title: DIPA-family coiled-coils bind conserved isoform-specific head domain of p120-catenin family: potential roles in hydrocephalus and heterotopia.
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.
authors.affiliation: Vanderbilt-Ingram Cancer Center, Cancer Biology Department, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Markham
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235.
authors.forename: Caleb A
authors.initials: CA
authors.lastname: Doll
authors.affiliation: Vanderbilt-Ingram Cancer Center, Cancer Biology Department, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Dohn
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Miller
authors.affiliation: Vanderbilt-Ingram Cancer Center, Cancer Biology Department, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Huapeng
authors.initials: H
authors.lastname: Yu
authors.affiliation: Epithelial Biology Center, Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Pierre D
authors.initials: PD
authors.lastname: McCrea
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Gamse
authors.affiliation: Vanderbilt-Ingram Cancer Center, Cancer Biology Department, Vanderbilt University Medical Center, Nashville, TN 37232 al.reynolds@vanderbilt.edu.
authors.forename: Albert B
authors.initials: AB
authors.lastname: Reynolds
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D051177:Catenins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D004285:Dogs; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D006849:Hydrocephalus / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008969:Molecular Sequence Data; D009436:Neural Tube Defects / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D015820:Cadherins; D051177:Catenins; D020033:Protein Isoforms; D000095002:Delta Catenin