The TGF-??signaling pathway represents a major growth inhibitory pathway in normal epithelial cells, and paradoxically, it promotes proliferation in cells of mesenchymal origins. Thus, TGF-??is a double-edge sword acting as both a tumor suppressor in early tumors and as a significant promoter of tumor invasion and metastasis in carcinomas. Whilst loss of TGF-??growth inhibitory actions is a hallmark in cancer, excess of TGF-??signaling has been associated with tumor metastasis, fibrotic, autoimmune and cardiovascular diseases. Improving the outlook for these diseases can benefit from a better understanding of the molecular mechanisms that govern the activation and termination of TGF-??signaling pathway. Our proposed research is to focus on the molecular mechanisms underlying the termination of TGF-??signaling by coupled dephosphorylationnuclear export steps. As a first step, we recently identified PPM1A as a critical protein phosphatase that initiates the TGF-??signal termination step. Now we demonstrated, for the first time, that the dephosphorylated Smad2/3 by PPM1A is ready to be exported out of the nucleus through a pathway dependent of Ran-binding protein RanBP3. Based on these discoveries, the unifying hypothesis of the current proposal is that the combined actions of PPM1A and RanBP3 terminate TGF-??signaling in the nucleus. To test this hypothesis, we have begun biochemical and cell biological studies to determine how RanBP3 regulates TGF-??-mediated activation of downstream signaling pathways and physiological responses.
Two specific aims are proposed: 1. To fully understand how RanBP3 controls the nuclear export of Smad2/3;2. To elucidate how RanBP3 specifically regulates TGF??responses in normal and cancer cells. The proposed studies should not only gain insights into the mechanisms of TGF-??and RanBP3 actions under physiological conditions, but also provide invaluable information on targeting TGF-??in cancer prevention and treatment.
We propose an etiological study to understand how nuclear protein RanBP3 regulates TGF- functions and responses in normal vs. cancer cells. Our basic research will help to understand how human diseases develop and how they can be cured.
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