Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell proliferation. Yet many cancer cells are resistant to the growth inhibition by TGF-beta while maintaining other aspects of TGF-beta responses that benefit tumor progression. The mechanism for such cell-context dependency in TGF-beta function remains a challenging and important question. Recent studies have suggested that the magnitude and duration of TGF-beta signaling into the nucleus is a critical determinant of the nature of TGF-beta response in the recipient cells. My laboratory is interested in studying the mechanism and regulation of nucleocytoplasmic translocation of Smad proteins, a process that controls the strength and duration of TGF-beta signaling. Modulation of nucleocytoplamic trafficking of Smads is also an important aspect of how TGF-beta signal is interpreted differently by cancer cells. In this proposal, we study regulation of Smad movement that leads to downregulation of TGF-beta signaling into the nucleus. Specifically, we will pursue the following:
Aim#1. TGF-beta-regulated nuclear export of Smad7.
Aim#2. Regulation of Smad trafficking by TGF-beta and mitogenic signals.
Aim#3. Protein Ser/Thr phosphatase against phosphorylated Smad2 (Smad2-P). The outcome of this study will shed light on how the level and duration of TGF-beta signaling into the nucleus is regulated. Identifying key molecules in controlling Smad trafficking will also afford us novel tools to sensitize or desensitize cells to TGF-beta. These regulators of subcellular localization of Smad may serve as potential targets for therapeutic interventions aimed at modulating TGF-beta signaling in treatment of diseases such as cancer.
| Chen, Xiaochu; Xu, Lan (2016) Genome-Wide RNAi Screening to Dissect the TGF-? Signal Transduction Pathway. Methods Mol Biol 1344:365-77 |
| Xu, Lan (2011) Averting a roadblock in transforming growth factor ýý signaling. Mol Cell Biol 31:3684-6 |
| Kaneko, Satoshi; Chen, Xiaochu; Lu, Peiyuan et al. (2011) Smad inhibition by the Ste20 kinase Misshapen. Proc Natl Acad Sci U S A 108:11127-32 |
| Cottonham, Charisa L; Kaneko, Satoshi; Xu, Lan (2010) miR-21 and miR-31 converge on TIAM1 to regulate migration and invasion of colon carcinoma cells. J Biol Chem 285:35293-302 |
| Chen, Xiaochu; Xu, Lan (2010) Specific nucleoporin requirement for Smad nuclear translocation. Mol Cell Biol 30:4022-34 |
| Chen, Shuyi; Kaneko, Satoshi; Ma, Xing et al. (2010) Lissencephaly-1 controls germline stem cell self-renewal through modulating bone morphogenetic protein signaling and niche adhesion. Proc Natl Acad Sci U S A 107:19939-44 |
| Yao, Xiaohao; Chen, Xiaochu; Cottonham, Charisa et al. (2008) Preferential utilization of Imp7/8 in nuclear import of Smads. J Biol Chem 283:22867-74 |
| Xu, Lan; Yao, Xiaohao; Chen, Xiaochu et al. (2007) Msk is required for nuclear import of TGF-{beta}/BMP-activated Smads. J Cell Biol 178:981-94 |
| Xu, Lan (2006) Regulation of Smad activities. Biochim Biophys Acta 1759:503-13 |
| Chen, Hong Bing; Rud, Jonathan G; Lin, Kai et al. (2005) Nuclear targeting of transforming growth factor-beta-activated Smad complexes. J Biol Chem 280:21329-36 |
