ABSTRACT
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.
Subject(s)
Cell Movement/drug effects , Colonic Neoplasms/pathology , Membrane Microdomains/enzymology , Neoplasm Invasiveness/pathology , CSK Tyrosine-Protein Kinase , Cell Movement/physiology , Colonic Neoplasms/enzymology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/physiopathology , Down-Regulation/drug effects , Humans , Membrane Microdomains/pathology , Membranes , Neoplasm Invasiveness/physiopathology , Phosphoproteins/metabolism , Protein-Tyrosine Kinases/metabolism , Protein-Tyrosine Kinases/pharmacology , src-Family Kinases/pharmacologyABSTRACT
The cytoplasmic tyrosine kinases of the Src family (SFK) play important roles in cell responses induced by growth factors, including cell growth, survival and migration. Here, we review how SFK participate in PDGF (platelet-derived growth factor) receptor signalling leading to DNA synthesis and actin assembly. Furthermore, evidence for a spatial compartmentalization of SFK signalling is also discussed.
