Dimeric Versions of Two Short N-cadherin Binding Motifs (HAVDI and INPISG) Function as N-cadherin Agonists

Williams, Gareth; Williams, Emma-Jane; Doherty, Patrick

doi:10.1074/jbc.m109185200

Cited by 55 publications

(57 citation statements)

References 46 publications

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“…Studies have shown that the identity of the amino acids that flank the HAV motif determines both the activity and specificity of the mimetic peptides (26). Furthermore, the cyclic form of cadherin mimetic peptides exhibits significantly higher activity than linear peptides (40). Therefore, further optimization of the peptide sequence and structure could produce an even more robust chondrogenic effect than that observed here.…”

Section: Discussioncontrasting

confidence: 44%

“…Monomeric versions of this motif generally function as antagonists by competing against natural binding sites in the N-cadherin ECD1 domain, whereas dimeric versions are capable of acting as agonists by promoting dimerization of N-cadherins in cells (40). In this study, because one end (C-terminal) of the peptide was conjugated to the HA hydrogel backbone, a monomeric linear peptide sequence containing the HAV motif was capable of mimicking N-cadherin agonistic activity.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis

Bian

Guvendiren

Mauck

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

359

300

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Methacrylated hyaluronic acid (HA) hydrogels provide a backbone polymer with which mesenchymal stem cells (MSCs) can interact through several cell surface receptors that are expressed by MSCs, including CD44 and CD168. Previous studies showed that this 3D hydrogel environment supports the chondrogenesis of MSCs, and here we demonstrate through functional blockade that these specific cell-material interactions play a role in this process. Beyond matrix interactions, cadherin molecules, a family of transmembrane glycoproteins, play a critical role in tissue development during embryogenesis, and N-cadherin is a key factor in mediating cellcell interactions during mesenchymal condensation and chondrogenesis. In this study, we functionalized HA hydrogels with Ncadherin mimetic peptides and evaluated their role in regulating chondrogenesis and cartilage matrix deposition by encapsulated MSCs. Our results show that conjugation of cadherin peptides onto HA hydrogels promotes both early chondrogenesis of MSCs and cartilage-specific matrix production with culture, compared with unmodified controls or those with inclusion of a scrambled peptide domain. This enhanced chondrogenesis was abolished via treatment with N-cadherin-specific antibodies, confirming the contribution of these N-cadherin peptides to chondrogenesis. Subcutaneous implantation of MSC-seeded constructs also showed superior neocartilage formation in implants functionalized with N-cadherin mimetic peptides compared with controls. This study demonstrates the inherent biologic activity of HA-based hydrogels, as well as the promise of biofunctionalizing HA hydrogels to emulate the complexity of the natural cell microenvironment during embryogenesis, particularly in stem cell-based cartilage regeneration.M esenchymal stem cells (MSCs) have emerged as a clinically relevant cell source for regenerative medicine due to their potential to differentiate into several mesenchymal lineages including cartilage, bone, and fat (1, 2). The multipotent differentiation of MSCs is tightly regulated by both soluble and physical cues present in the pericellular microenvironment, including cell-cell and cell-matrix interactions, cues that can be engineered into a variety of natural and synthetic biomaterial scaffolds (3). These materials may be either permissive to chondrogenesis (inert materials including agarose and PEG) or inductive to chondrogenesis by mimicking components of the natural pericellular microenvironment (4, 5). For example, photopolymerizable hydrogels composed of methacrylated (Me) hyaluronic acid (HA) may provide biological cues such as CD44 and CD168 interactions based on the role of HA in cellular signaling (6-8) (Fig. 1). Coincident with the onset of condensation and the first appearance of cartilage in the embryo is the appearance of specific binding sites for HA on bud limb mesenchymal cells (9). Large HA molecules are involved in the aggregation of these cells during condensation via multivalent cross-bridging (10), and HA has already been shown to enhan...

