with normal cells lines ( Figure S1A). This finding was supported by the result of immunohistochemistry showing that NPTNβ was highly positive in lung cancer cells and that S100A8/A9 appeared in either cancer cells or the surrounding stroma in clinical specimens, suggesting that extracellular S100A8/A9 physiologically acts on cell surface NPTNβ in cancer cells in an autocrine manner as well as a paracrine manner ( Figure 1).…”

Section: Nptn and S100a8/a9 Are Highly Expressed In Lung Cancermentioning

confidence: 99%

Neuroplastin‐β mediates S100A8/A9‐induced lung cancer disseminative progression

Sumardika

Chen

Tomonobu

et al. 2019

Molecular Carcinogenesis

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Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin‐β (NPTNβ), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNβ showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNβ as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNβ has strong ability to induce cancer‐related cellular events, including anchorage‐independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNβ mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage‐independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9‐NPTNβ axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS‐NFIA/NFIB‐SPDEF, in linking to the aggressive development of lung cancers.

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Section: Nptn and S100a8/a9 Are Highly Expressed In Lung Cancermentioning

confidence: 99%

Neuroplastin‐β mediates S100A8/A9‐induced lung cancer disseminative progression

Sumardika

Chen

Tomonobu

et al. 2019

Molecular Carcinogenesis

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“…1 After publication of the report by Hiratsuka et al, the RAGE was also included as a soil sensor for S100A8/A9. 2 We then found further evidence of other important novel soil sensors for S100A8/A9: EMMPRIN, 3 NPTNβ, 4 MCAM and ALCAM. 5,6 We named the proteins "S100 soil sensor receptors, abbreviated as SSSRs."…”

Section: Introductionmentioning

confidence: 65%

“…After publication of the report by Hiratsuka et al ., the RAGE was also included as a soil sensor for S100A8/A9 . We then found further evidence of other important novel soil sensors for S100A8/A9: EMMPRIN, NPTNβ, MCAM and ALCAM . We named the proteins “S100 soil sensor receptors, abbreviated as SSSRs.” The relationship between S100A8/A9 and these receptors may be applicable to broad cancer species since S100A8/A9 is also utilized by breast cancer cells for lung tropic metastasis .…”

Section: Introductionmentioning

confidence: 87%

“…To initiate a project to investigate this possibility, we first developed an original plasmid vector that facilitates transgene expression in CHO cells with significantly higher levels in a stable manner. By using this plasmid vector, a marked increase in the production of exNPTNβ‐Fc was consistently obtained . The plasmid vector, which we named pSAKA‐1B, produced large amounts of all exSSSRs‐Fc chimera proteins (exRAGE‐Fc, exMCAM‐Fc, exALCAM‐Fc, exEMMPRIN‐Fc and exNPTNβ‐Fc) from each established CHO‐stable clone.…”

Section: Introductionmentioning

confidence: 99%

“…By using this plasmid vector, a marked increase in the production of exNPTNβ-Fc was consistently obtained. 4 The plasmid vector, which we named pSAKA-1B, produced large amounts of all exSSSRs-Fc chimera proteins (exRAGE-Fc, exMCAM-Fc, exALCAM-Fc, exEMMPRIN-Fc and exNPTNβ-Fc) from each established CHO-stable clone. The aim of our study was to determine the suppressive effects of the purified decoy proteins on S100A8/A9-mediated lung tropic cancer metastasis.…”

Section: Introductionmentioning

confidence: 99%

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exSSSRs (extracellular S100 soil sensor receptors)‐Fc fusion proteins work as prominent decoys to S100A8/A9‐induced lung tropic cancer metastasis

Kinoshita

Sato

Yamauchi

et al. 2018

Intl Journal of Cancer

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Within the “seed and soil” theory of organ tropic cancer metastasis is a growing compilation of evidence that S100A8/A9 functions as a soil signal that attracts cancer cells to certain organs, which prove beneficial to their growth. S100A8/A9‐sensing receptors including Toll‐like receptor 4 (TLR4), advanced glycation end products (RAGE), and also important receptors we recently succeeded in identifying (EMMPRIN, NPTNβ, MCAM, and ALCAM) have the potential to become promising therapeutic targets. In our study, we prepared extracellular regions of these novel molecules and fused them to human IgG2‐Fc to extend half‐life expectancy, and we evaluated the anti‐metastatic effects of the purified decoy proteins on metastatic cancer cells. The purified proteins markedly suppressed S100A8/A9‐mediated lung tropic cancer metastasis. We hence expect that our novel biologics may become a prominent medicine to prevent cancer metastasis in clinical settings through cutting the linkage between “seed and soil”.

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Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes

et al. 2022

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Mechanisms keeping leukocytes distant of local inflammatory processes in a resting state despite systemic release of inflammatory triggers are a pivotal requirement for avoidance of overwhelming inflammation but are ill defined. Dimers of the alarmin S100A8/S100A9 activate Toll‐like receptor‐4 (TLR4) but extracellular calcium concentrations induce S100A8/S100A9‐tetramers preventing TLR4‐binding and limiting their inflammatory activity. So far, only antimicrobial functions of released S100A8/S100A9‐tetramers (calprotectin) are described. It is demonstrated that extracellular S100A8/S100A9 tetramers significantly dampen monocyte dynamics as adhesion, migration, and traction force generation in vitro and immigration of monocytes in a cutaneous granuloma model and inflammatory activity in a model of irritant contact dermatitis in vivo. Interestingly, these effects are not mediated by the well‐known binding of S100A8/S100A9‐dimers to TLR‐4 but specifically mediated by S100A8/S100A9‐tetramer interaction with CD69. Thus, the quaternary structure of these S100‐proteins determines distinct and even antagonistic effects mediated by different receptors. As S100A8/S100A9 are released primarily as dimers and subsequently associate to tetramers in the high extracellular calcium milieu, the same molecules promote inflammation locally (S100‐dimer/TLR4) but simultaneously protect the wider environment from overwhelming inflammation (S100‐tetramer/CD69).

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Identification of an S100A8 Receptor Neuroplastin-β and its Heterodimer Formation with EMMPRIN

Cited by 51 publications

References 35 publications

Neuroplastin‐β mediates S100A8/A9‐induced lung cancer disseminative progression

Neuroplastin‐β mediates S100A8/A9‐induced lung cancer disseminative progression

exSSSRs (extracellular S100 soil sensor receptors)‐Fc fusion proteins work as prominent decoys to S100A8/A9‐induced lung tropic cancer metastasis

Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes

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