Molecular and Cellular Properties of the Rat AA4 Antigen, a C-type Lectin-like Receptor with Structural Homology to Thrombomodulin

Dean, Yann; McGreal, Eamon Patrick; Akatsu, Hiroyasu; Gasque, Philippe

doi:10.1074/jbc.m006229200

Cited by 42 publications

(54 citation statements)

References 45 publications

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“…2/2 mice of both genders have an increased infarct volume when compared with WT-mice at 72 h after induction of transient focal cerebral ischemia BecauseoftheinvolvementascribedtoCD93inphagocytoticprocesses and angiogenesis, we analyzed infarct volumes in a second experimental stroke model, which does not cause infarction (i.e., pannecrosis) but rather selective neuronal cell death with a profound neuroinflammatory response (36,37). In contrast to the findings after 60 min MCAO (Fig.…”

Section: Cd93mentioning

confidence: 79%

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CD93/AA4.1: A Novel Regulator of Inflammation in Murine Focal Cerebral Ischemia

Harhausen¹,

Prinz²,

Ziegler

et al. 2010

The Journal of Immunology

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International audienceThe stem-cell marker CD93 (AA4.1/C1qRp) has been described as a potential complement C1q-receptor. Its exact molecular function, however, remains unknown. By using global expression profiling we showed that CD93-mRNA is highly induced after transient focal cerebral ischemia. CD93 protein is upregulated in endothelial cells, but also in selected macrophages and microglia. To elucidate the potential functional role of CD93 in postischemic brain damage, we used mice with a targeted deletion of the CD93 gene. After 30 min of occlusion of the middle cerebral artery and 3 d of reperfusion these mice displayed increased leukocyte infiltration into the brain, increased edema, and significantly larger infarct volumes (60.8 ± 52.2 versus 23.9 ± 16.6 mm3) when compared with wild-type (WT) mice. When the MCA was occluded for 60 min, after 2 d of reperfusion the CD93 knockout mice still showed more leukocytes in the brain, but the infarct volumes were not different from those seen in WT animals. To further explore CD93-dependent signaling pathways, we determined global transcription profiles and compared CD93-deficient and WT mice at various time points after induction of focal cerebral ischemia. We found a highly significant upregulation of the chemokine CCL21/Exodus-2 in untreated and treated CD93-deficient mice at all time points. Induction of CCL21 mRNA and protein was confirmed by PCR and immunohistochemistry. CCL21, which was formerly shown to be released by damaged neurons and to activate microglia, contributes to neurodegeneration. Thus, we speculate that CD93-neuroprotection is mediated via suppression of the neuroinflammatory response through downregulation of CCL21

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Section: Cd93mentioning

confidence: 79%

“…The molecular structure of CD93 is reminiscent of thrombomodulin, a receptor for thrombin that is recognized as a major natural anticoagulant mainly expressed on endothelial cells and platelets (31,36). CD93 and thrombomodulin seem to be derived from a common ancestor (31).…”

Section: Discussionmentioning

confidence: 99%

CD93/AA4.1: A Novel Regulator of Inflammation in Murine Focal Cerebral Ischemia

Harhausen¹,

Prinz²,

Ziegler

et al. 2010

The Journal of Immunology

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“…In this context, the NH 2 -terminal lectin-like domain of thrombomodulin is structurally similar to human phagocytic C1q receptor, which acts as an adhesion molecule for innate immune host defense. The evidence is also suggesting that the lectin-like domain of thrombomodulin may have an important role for cell-cell interaction (37,38). Thus, we strongly put forth the hypothesis that thrombomodulin may be an essential antimetastatic factor in ␤-cell tumors, acting as a counter-ligand or associate molecule for neural cell adhesion molecule.…”

Section: Discussionmentioning

confidence: 99%

The Antimetastatic Role of Thrombomodulin Expression in Islet Cell-Derived Tumors and Its Diagnostic Value

