Dissecting the CD93-Multimerin 2 interaction involved in cell adhesion and migration of the activated endothelium

Galvagni, Federico; Nardi, Federica; Spiga, Ottavia; Trezza, Alfonso; Tarticchio, Giulia; Pellicani, Rosanna; Andreuzzi, Eva; Caldi, Elena; Toti, Paolo; Tosi, Gian Marco; Santucci, Annalisa; Iozzo, Renato V.; Mongiat, Maurizio; Orlandini, Maurizio

doi:10.1016/j.matbio.2017.08.003

Cited by 59 publications

(82 citation statements)

References 51 publications

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“…Rather, all known ligands are proteins-thrombomodulin binds thrombin [36], while multimerin-2 is a ligand for CLEC14A, CD248, and CD93 [37]. The CD93-multimerin-2 interaction has been characterized in depth, with CD93 binding a coiled-coiled domain in multimerin-2 via its CTLD [38]. Consistent with this, apoptotic cell binding by CD93 was dependent on the CTLD domain, but was not correlated with the presence of phosphatidylserine, suggesting that CD93 recognizes a potentially proteinaceous "eat me" signal.…”

Section: Discussionmentioning

confidence: 99%

Soluble CD93 is an apoptotic cell opsonin recognized by α_xβ₂

et al. 2019

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Efferocytosis is essential for homeostasis and prevention of the inflammatory and autoimmune diseases resulting from apoptotic cell lysis. CD93 is a transmembrane glycoprotein previously implicated in efferocytosis, with mutations in CD93 predisposing patients to efferocytosis‐associated diseases. CD93 is a cell surface protein, which is proteolytically shed under inflammatory conditions, but it is unknown how CD93 mediates efferocytosis or whether its efferocytic activity is mediated by the soluble or membrane‐bound form. Herein, using cell lines and human monocytes and macrophages, we demonstrate that soluble CD93 (sCD93) potently opsonizes apoptotic cells but not a broad range of microorganisms, whereas membrane‐bound CD93 has no phagocytic, efferocytic, or tethering activity. Using mass spectrometry, we identified αxβ2 as the receptor that recognizes sCD93, and via deletion mutagenesis determined that sCD93 binds to apoptotic cells via its C‐type lectin‐like domain and to αxβ2 by its EGF‐like repeats. The bridging of apoptotic cells to αxβ2 markedly enhanced efferocytosis by macrophages and was abrogated by αxβ2 knockdown. Combined, these data elucidate the mechanism by which CD93 regulates efferocytosis and identifies a previously unreported opsonin‐receptor system utilized by phagocytes for the efferocytic clearance of apoptotic cells.

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Section: Discussionmentioning

confidence: 99%

Soluble CD93 is an apoptotic cell opsonin recognized by α_xβ₂

et al. 2019

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“…Further, we found proteins such as Nidogen 1 (NID1), Cadherin 2 (CDH2) and Multimerin 2 (MMRN-2) to be downregulated in serum samples. These proteins play important roles in cell adhesion and growth (Galvagni et al, 2017, Maitre and Heisenberg et al, 2013, Miosge et al, 2001. NID1 is a basement membrane glycoprotein which interacts with other components of basement membranes and plays a role in cell interactions with the extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

Proteome-wide characterization and biomarker identification of intracranial aneurysm

