Down-modulation of keratin 8 phosphorylation levels by PRL-3 contributes to colorectal carcinoma progression

Int J Cancer. 2009 Apr 15;124(8):1802-10. doi: 10.1002/ijc.24111.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma / metabolism*
  • Carcinoma / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Cytoskeleton / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Keratin-8 / metabolism*
  • Models, Biological
  • Mutation
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Proteins / metabolism*
  • Phosphorylation
  • Protein Tyrosine Phosphatases / metabolism*
  • Wound Healing


  • Keratin-8
  • Neoplasm Proteins
  • PTP4A3 protein, human
  • Protein Tyrosine Phosphatases