Iino¹,

Abeyama²,

Kikuchi³

et al. 2004

Clinical Cancer Research

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Islet cell tumors, endocrine neoplasm arising from pancreatic islets of Langerhans, are histologically difficult to diagnose as benign or malignant. Molecular markers are associated with the clinical characteristics that most of insulinoma are usually benign tumors, whereas other islet cell tumors are malignant but have not been identified. In this context, we newly found that an endothelial anticoagulant thrombomodulin was expressed in the normal islet ␤ cells and insulinoma, but not of other islet components or noninsulinoma islet cell tumors. Clinically, all of the subjects (n ‫؍‬ 15) of the insulinoma group showed no metastasis together with thrombomodulin expression in the lesions, whereas the other islet cell tumor groups showed a high incidence of metastasis (82%) and a low expression rate of thrombomodulin (6%). To examine the functional role of thrombomodulin, especially regarding the clinical characteristics of islet cell tumors, we tested the effect of exogenous thrombomodulin overexpression on cell adhesiveness and proliferation using MIN6 insulinoma cell line. In cell-based experiments, thrombomodulin overexpression reduced cell proliferation and enhanced Ca 2؉ -independent cell aggregation, possibly through direct interaction with neural cell adhesion molecule. Taken together, these results are suggesting that thrombomodulin may act as antimetastatic molecule of insulinomas. In addition, thrombomodulin is a clinically useful molecular marker not only for identifying ␤-cell-origin islet cell tumors (i.e., insulinomas) but also for predicting disease prognosis of islet cell tumors.

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“…Western blotting analysis revealed CD93 to be a 126-kDa protein in reducing conditions and a 90 to 100-kDa protein in non-reducing conditions (13,30,38). Glycosylation studies showed human CD93 to be a heavily O-glycosylated type I transmembrane protein consisting of unique C-type lectin domains displaying a 68% homology to rat or mouse AA4 antigen (6,7).…”

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confidence: 99%

Regulation of CD93 Cell Surface Expression by Protein Kinase C Isoenzymes

Ikewaki

Kulski

Inoko

2006

Microbiology and Immunology

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Human CD93, also known as complement protein 1, q subcomponent, receptor (C1qRp), is selectively expressed by cells with a myeloid lineage, endothelial cells, platelets, and microglia and was originally reported to be involved in the complement protein 1, q subcomponent (C1q)‐mediated enhancement of phagocytosis. The intracellular molecular events responsible for the regulation of its expression on the cell surface, however, have not been determined. In this study, the effect of protein kinases in the regulation of CD93 expression on the cell surface of a human monocyte‐like cell line (U937), a human NK‐like cell line (KHYG‐1), and a human umbilical vein endothelial cell line (HUV‐EC‐C) was investigated using four types of protein kinase inhibitors, the classical protein kinase C (cPKC) inhibitor Go6976, the novel PKC (nPKC) inhibitor Rottlerin, the protein kinase A (PKA) inhibitor H‐89 and the protein tyrosine kinase (PTK) inhibitor herbimycin A at their optimum concentrations for 24 hr. CD93 expression was analyzed using flow cytometry and glutaraldehyde‐fixed cellular enzyme‐linked immunoassay (EIA) techniques utilizing a CD93 monoclonal antibody (mAb), mNI‐11, that was originally established in our laboratory as a CD93 detection probe. The nPKC inhibitor Rottlerin strongly down‐regulated CD93 expression on the U937 cells in a dose‐dependent manner, whereas the other inhibitors had little or no effect. CD93 expression was down‐regulated by Go6976, but not by Rottlerin, in the KHYG‐1 cells and by both Rottlerin and Go6976 in the HUV‐EC‐C cells. The PKC stimulator, phorbol myristate acetate (PMA), strongly up‐regulated CD93 expression on the cell surface of all three cell‐lines and induced interleukin‐8 (IL‐8) production by the U937 cells and interferon‐γ (IFN‐γ) production by the KHYG‐1 cells. In addition, both Go6976 and Rottlerin inhibited the up‐regulation of CD93 expression induced by PMA and IL‐8 or IFN‐γ production in the respective cell‐lines. Whereas recombinant tumor necrosis factor‐α (rTNF‐α) slightly up‐regulated CD93 expression on the U937 cells, recombinant interleukin‐1β (rIL‐1β), recombinant interleukin‐2 (rIL‐2), recombinant interferon‐γ (rIFN‐γ) and lipopolysaccharide (LPS) had no effect. Taken together, these findings indicate that the regulation of CD93 expression on these cells involves the PKC isoenzymes.

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Molecular and Cellular Properties of the Rat AA4 Antigen, a C-type Lectin-like Receptor with Structural Homology to Thrombomodulin

Cited by 42 publications

References 45 publications

CD93/AA4.1: A Novel Regulator of Inflammation in Murine Focal Cerebral Ischemia

CD93/AA4.1: A Novel Regulator of Inflammation in Murine Focal Cerebral Ischemia

The Antimetastatic Role of Thrombomodulin Expression in Islet Cell-Derived Tumors and Its Diagnostic Value

Regulation of CD93 Cell Surface Expression by Protein Kinase C Isoenzymes

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