Molecular Basis for E-cadherin Recognition by Killer Cell Lectin-like Receptor G1 (KLRG1)

Nakamura, Sachiyo; Kuroki, Kazuhiko; Ohki, Izuru; Sasaki, Kaori; Kajikawa, Mizuho; Maruyama, Takuma; Itô, Masayuki; Kameda, Yukihiko; Ikura, Mitsuhiko; Yamamoto, Kazuo; Matsumoto, Naoki; Maenaka, Katsumi

doi:10.1074/jbc.m109.038802

Cited by 34 publications

(29 citation statements)

References 27 publications

(26 reference statements)

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“…E-, N-, and R-cadherin are known to be ligands for the inhibitory receptor KLRG1. 18–20 E-cadherin binds to 2 members of the integrin family, αEβ7 and α2β1. 21–25 In the protocadherins, an RGD motif has been identified in the first extracellular domain of the mammalian protocadherin-α family members.…”

Section: Discussionmentioning

confidence: 99%

Cadherin 6 Has a Functional Role in Platelet Aggregation and Thrombus Formation

Dunne

Spring

Adili

et al. 2012

ATVB

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Objective Thrombosis occurs at sites of vascular injury when platelets adhere to subendothelial matrix proteins and to each other. Platelets express many surface receptor proteins, the function of several of these remains poorly characterized. Cadherin 6 is expressed on the platelet surface and contains an arginine-glycine-aspartic acid motif, suggesting that it might have a supportive role in thrombus formation. The aim of this study was to characterize the role of cadherin 6 in platelet function. Methods and Results Platelet aggregation was inhibited by both antibodies and exogenous soluble cadherin 6. Platelet adhesion to immobilized cadherin 6 was inhibited by arginine-glycine-aspartic acid-serine tetrapeptides. Antibodies to αIIbβ3 inhibited platelet adhesion to cadherin 6. Because platelet aggregation occurs in fibrinogen and von Willebrand factor double-deficient mice, we investigated whether cadherin 6 is an alternative ligand for the integrin αIIbβ3. Platelet aggregation in fibrinogen and von Willebrand factor double-deficient mice was significantly inhibited by an antibody to cadherin 6. In flow-based assays, inhibition of cadherin 6 caused a marked reduction in thrombus formation in both human and mouse blood. Conclusion This study demonstrates the role of cadherin 6 as a novel ligand for αIIbβ3 and highlights its function in thrombus formation.

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Section: Discussionmentioning

confidence: 99%

Cadherin 6 Has a Functional Role in Platelet Aggregation and Thrombus Formation

Dunne

Spring

Adili

et al. 2012

ATVB

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“…Another receptor for E-cadherin, KLRG1, is expressed on T cells and natural killer (NK) cells, where the binding of KLRG1 to E-cadherin-expressing cells prevents the lysis of epithelial targets (5). The interaction between KLRG1 and E-cadherin is mediated by the homodimeric interface on EC1, suggesting that monomeric E-cadherin at epithelial cell surfaces is responsible for controlling the activation threshold of NK and T cells and thereby suppressing immune response (6). E-cadherin, therefore, can serve as an adhesion molecule or a targeting molecule, depending on binding partner.…”

Section: Introductionmentioning

confidence: 99%

Soluble E-cadherin: more than a symptom of disease

Grabowska

Day²

2012

Front Biosci

114

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Epithelial (E)-cadherin is a homophilic adhesion molecule which is responsible for maintenance of baso-lateral cell adhesion and polarity. E-cadherin can be lost from the cell surface by proteolytic cleavage, resulting in the generation of an 80kDa fragment referred to a soluble E-cadherin (sE-cad). Although originally discovered in the conditioned media of breast cancer cells and later verified in the fluids of cancer patients, today sE-cad has been reported in patients with viral and bacterial infections, organ failure, and benign disease. The proteases implicated in this cleavage event include members of the disintegrin family (ADAM10 and 15), bacterial proteases (gingipains and BFT), cathepsins (B, L, S), matrix metalloproteases (MMP-2, 3, 7, 9, and 14), Kallikrein-7 (KLK7), and plasmin. Stimulus that induces sE-cad generation by ADAMs, MMPs, KLK7, and plasmin in vitro ranges from serum withdrawal to pro-inflammatory cytokines to growth factors. The cellular or physiologic consequences of sE-cad accumulation include the disruption of adherens junctions, cellular migration and invasion, induction of MMPs, as well as cell signaling, suggesting that sE-cad may contribute to disease progression.

