Src-specific activity has been reported to be elevated in a high percentage of
colon cancer cell lines and
tumors, but the underlying mechanisms are largely unknown. In this study, we report that, in the seven
cancer cell lines tested, Src-specific activity was elevated (5.2- to 18.7-fold) relative to normal colon cells (FHC). This activation of Src correlated with reduced phosphorylation at Y530 of Src, whereas there was no significant change in the level of phosphorylation at Y419. The membrane
tyrosine phosphatase activity for a Src family-specific
phosphopeptide substrate FCP (Fyn COOH-terminal
peptide phosphorylated by Csk) was greatly increased in the
cancer cells and was attributed to PTP1B in most of the cell lines. Membrane PTP1B
protein levels were also greatly increased. Overexpression of PTP1B increased Src specific activity in
colon cancer cells by reducing phosphorylation at Y530 of Src. It also increased anchorage-independent cell growth and this increase was blocked by the Src inhibitor PP2 and Src
small interfering RNA (
siRNA). Down-regulating PTP1B activity by PTP1B inhibitor
CinnGEL 2Me or knocking down PTP1B using
siRNA also reduced
Src kinase activity and colony formation ability of
colon cancer cells. PTP1B
siRNA reduced
tumor growth in nonobese diabetic/severe combined immunodeficient mice. This study suggests that (a) PTP1B can act as an important activator of Src in
colon cancer cells via dephosphorylation at Y530 of Src and (b) elevated levels of PTP1B can increase tumorigenicity of
colon cancer cells by activating Src.