Mechanisms regulating the rapid turnover and continuous differentiation of the multiple epithelial cell types in the gastrointestinal tract are not well understood. Efforts to identify genes that regulate intestinal epithelial cell differentiation led to the isolation of a novel epithelial-specific tyrosine kinase from the mouse small intestine that the investigator named Sik, for Src-related intestinal kinase. Sik expression is developmentally regulated and restricted to differentiating epithelial linings, and it is expressed at highest levels in the intestinal tract. The investigator identified the human homologue of Sik and determined that it is the breast tumor kinase BRK, which had been isolated from a metastatic breast tumor. BRK is expressed in differentiating cells of the human gastrointestinal tract and its expression is increased in colon tumors. In colon cancer cell lines, BRK is present in novel nuclear structures called Sam68/SLM nuclear bodies (SNBs) where it associates with the RNA-binding protein Sam68. Phosphorylation of Sam68 by Sik/BRK inhibits Sam68 RNA-binding and the ability of Sam68 to act as an HIV1 Rev cellular homologue in nuclear RNA export. Sam68 has been shown to play a positive role in promoting mitosis, and it is a member of a growing family of RNA-binding proteins called STAR (Signal Transducers and Activators of RNA). STAR proteins have been shown to regulate gene expression at both the transcriptional and posttranscriptional levels. The investigator has determined that Sik/BRK can also phosphorylate additional members of the STAR family, the Sam68-like mammalian proteins SLM1 and SLM2. The investigator hypothesizes that Sik/BRK regulates gene expression associated with intestinal epithelial differentiation and/or transformation by modifying the activities of the STAR proteins. In the work proposed, the investigator will focus on gaining a better understanding of the role of phosphorylation of RNA-binding proteins of the STAR family by Sik/BRK in normal and transformed intestinal cells. The investigator will continue to explore the biological role of Sik in transgenic mice expressing a dominant negative or myristoylated Sik protein in the intestine, and mice with a disruption of the Sik gene. Although the Sik knockout mice are viable and have no apparent intestinal phenotype, the investigator will challenge them to determine if they have altered susceptibility to agents that induce injury or tumors. These experiments will enhance our understanding of BRK/Sik signaling and the role of STAR proteins in the normal intestinal tract and in colon tumors.
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