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“…KLRG1 recognizes the N-terminal homodimeric interface of E-cadherin EC1 and binds only the monomeric form of E-cadherin. 9,10 KLRG1 is a type II transmembrane inhibitory receptor of the C-type lectin superfamily that contains an ITIM in its cytoplasmic domain. Phosphorylation of the ITIM recruits the SHIP-1 and SHP-2 phosphatases, 11 thereby inhibiting NK cytotoxicity.…”

Section: Functions Of the E-cadherin/catenin Complex: Heterophilic Admentioning

confidence: 99%

Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

Bossche

Malissen

Mantovani

et al. 2012

Blood

139

121

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E-cadherin is best characterized as adherens junction protein, which through homotypic interactions contributes to the maintenance of the epithelial barrier function. In epithelial cells, the cytoplasmic tail of E-cadherin forms a dynamic complex with catenins and regulates several intracellular signal transduction pathways, including Wnt/␤-catenin, PI3K/Akt, Rho GTPase, and NF-B signaling. Recent progress uncovered a novel and critical role for this adhesion molecule in mononuclear phagocyte functions. Ecadherin regulates the maturation and migration of Langerhans cells, and its ligation prevents the induction of a tolerogenic state in bone marrow-derived dendritic cells (DCs). In this respect, the functionality of ␤-catenin could be instrumental in determining the balance between immunogenicity and tolerogenicity of DCs in vitro and in vivo. Fusion of alternatively activated macrophages and osteoclasts is also Ecadherin-dependent. In addition, the Ecadherin ligands CD103 and KLRG1 are expressed on DC-, T-, and NK-cell subsets and contribute to their interaction with E-cadherin-expressing DCs and macrophages. Here we discuss the regulation, function, and implications of Ecadherin expression in these central orchestrators of the immune system. (Blood. 2012;119(7):1623-1633) IntroductionCadherins are transmembrane or membrane-associated glycoproteins that mediate Ca 2ϩ -dependent cell-cell adhesion and have mainly been described for their instrumental role during morphogenesis of a variety of organs. 1 The cadherin superfamily composes classic type I cadherins, closely related type II cadherins, desmosomal cadherins, protocadherins, and several cadherin-related molecules. Cadherin-1 (encoded by Cdh1), also known as CD324, uvomorulin, or E-cadherin, in which the "E" stands for "epithelial," is the founding member of the classic type I cadherin family, which also includes N-cadherin (neural, Cdh2), P-cadherin (placental, Cdh3), Cdh4), and VE-cadherin (vascular endothelial, Cdh5). For several decades, E-cadherin has been known as a major constituent of adherens junctions (AJs), mediating strong homotypic adhesion between neighboring epithelial cells, thereby safeguarding epithelial barrier integrity. 2 The lack of functional tight junction and desmosome formation in the absence of E-cadherin emphasizes its central role in the regulation of epithelial cell-cell contacts. 3 Cell-cell adhesion is mainly executed by the formation of E-cadherin trans-homodimers. Indeed, the E-cadherin molecule contains an ectodomain composed of 5 extracellular cadherin (EC1-5) repeats (550 aa in total), in which EC1 composes the HAV peptide sequence responsible for homophilic interactions, a transmembrane region, and a cytoplasmic tail (150 aa). 2 The latter can be further subdivided into a ␤-catenin binding domain and a membrane proximal cytoplasmic/conserved domain, whose core sequence motif DEEGGGEED is important for p120-catenin binding, resulting in the stabilization of the E-cadherin/catenin complex at the cell surface. 4 E-cadhe...

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Molecular Basis for E-cadherin Recognition by Killer Cell Lectin-like Receptor G1 (KLRG1)

Cited by 34 publications

References 27 publications

Cadherin 6 Has a Functional Role in Platelet Aggregation and Thrombus Formation

Cadherin 6 Has a Functional Role in Platelet Aggregation and Thrombus Formation

Soluble E-cadherin: more than a symptom of disease

Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

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