Zhi-Chun Lai
Education
Ph.D., Albert Einstein College of Medicine, 1989
M.S., Albert Einstein College of Medicine, 1985
B.S., Peking University, 1982
Postdoctoral Training
University of California at Berkeley
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
Research Interests
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).