BIOL, BMMB, MCIBS, NEURS
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.