Zhi-Chun Lai
Professor of Biology and
Professor of Biochemistry and Molecular Biology
University Park, PA 16802
Research Interests
Growth control and cancer genetics
Research Summary
Growth Control and Cancer Genetics
My research group is interested in understanding how tissue growth and organ size are normally regulated during animal development and how disruption of such regulation can lead to tissue overgrowth and cancer development.
During development of multicellular organisms, cells communicate with each other through some highly conserved signaling pathways such as the Hippo signal transduction pathway. Hippo signaling, first discovered in Drosophila, restricts tissue growth and organ size by limiting cell proliferation and promoting apoptosis. In 2005, my laboratory discovered a novel component of this pathway, Mob as tumor suppressor (Mats) (Lai et al., 2005). Mats functions as a co-activator of another tumor suppressor, the Wts/Lats protein kinase. When expressed in fly’s body, human MATS can functionally replace the Drosophila Mats protein. Moreover, we found that Mats is a target of Hippo kinase. Mats phosphorylation by Hippo increases its affinity with Wts/Lats and ability to increase Wts catalytic activity to target a key downstream growth-promoting protein Yorkie (Yki). Importantly, the mechanism by which Mats is activated by Hippo via phosphorylation is conserved from fly to human (Wei et al., 2007). Our discovery of the mats gene family has led us into studies using zebrafish, mice and human cells (e.g. Zhao et al., 2007; 2008; 2009; Yuan et al., 2009).
Our knowledge of Hippo signaling is still very limited. It is not clear how the initial signal is generated to stimulate Hippo signaling in developing tissues. It is also not known how exactly the Hippo protein kinase is activated by upstream molecules. Although all Hippo pathway components are known to exist in mammalian cells, how they might operate to regulate tissue growth and organ size is not fully understood. We know that human YAP (fly Yki ortholog) is a candidate oncogene and human NF2 (fly Merlin ortholog) is a well-known tumor suppressor). Obviously, how Hippo signaling is relevant to human cancer development is an important question do address in the coming years.
Representative Publications
- Ho, L.-L., Wei, X., Shimizu, T. and Lai, Z.-C. (2010). Mob as tumor suppressor is activated at the cell membrane to control tissue growth and organ size in Drosophila. Developmental Biology 337:274-283.
- Zhao, B., Kim, J., Ye, X., Lai, Z.-C. and Guan, K.-L. (2009). Both TEAD binding and WW domains are required for the growth stimulation and oncogenic transformation activity of YAP. Cancer Research 69:1089-1098.
- Yuan, Y., Lin, S., Zhu, Z., Zhang, W., and Lai, Z.-C. (2009). The mob as tumor suppressor gene mats1 is required for growth control in developing zebrafish embryos. The International Journal of Developmental Biology 53:525-533.
- Ye, X., Nikolaidis, N., Nei, M. and Lai, Z.-C. (2009). Evolution of the mob gene family. The Open Cell Signaling Journal 1:1-11.
- Zhao, B., Ye, X., Yu, J., Li, L., Li, W., Li, S., Yu, J., Lin, J. D., Chinnaiyan, A. M., Lai, Z.-C. and Guan, K.-L. (2008). TEAD mediates YAP dependent gene induction and growth control. Genes and Development 22:1962-1971.
- Yang, Y., Gupta, V., Ho, L.-L., Zhou, B., Fan, Q., Zhu, Z., Zhang, W., and Lai, Z.-C. (2008). Both upstream and downstream intergenic regions are critical for the mob as tumor suppressor gene activity in Drosophila. FEBS Letters 582:1766-1770.
- Shimizu, T., Ho, L.-L. and Lai, Z.-C. (2008). The mob as tumor suppressor gene is essential for early development and regulates tissue growth in Drosophila. Genetics 178:957-965.
- Zhao, B., Wei, X. Li, W., Udan, R. S., Yang, Q., Kim, J., Xie, J., Ikenoue, T., Yu, J., Li, L., Zheng, P., Ye, K., Chinnaiyan, A., Halder, G., Lai, Z.-C. and Guan, K.-L. (2007). Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes and Development 21: 2747-2761. (This paper was selected by Faculty of 1000).
- Wei, X., Shimizu, T., and Lai, Z.-C. (2007). Mob as tumor suppressor is activated by Hippo kinase in growth inhibition in Drosophila. The EMBO Journal 26: 1772-1781.
- Lai, Z.-C. Wei, X., Shimizu, T., Ramos, E., Rohrbaugh, M., Nikolaidis, N., Ho, L.-L., and Li, Y. (2005). Control of cell proliferation and apoptosis by Mob as tumor suppressor, Mats. Cell 120: 675-685. (This paper was selected by Faculty of 1000)
