P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome.

p63, a p53 family member, is required for craniofacial and limb development as well as proper skin differentiation. However, p63 mutations associated with the ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (Hay-Wells syndrome) were found in the p63 carboxyl-terminal region with a sterile alpha-motif. By two-hybrid screen we identified several proteins that interact ...
with the p63alpha carboxyl terminus and its sterile alpha-motif, including the apobec-1-binding protein-1 (ABBP1). AEC-associated mutations completely abolished the physical interaction between ABBP1 and p63alpha. Moreover the physical association of p63alpha and ABBP1 led to a specific shift of FGFR-2 alternative splicing toward the K-SAM isoform essential for epithelial differentiation. We thus propose that a p63alpha-ABBP1 complex differentially regulates FGFR-2 expression by supporting alternative splicing of the K-SAM isoform of FGFR-2. The inability of mutated p63alpha to support this splicing likely leads to the inhibition of epithelial differentiation and, in turn, accounts for the AEC phenotype.
Mesh Terms:
Abnormalities, Multiple, Animals, Cell Differentiation, DNA-Binding Proteins, Ectodermal Dysplasia, Epithelial Cells, Gene Expression Regulation, Genes, Tumor Suppressor, Humans, Membrane Proteins, Mice, Mouth Abnormalities, Mutation, Phosphoproteins, Protein Binding, Protein Isoforms, Protein Splicing, RNA-Binding Proteins, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Fibroblast Growth Factor, Syndrome, Trans-Activators, Tumor Suppressor Proteins, Two-Hybrid System Techniques
J. Biol. Chem.
Date: Jun. 27, 2003
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