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Mol Biol Cell. 2014 Sep 1;25(17):2592-603. doi: 10.1091/mbc.E13-08-0492. Epub 2014 Jul 9.

DIPA-family coiled-coils bind conserved isoform-specific head domain of p120-catenin family: potential roles in hydrocephalus and heterotopia.

Author information

1
Vanderbilt-Ingram Cancer Center, Cancer Biology Department, Vanderbilt University Medical Center, Nashville, TN 37232.
2
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235.
3
Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
4
Epithelial Biology Center, Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232.
5
Vanderbilt-Ingram Cancer Center, Cancer Biology Department, Vanderbilt University Medical Center, Nashville, TN 37232 al.reynolds@vanderbilt.edu.

Abstract

p120-catenin (p120) modulates adherens junction (AJ) dynamics by controlling the stability of classical cadherins. Among all p120 isoforms, p120-3A and p120-1A are the most prevalent. Both stabilize cadherins, but p120-3A is preferred in epithelia, whereas p120-1A takes precedence in neurons, fibroblasts, and macrophages. During epithelial-to-mesenchymal transition, E- to N-cadherin switching coincides with p120-3A to -1A alternative splicing. These isoforms differ by a 101-amino acid "head domain" comprising the p120-1A N-terminus. Although its exact role is unknown, the head domain likely mediates developmental and cancer-associated events linked to p120-1A expression (e.g., motility, invasion, metastasis). Here we identified delta-interacting protein A (DIPA) as the first head domain-specific binding partner and candidate mediator of isoform 1A activity. DIPA colocalizes with AJs in a p120-1A- but not 3A-dependent manner. Moreover, all DIPA family members (Ccdc85a, Ccdc85b/DIPA, and Ccdc85c) interact reciprocally with p120 family members (p120, δ-catenin, p0071, and ARVCF), suggesting significant functional overlap. During zebrafish neural tube development, both knockdown and overexpression of DIPA phenocopy N-cadherin mutations, an effect bearing functional ties to a reported mouse hydrocephalus phenotype associated with Ccdc85c. These studies identify a novel, highly conserved interaction between two protein families that may participate either individually or collectively in N-cadherin-mediated development.

PMID:
25009281
PMCID:
PMC4148249
DOI:
10.1091/mbc.E13-08-0492
[Indexed for MEDLINE]
Free PMC Article

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