PECAM-1 functions as a specific and potent inhibitor of mitochondrial-dependent apoptosis

Abstract Programmed cell death, or apoptosis, is a tightly regulated, naturally occurring process by which damaged or unwanted cells are removed. Dysregulated apoptosis has been implicated in a variety of pathophysiological conditions, including degenerative diseases, tissue remodeling, and tumorogenesis. The decision to live or die results from integration of numerous environmental signals transmitted by specific classes of cell surface receptors that bind hormones, growth factors, or components of the extracellular matrix. Here we show that platelet endothelial cell adhesion molecule-1 (PECAM-1), a homophilic-binding member of the immunoreceptor tyrosine-based inhibitory motif (ITIM) family of inhibitory receptors, functions prominently to inhibit apoptosis in naturally occurring vascular cells subjected to apoptotic stimuli. Murine endothelial cells and human T lymphocytes lacking PECAM-1 were found to be far more sensitive than their PECAM-1—expressing counterparts to multiple death signals that stimulate Bax, a multidomain, proapoptotic member of the Bcl-2 family that plays a central role in mitochondrial dysfunction-dependent apoptosis. In addition, PECAM-1 markedly suppressed Bax overexpression—induced cytochrome c release, caspase activation, and nuclear fragmentation. Amino acid substitutions within PECAM-1's extracellular homophilic binding domain, or within its cytoplasmic ITIM, completely abolished PECAM-1—mediated cytoprotection. Taken together, these data implicate PECAM-1 as a novel and potent suppressor of Bax-mediated apoptosis and suggest that members of the immunoglobulin gene (Ig) superfamily, like cell surface integrins, may also transmit survival signals into blood and vascular cells. (Blood. 2003;102:169-179)

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PECAM-1 Leu125Val (rs688) Polymorphism and Diabetic Nephropathy in Caucasians with Type 2 Diabetes Mellitus

Analytical Cellular Pathology ◽

10.1155/2016/3152967 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Matej Završnik ◽

Stojan Kariž ◽

Jana Makuc ◽

Maja Šeruga ◽

Ines Cilenšek ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Diabetic Nephropathy ◽

Homophilic Binding ◽

Platelet Endothelial Cell Adhesion ◽

Endothelial Integrity ◽

Design And Methods ◽

Cell Adhesion Molecule 1

Objectives. Platelet endothelial cell adhesion molecule-1 (PECAM-1) plays a key role in the transendothelial migration of circulating leukocytes during inflammation and in the maintenance of vascular endothelial integrity. We hypothesized that genetic variation inPECAM-1gene could be associated with diabetic nephropathy (DN) and with the level of soluble PECAM-1 in Caucasians with type 2 diabetes mellitus (T2DM).Design and Methods. We analyzed the rs688 single nucleotide polymorphism ofPECAM-1gene C373G (Leu125Val) at exon 3, which encodes the first extracellular Ig-like domain that mediates the homophilic binding of PECAM-1, in 276 T2DM subjects with documented DN (cases) and 375 T2DM subjects without DN (controls), using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy. Level of plasma soluble PECAM-1 (sPECAM-1) was measured by ELISA in a subpopulation of 120 diabetics with DN.Results. We found no association between the Leu125Val polymorphism and DN in subjects with T2DM. Likewise, the Leu125Val polymorphism was not associated with serum sPECAM-1 levels in a subpopulation of 120 diabetics with DN.Conclusion. The Leu125Val polymorphism of PECAM-1 and the level of sPECAM-1 are not associated with DN in T2DM subjects of Slovenian origin.

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Platelet/endothelial cell adhesion molecule-1 (CD31)-mediated cellular aggregation involves cell surface glycosaminoglycans

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)82354-7 ◽

1993 ◽

Vol 268 (21) ◽

pp. 16037-16046

Author(s):

H.M. DeLisser ◽

H.C. Yan ◽

P.J. Newman ◽

W.A. Muller ◽

C.A. Buck ◽

...

