Zhu S, Bjorge J D, Cheng H C, Fujita D J
Department of Biochemistry and Molecular Biology, and Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
Oncogene. 2008 Mar 27;27(14):2027-34. doi: 10.1038/sj.onc.1210838. Epub 2007 Oct 15.
Src activation has been associated with colon cancers but the mechanism underlying Src activation is largely unknown. Csk-homologous kinase (CHK) can inhibit the kinase activity of certain Src kinase family members in vitro by phosphorylating the C-terminal tyrosine and by a non-catalytic mechanism. CHK was previously reported to be expressed primarily in brain and hematopoietic cells. We report herein that CHK is also expressed in normal colon cell lines. Furthermore, CHK protein levels are significantly decreased in various colon cancer cell lines and the decrease correlates with the increased specific activity of Src in these cell lines, while the level of the other Src inhibitory kinase, C-terminal Src kinase, is not significantly changed. CHK is also expressed in normal colon tissues but its expression level is decreased in colon cancer tissues collected from the same patients. Immunofluorescence microscopy shows that CHK colocalizes with Src in normal colon FHC cells. Overexpression of CHK in colon cancer cells results in inactivation of Src without phosphorylating Y530 at its C-terminus. In addition, CHK suppresses anchorage-independent cell growth and cell invasion of colon cancer cells. These results reveal a potentially important role for CHK in Src activation and tumorigenicity in colon cancer cells.
Src激活与结肠癌有关，但Src激活的潜在机制在很大程度上尚不清楚。Csk同源激酶（CHK）可通过磷酸化C末端酪氨酸并通过非催化机制在体外抑制某些Src激酶家族成员的激酶活性。之前报道CHK主要在脑和造血细胞中表达。我们在此报告CHK也在正常结肠细胞系中表达。此外，CHK蛋白水平在各种结肠癌细胞系中显著降低，且这种降低与这些细胞系中Src比活性的增加相关，而另一种Src抑制激酶C末端Src激酶的水平没有显著变化。CHK也在正常结肠组织中表达，但其在从同一患者收集的结肠癌组织中的表达水平降低。免疫荧光显微镜显示CHK在正常结肠FHC细胞中与Src共定位。在结肠癌细胞中过表达CHK导致Src失活，而其C末端的Y530未被磷酸化。此外，CHK抑制结肠癌细胞的非锚定依赖性细胞生长和细胞侵袭。这些结果揭示了CHK在结肠癌细胞Src激活和致瘤性中潜在的重要作用。