Sharma

Datta

Kumar

et al. 2019

Preprint

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The scientific basis of intracranial aneurysm (IA) formation, its rupture and further development of cerebral vasospasm remains incompletely understood. Deciphering the molecular mechanisms underlying these events will lead to identification of early detection biomarkers and in turn, improved treatment outcomes. Aberrant protein expression may drive structural alterations of vasculature found in IA. To unravel these aberrations, we performed untargeted, global, quantitative proteomic analysis of aneurysm tissue and serum from patients with IA. Samples were derived from patients of three clinical sub groups-1) unruptured aneurysm 2) ruptured aneurysm without vasospasm 3) ruptured aneurysm who developed vasospasm. A total of 937 and 294 proteins were identified in aneurysm tissue and serum samples respectively. Several proteins that are known to maintain the structural integrity of vasculature were found to be dysregulated. ORM1, a glycoprotein, was significantly upregulated in both the aneurysm tissue and serum samples of unruptured IA patients. We employed a larger cohort of patients and validated ORM1 as a potential biomarker for screening of unruptured aneurysm using ELISA. Samples from ruptured aneurysm with vasospasm showed significant upregulation of MMP9 as compared to ruptured aneurysm without vasospasm. Using a cohort of ruptured aneurysm patients with and without vasospasm, we validated MMP9 as a potential biomarker for vasospasm. This study reveals pathophysiology underlying different clinical sub groups of IA and also suggests potential biomarkers.

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“…Finally the authors showed that MMRN2 and fibronectin expressions are upregulated in high grade human glioma . Co‐localisation of CD93 and MMRN2 expressions has been demonstrated in vessels of a range of different solid human tumours including melanoma, Ewing's sarcoma, ovarian carcinoma and glioma amongst others . There are likely other partner proteins for CD93 as a study showed that the recombinant form of the CD93 ECD can engage the cell surface of THP‐1 cells indicating the expression of a currently unknown CD93 ligand in this monocyte cell line .…”

Section: Cd93 Interaction Partners and Biologymentioning

confidence: 95%

“…This offers a platform for developing innovative therapeutics that specifically target CD93 to interrupt this interaction. The CD93‐MMRN2 interaction was later independently validated and surface plasmon resonance was used to characterise the interaction and determine binding affinities . A key residue within the coiled‐coil domain of MMRN2 (F238) was proposed as being integral for CD93 binding.…”

Section: Cd93 Interaction Partners and Biologymentioning

confidence: 99%

C‐type lectin domain group 14 proteins in vascular biology, cancer and inflammation

et al. 2019

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The C‐type lectin domain (CTLD) group 14 family of transmembrane glycoproteins consist of thrombomodulin, CD93, CLEC14A and CD248 (endosialin or tumour endothelial marker‐1). These cell surface proteins exhibit similar ectodomain architecture and yet mediate a diverse range of cellular functions, including but not restricted to angiogenesis, inflammation and cell adhesion. Thrombomodulin, CD93 and CLEC14A can be expressed by endothelial cells, whereas CD248 is expressed by vasculature associated pericytes, activated fibroblasts and tumour cells among other cell types. In this article, we review the current literature of these family members including their expression profiles, interacting partners, as well as established and speculated functions. We focus primarily on their roles in the vasculature and inflammation as well as their contributions to tumour immunology. The CTLD group 14 family shares several characteristic features including their ability to be proteolytically cleaved and engagement of some shared extracellular matrix ligands. Each family member has strong links to tumour development and in particular CD93, CLEC14A and CD248 have been proposed as attractive candidate targets for cancer therapy.

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Dissecting the CD93-Multimerin 2 interaction involved in cell adhesion and migration of the activated endothelium

Cited by 59 publications

References 51 publications

Soluble CD93 is an apoptotic cell opsonin recognized by α_xβ₂

Soluble CD93 is an apoptotic cell opsonin recognized by α_xβ₂

Proteome-wide characterization and biomarker identification of intracranial aneurysm

C‐type lectin domain group 14 proteins in vascular biology, cancer and inflammation

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Dissecting the CD93-Multimerin 2 interaction involved in cell adhesion and migration of the activated endothelium

Cited by 59 publications

References 51 publications

Soluble CD93 is an apoptotic cell opsonin recognized by αxβ2

Soluble CD93 is an apoptotic cell opsonin recognized by αxβ2

Proteome-wide characterization and biomarker identification of intracranial aneurysm

C‐type lectin domain group 14 proteins in vascular biology, cancer and inflammation

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Product

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Soluble CD93 is an apoptotic cell opsonin recognized by α_xβ₂

Soluble CD93 is an apoptotic cell opsonin recognized by α_xβ₂