Keyword(s):

Cell Adhesion ◽

Endothelial Cell ◽

Cell Surface ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Endothelial Cell Adhesion Molecule ◽

Platelet Endothelial Cell Adhesion ◽

Cellular Aggregation ◽

Cell Adhesion Molecule 1 ◽

Endothelial Cell Adhesion

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Regulation of Leukocyte-Endothelium Interaction by Fibrinogen

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615911 ◽

1999 ◽

Vol 82 (08) ◽

pp. 781-786 ◽

Cited By ~ 23

Author(s):

Dario Altieri

Keyword(s):

Mononuclear Cells ◽

Inflammatory Responses ◽

Vascular Diseases ◽

Cell Types ◽

Immunoglobulin Gene ◽

Vascular Cells ◽

Environmental Signals ◽

Molecular Events ◽

Alternate Mechanism ◽

Adhesive Interactions

IntroductionThe binding of neutrophils and mononuclear cells to vascular endothelium is an essential prerequisite in maintaining effective immune-inflammatory responses. This process has been unraveled as a regulated “adhesion cascade” that involves the expression of multiple adhesion receptors of the integrin, selectin, and immunoglobulin gene superfamilies on both cell types. These adhesive interactions are modulated by disparate environmental signals, ranging from inflammatory and chemotactic cytokines to changes in shear force at the vessel wall. Although of paramount importance in the preservation of immune-inflammatory surveillance, dysregulation of leukocyte-endothelium interaction also constitutes one of the earliest molecular events in the pathogenesis of such vascular diseases as atherosclerosis. This dysregulation leads to the aberrant accumulation of mononuclear cells in the damaged intima.Recently, the interaction of fibrinogen with vascular cells has emerged as an alternate mechanism for recruiting leukocytes at the site of vascular injury. Although the role of fibrinogen as a risk factor for atherosclerosis has long been recognized, this pathway has been associated with complex mechanisms of intercellular adhesion, signal transduction, second-messenger generation, and modulation of gene expression in vascular cells. These studies have revealed a multifaceted and far-reaching molecular link between inflammation and hemostasis–a link that is of potential therapeutic relevance for the pathogenesis of vascular diseases.

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Expression cloning of a human Fc receptor for IgA.

Journal of Experimental Medicine ◽

10.1084/jem.172.6.1665 ◽

1990 ◽

Vol 172 (6) ◽

pp. 1665-1672 ◽

Cited By ~ 174

Author(s):

C R Maliszewski ◽

C J March ◽

M A Schoenborn ◽

S Gimpel ◽

L Shen

Keyword(s):

Cell Surface ◽

Myeloid Cell ◽

Expression Cloning ◽

Immunoglobulin Gene ◽

Cell Surface Molecule ◽

Immune Effector ◽

Surface Receptors ◽

Molecular Features ◽

Myeloid Cell Line ◽

A Cell

IgA, the predominant isotype in secretions, mediates the neutralization and removal of environmental antigens from mucosal sites. Although cell surface receptors for the Fc region of IgA (Fc alpha R) have been implicated in a variety of immune effector mechanisms, the molecular features of Fc alpha R remain only marginally characterized. In this report, we describe the isolation of a clone from a myeloid cell line cDNA library that directs the expression of a cell surface molecule with IgA binding specificity. The cDNA encodes a peptide of Mr 30,000 including a putative transmembrane region with features atypical of conventional membrane-anchored proteins. Databank searches indicate that the human myeloid cell Fc alpha R sequence is unique, is a member of the immunoglobulin gene superfamily, and is related to Fc receptors for IgG (Fc gamma RI, II, and III) and IgE (Fc epsilon RI).

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Atomic Level Dissection of the Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) Homophilic Binding Interface: Implications for Endothelial Cell Barrier Function

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.316668 ◽

2021 ◽

Author(s):

Danying Liao ◽

Jesse Sundlov ◽

Jieqing Zhu ◽

Heng Mei ◽

Yu Hu ◽

...

