Dr. Angela L. Tyner
- PhD, University of Chicago
Protein Tyrosine Kinase 6 (PTK6): a novel intracellular tyrosine kinase expressed in epithelia
Most human cancers are derived from epithelial cells in which control of cell proliferation, differentiation, survival and/or migration is inappropriately regulated. The epithelial linings of the small and large intestine normally rapidly regenerate and proliferation and differentiation must be tightly regulated to maintain normal tissue homeostasis. Deregulation of these processes can lead to colon cancer, the third leading cause of new cancer cases in men and women, and the third leading cause of cancer deaths. Our efforts to identify novel regulatory genes that control the normal rapid renewal of the intestinal epithelium resulted in the cloning of a gene encoding a novel protein tyrosine kinase named PTK6 (also called Brk for Breast tumor kinase).PTK6 is expressed in differentiated cells in the linings of the gastrointestinal tract (tongue, esophagus, stomach, small and large intestine) and skin, where it is activated during differentiation.
Figure 1: PTK6 is expressed in differentiated cells in the mouse small intestine. PTK6 antibody binding is visualized with DAB (brown).
Figure 2: PTK6 induces formation of peripheral adhesion complexes that contain high levels of tyrosine-phosphorylated proteins. Immunofluorescence showing co localization of activated PTK6 (P-Y342) visualized with rhodamine and phospho-tyrosine visualized with FITC in peripheral adhesion complexes in PC3 prostate cancer cells expressing membrane targeted PTK6. Colocalization appears yellow.
Figure 3: Ectopic expression of membrane targeted active PTK6 (Palm-YF) in SYF (Src-/-, Yes-/-, Fyn-/- MEF) cells dramatically changes the cell morphology. (Blue:DAPI, Green:PY, Red: F-actin).
Although it is not expressed in the normal mammary gland, PTK6 is expressed at high levels in the majority of human breast tumors and breast tumor cell lines examined. PTK6 is expressed in nuclei of normal prostate epithelial cells, but then relocalized to the cytoplasm in prostate tumors. Data suggest that PTK6 plays roles in a number of epithelial cancers including breast, prostate and colon cancer, but its functions are still not well understood. Using transgenic and knockout mice, we are currently trying to understand roles of PTK6 in normal epithelial cell biology and cancer. In addition, we are using biochemical approaches to identify PTK6 substrates and interacting proteins. Drugs designed to target specific protein tyrosine kinases have efficacy in treating some types of cancer. Our studies will clarify if PTK6 is a potential therapeutic target. In addition, we are also examining the expression and activity of PTK6 in human cancers to determine whether it can be used as a prognostic or diagnostic cancer marker.
Regulation of gene expression in regenerating liver and hepatocellular carcinoma
The liver is the largest epithelial gland in the body and it has an amazing capacity to regenerate in response to injury. The transcription factor Forkhead Box M1 (FoxM1) regulates expression of cell cycle proteins that are essential for DNA replication and mitosis during liver regeneration and cancer progression. FoxM1 promotes normal liver regeneration and plays an essential role in development of hepatocellular carcinoma (HCC). Liver specific disruption of the FoxM1 gene effectively diminished proliferation and induced apoptosis of hepatocellular carcinoma cells in animal models. We are currently investigating mechanisms that regulate FoxM1 and its target genes in promoting liver tumorigenesis in mouse models of liver cancer. We are also investigating the efficacy of targeting FoxM1for the treatment of liver cancer.