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.
Fomenkov
Alexey
A
Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Huang
Yi-Ping
YP
Topaloglu
Ozlem
O
Brechman
Anna
A
Osada
Motonobo
M
Fomenkova
Tanya
T
Yuriditsky
Eugene
E
Trink
Barry
B
Sidransky
David
D
Ratovitski
Edward
E
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins; D004476:Ectodermal Dysplasia / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D009056:Mouth Abnormalities / Q000235:genetics; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019154:Protein Splicing; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis* / Q000502:physiology; D013577:Syndrome; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques
C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; C103749:HNRNPAB protein, human; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D008565:Membrane Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D017468:Receptors, Fibroblast Growth Factor; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor