Down-modulation of keratin 8 phosphorylation levels by PRL-3 contributes to colorectal carcinoma progression.
Phosphatase of regenerating liver-3 (PRL-3) is a member of the PRL protein tyrosine phosphatase family and has been proposed to promote the invasiveness and metastastic capability of colorectal cancers (CRCs); however, the underlying mechanisms and target molecules of PRL-3 protein remain unknown. On the basis of the biological significance of PRL-3 phosphatase activity confirmed by the catalytically inactive PRL-3 mutant (C104S) and a PRL-3 inhibitor in CRC-derived SW480 cells, we performed protein expression profiling to search for PRL-3-mediated effector proteins. By a comparative study of phosphorylated proteins that differentially expressed in wild type and C104S mutant PRL-3-transfected SW480 cells; the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431. Moreover, we detected the physiological interaction between PRL-3 and KRT8 and their colocalization at cellular lamellipodias and ruffles in vivo. In CRC tissue samples, tumor cells with high PRL-3 expression showed reduction or loss of phosphorylated KRT8 expression, particularly at the invasive front and in the liver metastases. In conclusion, our results indicate that PRL-3 may play an important role for the promotion of CRC cell migration and metastatic potential through direct KRT8 dephosphorylation.
Mizuuchi
Eri
E
Department of Pathology, Division of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan.
Semba
Shuho
S
Kodama
Yoshinori
Y
Yokozaki
Hiroshi
H
D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D003599:Cytoskeleton / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053533:Keratin-8 / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D014945:Wound Healing
D053533:Keratin-8; D009363:Neoplasm Proteins; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases