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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Salnikow, Konstantin
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Baylor College of Medicine
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