- Ph.D., Albert Einstein College of Medicine, 1989
- M.S., Albert Einstein College of Medicine, 1985
- B.S., Peking University, 1982
- University of California at Berkeley
Honors and Awards
- The Global Classroom Award, Penn State, 2011
- Faculty Travel Award for Global Studies, Penn State, 2010
- Collaborative Instructional and Curricular Innovation Award, Penn State, 1998
- March of Dimes Basil O’Connor Starter Scholar Research Award, 1996-1998
- The Merck Academic Development Award, 1992-1994
- Mechanisms of Development Young Investigator Award, 1991
Signal Transduction, Growth Control, and Cancer Genetics
Proper intercellular communication is essential for the normal development of multi-cellular organisms. Our research focuses on a growth-inhibitory signaling pathway, the Hippo pathway, in order to address how tissue growth and organ size are regulated during animal development and how defective cellular signaling can lead to diseases such as cancer.
The Hippo growth-inhibitory pathway is mediated by a number of tumor suppressors, including Hippo and Warts (Wts)/Lats protein kinases. In 2005, my laboratory discovered a novel component of this pathway: Mob as tumor suppressor (Mats) (Lai et al. 2005). Mats functions as a coactivator of Wts kinase, and this function is conserved in evolution. We also found that mats is a target of Hippo kinase. Mats’ phosphorylation by Hippo increases its affinity with Wts/Lats and its ability to increase Wts catalytic activity to target a key downstream oncogeneic protein: Yorkie (Yki). Importantly, the mechanism by which Mats is activated by Hippo via phosphorylation is conserved from flies to humans (Wei et al. 2007). Moreover, the plasma membrane was found to be an important subcellular site for activating tumor suppressors such as Mats (Ho et al. 2010). Our discovery of the mats gene family has led us into studies using other experimental models such as cultured mammalian cells and zebrafish.
Most of our current knowledge about Hippo signaling has come from studies in Drosophila. It is not clear how Hippo pathway components in mammals, such as humans, might function to regulate tissue growth. In collaboration with Dr. K.-L. Guan’s laboratory at the University of California, San Diego, a human oncoprotein YAP (a human homolog of fly Yki) has been investigated. It turned out that Lats/Mats-mediated phosphorylation and cytoplamic localization is critical for YAP inhibition in controlling tissue growth and cell contact inhibition. This is the first time that Hippo signaling has been shown to mediate growth inhibition by targeting the YAP oncoprotein in mammals (Zhao et al. 2007). Moreover, transcription coactivator Yki was found to function as a binding partner with a DNA-binding transcription factor Scalloped (Sd) to control cell number and tissue growth. Similarly, human YAP works with the TEAD family of transcription factors (human Sd proteins) to regulate target gene expression to induce cell growth and epithelial-mesenchymal transition (Zhao et al. 2008; Zhao et al. 2009). Thus, Sd/TEAD and Yki/YAP proteins function together to promote tissue growth by regulating target gene transcription. These studies support a model that defective Hippo signaling leads to human cancer development.
We also have used zebrafish as a model to test the hypothesis that the function of mats as a growth regulator is evolutionarily conserved in vertebrate animals. Through a morpholino-based knockdown approach, we found that mats1 plays a critical role during the early development of zebrafish as mats1 morphant embryos exhibited severe developmental delay similar to that of Drosophila homozygous mats mutants. This abnormal phenotype was caused mainly by defective cell proliferation and apoptosis. Interestingly, mats1 morphant cells proliferate faster than normal cells in chimeric embryos similar to what was observed in Drosophila mats mosaic individuals. These results support the idea that the growth regulatory function of mats genes is conserved during evolution (Yuan et al. 2009).
In collaboration with Dr. Masatoshi Nei’s laboratory, we have done a molecular evolutionary analysis of all the mob genes and found that the mob gene family is a molecular innovation of eukaryotes. From an initial mob ancestor, three duplications occurred very early to generate four groups of mob genes, which continue to exist in most eukaryotes today. This analysis revealed the evolutionary history of the mob gene family and shall help functional studies of the Mob family of proteins (Ye et al. 2009).
- Zhang, Y., Cui, C., and Z.-C. Lai. (2016). The defender against cell death 1 gene is required for tissue growth and efficient N-glycosylation in Drosophila melanogaster. Developmental Biology, in press.
