Our long-term goal is to understand the cellular signaling mechanisms in the intestinal epithelia with an emphasis on how protein-protein interaction affects the specificity and efficacy of signaling processes. Lysophosphatidic acid (LPA) has been shown to exert growth factor-like effects. Signaling by LPA is primarily mediated through a family of G-protein-coupled receptors, LPA^ LPA2 and LPA3. Despite more than a decade of study on LPA signaling, receptor subtype specific signaling and functions are not fully elucidated. However, this knowledge is a key to the rational design of therapeutic interventions targeting the novel intermediates and the pivotal pathways. We have recently found that there is an increase in LPA2 expression in several types of cancer, including colon cancer. This observation suggests that LPA2 is likely to play an essential pathophysiologic role that enhances cancer development and a better understanding of the signaling pathways and mechanism elicited by LPA2 is necessary. Our studies show that LPA activates the transcription factor KLF5, which is a promoter of cellular proliferation in the intestine, suggesting that KLF5 may be an intermediate transducing the biological effects of LPA. Recently, we and others have also shown that LPA2 interacts with a scaffold protein NHERF2. In addition, we have identified MAGI-3 as another LPA2 binding protein. Our preliminary studies show that the effects of MAGI-3 on LPA2-mediated signaling are unique and MAGI-3 negatively impacts the LPA-mediated signaling. Our data suggest that one reason for the divergence in LPA signaling under different conditions may be the presence or absence of interacting partners. Based on these data, we hypothesize that LPA2 facilitates tumor development in the colon by mediating multiple biological effects that promote proliferation and survival of cancer cells. We further hypothesize that the activity of LPA2 is regulated via the interaction with MAGI-3 and NHERF2. We propose the following studies. (1) We will define the biological effects mediated by LPA2 and the underlying mechanisms that enhance the formation of colorectal cancer. (2) We will determine the role of MAGI-3 in regulation of LPA2-mediated signaling in colon cancer cells. (3) We will delineate the effect of LPA and the LPA2 in vivo by using transgenic mice. Our studies will enhance our understanding of the importance and mechanism of tumorigenesis of colorectal cancer by LPA and LPA2 receptor. Our findings should help the therapeutic development against colorectal cancer.
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