Academic Background:
Lan Xu received his Ph.D degree at the University of California at San Diego in 1998. Supported by fellowships from the Damon Runyon-Walter Winchell Cancer Fund and the American Cancer Society, he did postdoctoral research in the Cell Biology Program at Memorial Sloan-Kettering Cancer Center. He joined the faculty of the Program in Molecular Medicine at the University of Massachusetts Medical School in 2003.
TGFβ Signal Transduction
TGF-β cytokines regulate a wide variety of cells, ranging from embryonic stem cells to tumor cells undergoing metastasis. The goal of my lab is to understand how TGF-β controls growth, differentiation and apoptosis of various cell types and apply such knowledge to combating diseases such as cancer and fibrosis.
Mechanism of TGF-β Signaling
My lab has undertaken a systems biology approach combining functional genomic and RNA interference (RNAi) techniques to dissect the TGF-β pathway. We have carried out a whole-genome RNAi screening to identify factors required for transducing TGF-β signal into the nucleus. This project is being pursued in collaboration with the RNAi Screening Center at Harvard Medical School and aims to provide a systematic analysis of TGF-β signaling. Among the hits identified through RNAi screening, we are particularly interested in those that are relevant to two aspects of TGF-β signal transduction:
1) Nucleo-cytoplasmic trafficking of Smad proteins. The sub-cellular distribution of Smad proteins is dictated by TGF-β signaling. This is essential for cells to respond to TGF-β stimulation. Through RNAi screening, we have uncovered factors critical for nuclear translocation of Smads. These will help us delineate the molecular machinery mediating nuclear import and export of Smads, and understand how these processes are regulated by TGF-β and other signals.
2) phosphatases modulating TGF-β signaling. Ser/Thr phosphatases were recently identified as new components of the TGF-β pathway. Through RNAi screening of a protein phosphatase library we have identified phosphatases that genetically interact with TGF-β signaling. We are now examining how these phosphatases regulate TGF-β signaling and their biological impact on the nature of cellular responses to TGF-β.
The current dogma on the mechanism of TGF-β signal transduction is inadequate to explain the complex biology TGF-β elicits in different cell types. MicroRNAs have emerged as a new class of regulators not only during normal development but also in the pathophysiology of diseases such as cancer. We are now investigating the role of microRNA in TGF-β signaling. Our ongoing study revealed that microRNA is an integral component of TGF-β pathway and is critical for TGF-β responses in recipient cells. We are studying this question in the context of TGF-β responses in colon and breast cancer cells.