- Deng, Y., Matsui, Y., Pan, W., Li, Q., and Z.-C. Lai. (2016). Yap1 plays a protective role in suppressing free fatty acid-induced apoptosis and promoting survival of pancreatic beta cells. Protein & Cell 7: 362-372.
- Li, Q. and Z.-C. Lai. (2015). Recent progress in studies of factors that elicit b-cell expansion. Protein & Cell 6: 81-87.
- Yu, T., J. Bachman, and Z.-C. Lai. (2015). Mutation analysis of large tumor suppressor genes LATS1 and LATS2 supports a tumor suppressor role in human cancer. Protein & Cell 6: 6-11.
- Li, J., Chen, X., Ding, X., Cheng, Y., Zhao, B., Lai, Z.-C., Hezaimi, K. A., Hakem, R., Guan, K.-L., and C.-Y. Wang. (2013). LATS2 suppresses oncogenic Wnt signaling by disrupting b-catenin/BCL9 interaction. Cell Reports 5: 1650-1663.
- Matsui, Y. and Z.-C. Lai. (2013). Mutual regulation between Hippo signaling and actin cytoskeleton. Protein & Cell 4: 904-910.
- Yu, T., J. Bachman, and Z.-C. Lai. (2013). Evidence for a tumor suppressor role for the Large Tumor Suppressor genes LATS1 and LATS2 in human cancer. Genetics 195: 1193-1196.
- Zhang, Y. and Z.-C. Lai. (2013). Mob as tumor suppressor is regulated by bantam microRNA through a feedback loop for growth control. Biochemical & Biophysical Research Communication 439: 438-442.
- Yu, F., Y. Zhang, H. W. Park, J. Jewell, Q. Chen, Y. Deng, D. Pan, S. S.Taylor, Z.-C. Lai, and K.-L. Guan. (2013). Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. Genes & Development 27: 1223-1232.
- Song, S., J. Lu, Q. Li, Y. Yuan, Z. Zhu, Q. Fan, Y. Xue, Z.-C. Lai, and W. Zhang. (2013). The Drosophila ortholog of breast cancer metastasis suppressor gene, dBrms1, is critical for developmental timing through regulating ecdysone signaling. Developmental Biology 380: 344-350.
- Deng, Y., Y. Matsui, Y. Zhang, and Z.-C. Lai. (2013). Hippo activation through homodimerization and membrane association for growth inhibition and organ size control. Developmental Biology 375: 152-159.
- Ye, X., Y. Deng, and Z.-C. Lai. (2012). Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila. Developmental Biology 369: 115-123.
- Ho, L.-L., X. Wei, T. Shimizu, and Z.-C. Lai. (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., J. Kim, X. Ye, Z.-C. Lai, and K.-L. Guan. (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., S. Lin, Z. Zhu, W. Zhang, and Z.-C. Lai. (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., N. Nikolaidis, M. Nei, and Z.-C. Lai. (2009). Evolution of the mob gene family. The Open Cell Signaling Journal 1: 1-11.
- Zhao, B., X. Ye, J. Yu, L. Li, W. Li, S. Li, J. Yu, J. D. Lin, A. M. Chinnaiyan, Z.-C. Lai, and K.-L. Guan. (2008). TEAD mediates YAP dependent gene induction and growth control. Genes & Development 22: 1962-1971.
- Yang, Y., Gupta, V., Ho, L.-L., Zhou, B., Fan, Q., Zhu, Z., Zhang, W., and Z.-C. Lai. (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., L.-L. Ho, and Z.-C. Lai. (2008). The mob as tumor suppressor gene is essential for early development and regulates tissue growth in Drosophila. Genetics 178: 957-965.
- Zhao, B., X. Wei, W. Li , R. S. Udan, Q. Yang, J. Kim, J. Xie, T. Ikenoue, J. Yu, L. Li, P. Zheng, K. Ye, A. Chinnaiyan, G. Halder, Z.-C. Lai, and K.-L. Guan. (2007). Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes & Development 21: 2747-2761. (This paper was selected by Faculty of 1000).
- Wei, X., T. Shimizu, and Z.-C. Lai. (2007). Mob as tumor suppressor is activated by Hippo kinase in growth inhibition in Drosophila. The EMBO Journal 26: 1772-1781.
- Lai, Z.-C., X. Wei, T. Shimizu, E. Ramos, M. Rohrbaugh, N. Nikolaidis, L.-L. Ho, and Y. Li. (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).