This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cell-cell junctions are important in physiological processes, with tight junctions helping to maintain the epithelial cell layer that protects multicellular organisms from the environment. Cell surface adhesion proteins involved in forming these junctions play a role in the loss of attachment, which leads cells to become migratory. We have identified and characterized a novel cell adhesion molecule, Junctional Adhesion Molecule-A (JAM-A), which is expressed at endothelial and epithelial cell tight junctions. Our results implicate JAM-A in the events leading to migratory behavior, including cancer cell metastasis, as well as in subfertility. We therefore propose to test the following hypotheses in this proposal: 1) Metastatic behavior of breast cancer cells is related to the expression level of JAM-A. We will determine the expression of JAM-A in breast cancer cell lines with a range of metastatic potentials. We will compare the expression of JAM-A to the metastatic potential, and use cellular and mouse models to confirm the relationship. 2) Post-translational modifications of JAM-A influence the metastatic ability of breast cancer cells. We will determine if post-translational modification of JAM-A is related to the metastatic behavior of these cells. Again we will utilize in vitro, as well as in vivo, models of tumor metastasis. 3) Signaling through JAM-A regulates the metastatic potential of breast cancer cells. The intracellular signaling pathway induced through JAM-A will be characterized. 4) Reduced expression and/or post-translational modification of JAM-A affect Sertoli cell tight junctions, leading to abnormal spermatogenesis. We will characterize the Sertoli-Sertoli tight junction dynamics in the testis of JAM-A WT and K/O mice, and the testicular histology in the latter, and then perform a transgenic rescue of the subfertility in JAM-A K/O mice using a Sertoli-cell specific promoter to drive the expression of a JAM-A transgene. Our results will help define the role of JAM-A in cancer cell metastasis and male subfertility, and can identify therapeutic targets.
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