Splicing variant of Cdc42 interacting protein-4 disrupts beta-catenin-mediated cell-cell adhesion: expression and function in renal cell carcinoma.
We have identified an alternative splicing variant in the Cdc42-interacting protein 4 (CIP4) gene in patients with renal cell carcinoma (RCC); almost 50% of the RCCs examined showed an aberrant splicing event in reverse transcription-PCR and the insertion of 19 nucleotides derived from intron9 based on a sequence analysis. This variant (CIP4-V) encodes a premature stop codon, resulting in the loss of a tyrosine phosphorylation site, the Cdc42 binding domain, and the SH3 domain. In this report, we show that overexpression of CIP4-V causes the formation of ubiquitinated aggresomes and a loss of cell-cell adhesion. We determined that CIP4-V increased the beta-catenin tyrosine phosphorylation levels that mediate Fer/Fyn tyrosine kinases and induced beta-catenin mistrafficking from cell membrane to cytoplasmic aggresome. These results indicate that CIP4 is critical for beta-catenin-mediated cell-cell adhesion and may be an important aspect of its functional contribution to RCC, especially with regard to metastasis and invasiveness.
Tsuji
Emiko
E
Tenjin Tsuji Clinic, Fukuoka, Japan. emikot@tt-clinic.com
Tsuji
Yuji
Y
Fujiwara
Toshiyuki
T
Ogata
Shigenori
S
Tsukamoto
Kyoko
K
Saku
Keijiro
K
D014408:Biomarkers, Tumor / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D004274:DNA, Recombinant / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D021381:Protein Transport; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000378:metabolism*
D014408:Biomarkers, Tumor; D004274:DNA, Recombinant; D008869:Microtubule-Associated Proteins; D015778:Minor Histocompatibility Antigens; C406285:TRIP10 protein, human; D051176:beta Catenin