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P120-catenin binding masks an endocytic signal conserved in classical cadherins.

ABSTRACT: p120-catenin (p120) binds to the cytoplasmic tails of classical cadherins and inhibits cadherin endocytosis. Although p120 regulation of cadherin internalization is thought to be important for adhesive junction dynamics, the mechanism by which p120 modulates cadherin endocytosis is unknown. In this paper, we identify a dual-function motif in classical cadherins consisting of three highly conserved acidic residues that alternately serve as a p120-binding interface and an endocytic signal. Mutation of this motif resulted in a cadherin variant that was both p120 uncoupled and resistant to endocytosis. In endothelial cells, in which dynamic changes in adhesion are important components of angiogenesis and inflammation, a vascular endothelial cadherin (VE-cadherin) mutant defective in endocytosis assembled normally into cell-cell junctions but potently suppressed cell migration in response to vascular endothelial growth factor. These results reveal the mechanistic basis by which p120 stabilizes cadherins and demonstrate that VE-cadherin endocytosis is crucial for endothelial cell migration in response to an angiogenic growth factor.

SUBMITTER: Nanes BA

PROVIDER: S-EPMC3471230 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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p120-catenin binding masks an endocytic signal conserved in classical cadherins.

Nanes Benjamin A BA Chiasson-MacKenzie Christine C Lowery Anthony M AM Ishiyama Noboru N Faundez Victor V Ikura Mitsuhiko M Vincent Peter A PA Kowalczyk Andrew P AP

The Journal of cell biology 20121001 2

p120-catenin (p120) binds to the cytoplasmic tails of classical cadherins and inhibits cadherin endocytosis. Although p120 regulation of cadherin internalization is thought to be important for adhesive junction dynamics, the mechanism by which p120 modulates cadherin endocytosis is unknown. In this paper, we identify a dual-function motif in classical cadherins consisting of three highly conserved acidic residues that alternately serve as a p120-binding interface and an endocytic signal. Mutatio ...[more]

PMID: 23071156

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Project description:BackgroundClassical cadherins are a metazoan-specific family of homophilic cell-cell adhesion molecules that regulate morphogenesis. Type I and type IV cadherins in this family function at adherens junctions in the major epithelial tissues of vertebrates and insects, respectively, but they have distinct, relatively simple domain organizations that are thought to have evolved by independent reductive changes from an ancestral type III cadherin, which is larger than derived paralogs and has a complicated domain organization. Although both type III and type IV cadherins have been identified in hexapods and branchiopods, the process by which the type IV cadherin evolved is still largely unclear.ResultsThrough an analysis of arthropod genome sequences, we found that the only classical cadherin encoded in chelicerate genomes was the type III cadherin and that the two type III cadherin genes found in the spider Parasteatoda tepidariorum genome exhibited a complex yet ancestral exon-intron organization in arthropods. Genomic and transcriptomic data from branchiopod, copepod, isopod, amphipod, and decapod crustaceans led us to redefine the type IV cadherin category, which we separated into type IVa and type IVb, which displayed a similar domain organization, except type IVb cadherins have a larger number of extracellular cadherin (EC) domains than do type IVa cadherins (nine versus seven). We also showed that type IVa cadherin genes occurred in the hexapod, branchiopod, and copepod genomes whereas only type IVb cadherin genes were present in malacostracans. Furthermore, comparative characterization of the type IVb cadherins suggested that the presence of two extra EC domains in their N-terminal regions represented primitive characteristics. In addition, we identified an evolutionary loss of two highly conserved cysteine residues among the type IVa cadherins of insects.ConclusionsWe provide a genomic perspective of the evolution of classical cadherins among bilaterians, with a focus on the Arthropoda, and suggest that following the divergence of early arthropods, the precursor of the insect type IV cadherin evolved through stepwise reductive changes from the ancestral type III state. In addition, the complementary distributions of polarized genomic characters related to type IVa/IVb cadherins may have implications for our interpretations of pancrustacean phylogeny.

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P120-catenin binding masks an endocytic signal conserved in classical cadherins.

Publications

p120-catenin binding masks an endocytic signal conserved in classical cadherins.

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