Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

Oncogene. 2010 Mar 4;29(9):1303-15. doi: 10.1038/onc.2009.450. Epub 2009 Dec 14.


The nonreceptor tyrosine kinases of the Src family (SFK) are frequently deregulated in human colorectal cancer (CRC), and they have been implicated in tumour growth and metastasis. How SFK are activated in this cancer has not been clearly established. Here, we show that the SFK-dependent invasion is induced by inactivation of the negative regulator C-terminal Src kinase, Csk. While the level of Csk was inconsistent with SFK activity in colon cancer cells, its membrane translocation, needed for efficient regulation of membrane-localized SFK activity, was impaired. Accordingly, Csk downregulation did not affect SFK oncogenic activity in these cells, whereas expression of a membrane-localized form of this kinase affected their invasive activity. Downregulation of the transmembrane and rafts-localized Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomain (PAG), was instrumental for the cytoplasmic accumulation of Csk. Re-expression of PAG in cells from late-stage CRC inhibited SFK invasive activity in a Csk-dependent manner. Conversely, inactivation of its residual expression in early-stage CRC cells promoted SFK invasive activity. Finally, this mechanism was specific to CRC as Csk coupling to SFK was readily detected in breast cancer cells. Therefore, Csk mis-localization defines a novel mechanism for SFK oncogenic activation in CRC cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CSK Tyrosine-Protein Kinase
  • Cell Movement / drug effects*
  • Cell Movement / physiology
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / pathology*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / physiopathology
  • Down-Regulation / drug effects
  • Humans
  • Membrane Microdomains / enzymology*
  • Membrane Microdomains / pathology
  • Membranes
  • Neoplasm Invasiveness / pathology*
  • Neoplasm Invasiveness / physiopathology
  • Phosphoproteins / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Protein-Tyrosine Kinases / pharmacology
  • src-Family Kinases / pharmacology


  • Phosphoproteins
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human