Keyword(s):

Crystal Structure ◽

Cell Adhesion ◽

Endothelial Cell ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Homophilic Binding ◽

Endothelial Cell Adhesion Molecule ◽

Platelet Endothelial Cell Adhesion ◽

Cell Adhesion Molecule 1 ◽

Endothelial Cell Adhesion

Objective: PECAM-1 (platelet endothelial cell adhesion molecule 1) is a 130 kDa member of the immunoglobulin (Ig) gene superfamily that is expressed on the surfaces of platelets and leukocytes and concentrated at the intercellular junctions of confluent endothelial cell monolayers. PECAM-1 Ig domains 1 and 2 (IgD1 and IgD2) engage in homophilic interactions that support a host of vascular functions, including support of leukocyte transendothelial migration and the maintenance of endothelial junctional integrity. The recently solved crystal structure of PECAM-1 IgD1 and IgD2 revealed a number of intermolecular interfaces predicted to play important roles in stabilizing PECAM-1/PECAM-1 homophilic interactions and in formation and maintenance of endothelial cell-cell contacts. We sought to determine whether the protein interfaces implicated in the crystal structure reflect physiologically important interactions. Approach and Results: We assessed the impact of single amino acid substitutions at the interfaces between opposing PECAM-1 molecules on homophilic binding and endothelial cell function. Substitution of key residues within the IgD1-IgD1 and IgD1-IgD2 interfaces but not those within the smaller IgD2-IgD2 interface, markedly disrupted PECAM-1 homophilic binding and its downstream effector functions, including the ability of PECAM-1 to localize at endothelial cell-cell borders, mediate the formation of endothelial tubes, and restore endothelial barrier integrity. Conclusions: Taken together, these results validate the recently described PECAM-1 IgD1/IgD2 crystal structure by demonstrating that specific residues visualized within the IgD1-IgD1 and IgD1-IgD2 interfaces of opposing molecules in the crystal are required for functionally important homophilic interactions. This information can now be exploited to modulate functions of PECAM-1 in vivo.

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Kinetic proofreading of lipochitooligosaccharides determines signal activation of symbiotic plant receptors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2111031118 ◽

2021 ◽

Vol 118 (44) ◽

pp. e2111031118

Author(s):

Kira Gysel ◽

Mette Laursen ◽

Mikkel B. Thygesen ◽

Damiano Lironi ◽

Zoltán Bozsóki ◽

...

Keyword(s):

Cell Surface ◽

Binding Site ◽

Receptor Activation ◽

Cell Surface Receptor ◽

Structural Basis ◽

Environmental Signals ◽

Surface Receptors ◽

Ligand Selectivity ◽

Hydrophobic Patch ◽

Kinetic Proofreading

Plants and animals use cell surface receptors to sense and interpret environmental signals. In legume symbiosis with nitrogen-fixing bacteria, the specific recognition of bacterial lipochitooligosaccharide (LCO) signals by single-pass transmembrane receptor kinases determines compatibility. Here, we determine the structural basis for LCO perception from the crystal structures of two lysin motif receptor ectodomains and identify a hydrophobic patch in the binding site essential for LCO recognition and symbiotic function. We show that the receptor monitors the composition of the amphiphilic LCO molecules and uses kinetic proofreading to control receptor activation and signaling specificity. We demonstrate engineering of the LCO binding site to fine-tune ligand selectivity and correct binding kinetics required for activation of symbiotic signaling in plants. Finally, the hydrophobic patch is found to be a conserved structural signature in this class of LCO receptors across legumes that can be used for in silico predictions. Our results provide insights into the mechanism of cell-surface receptor activation by kinetic proofreading of ligands and highlight the potential in receptor engineering to capture benefits in plant–microbe interactions.

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