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Section: Discussioncontrasting

confidence: 44%

Section: Discussionmentioning

confidence: 99%

Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis

Bian

Guvendiren

Mauck

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

359

300

View full text Add to dashboard Cite

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“…It would have been more informative if the E-cadherin-derived cyclic peptides were shown to inhibit E-cadherin, but not N-cadherin adhesion. Further evidence for the involvement of EC1 in cadherin adhesion was revealed in a study from the same group on small peptide agonists of cadherin adhesion (Williams et al 2002). The authors demonstrated that a recombinant N-cadherin EC1 domain was able to inhibit neurite outgrowth from cerebellar neurons over 3T3 cells expressing N-cadherin.…”

Section: Early Studiesmentioning

confidence: 93%

“…Cis-dimerization has also been examined using peptides (Williams et al 2002). Short peptide HAV-containing antagonists were dimerized so that two adhesion sites were on the same molecule.…”

Section: Cadherin Adhesion Structure: Cis-dimermentioning

confidence: 99%

Cadherin Adhesion: Mechanisms and Molecular Interactions

Perez

Nelson

2004

Handbook of Experimental Pharmacology

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Cadherins constitute a superfamily of cell-cell adhesion molecules expressed in many different cell types that are required for proper cellular function and maintenance of tissue architecture. Classical cadherins are the best understood class of cadherins. They are single membrane spanning proteins with a divergent extracellular domain of five repeats and a conserved cytoplasmic domain. Binding between cadherin extracellular domains is weak, but strong cell-cell adhesion develops during lateral clustering of cadherins by proteins that link the cadherin cytoplasmic domain to the actin cytoskeleton. Understanding how different regions of cadherins regulate cellcell adhesion has been a major focus of study. Here, we examine evidence of the structure and function of the extracellular domain of classical cadherins in regard to the control of recognition and adhesive contacts between cadherins on opposing cell surfaces. Early experiments that focused on understanding the homotypic, Ca ++ -dependent characteristics of cadherin adhesion are discussed, and data supporting the widely accepted cis-and trans-dimer models of cadherins are analyzed.

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“…Several experiments have been published with substratum bound N-cadherin peptides containing HAV-sequence dimeric versions of the N-CAD peptides promote neuronal cell survival and neurite outgrowth, while cyclic peptides containing the HAV-sequence of extracellular domain 1 induce FGF-receptor-mediated apoptosis in endothelial cells [36] and inhibit neurite outgrowth [37]. When presented as soluble molecules, dimeric peptides stimulate neurite outgrowth in a manner similar to native N-cadherin [38,39].…”

Section: Discussionmentioning

confidence: 99%

Soluble N-cadherin fragment promotes angiogenesis

Derycke

Morbidelli

Ziche

et al. 2006

Clin Exp Metastasis

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Endothelial cells express two dependent intercellular adhesion molecules: vascular endothelial (VE)-cadherin, specific for endothelial cells, and Ncadherin, also present in neuronal, lens, skeletal and heart muscle cells, osteoblasts, pericytes and fibroblasts. While there exists a vast amount of evidence that VE-cadherin promotes angiogenesis, the role of N-cadherin still remains to be elucidated. We found that a soluble 90-kDa fragment N-cadherin promotes angiogenesis in the rabbit cornea assay and in the chorioallantoic assay when cleaved enzymatically from the extracellular domain of N-cadherin. Soluble N-cadherin stimulates migration of endothelial cells in the wound healing assay and stimulates phosphorylation of extracellular regulated kinase. In vitro experiments with PD173074 and knock-down of N-cadherin and fibroblast growth factor (FGF)-receptor, showed that the pro-angiogenic effect of soluble N-cadherin is N-cadherin-and FGF-receptor-dependent. Our results suggest that soluble N-cadherin stimulates migration of endothelial cells through the FGF-receptor.

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Dimeric Versions of Two Short N-cadherin Binding Motifs (HAVDI and INPISG) Function as N-cadherin Agonists

Cited by 55 publications

References 46 publications

Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis

Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis

Cadherin Adhesion: Mechanisms and Molecular Interactions

Soluble N-cadherin fragment promotes angiogenesis

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