Life-or-death, our cells or ourselves are struggling throughout the life cycle, decisions are made whenever a genetic aberration or an environmental challenge is encountered. For instance, unsuccessful pregnancy or birth defects occurs at early stage of the development, tissue regeneration or degeneration happens following tissue damages, and tumorigenesis initiates when cell growth is out of control. The fitness of a tissues is heavily depended on the proliferation and differentiation of tissue specific stem cells, the latter is regulated by different signals at the stem cell niche. The communication between stem cells and niche factors is mediated by diverse signaling pathways, such as Wnt, Shh, TGF-β,Notch and Hippo. These pathways, via a cell-autonomous or a non-cell-autonomous approach, instruct cells to proliferate, differentiate, die, migrate, or hibernate. Our group is interested in the Hippo signaling pathway—a pathway plays a pivotal role in early development, tissue regeneration, and tumorigenesis. Currently, we are dissecting the regulatory mechanisms of the Hippo pathway, and studying its biological/pathological functions, particularly in tissue regeneration and cancer.
The Hippo Pathway
The Hippo pathway, represented by a kinase cascade, has been exquisitely established by genetic studies in both Drosophila and mice: MST1/2 (the Hippo kinases) or MAP4Ks phosphorylate and activate LATS1/2, and LATS1/2 phosphorylate and inactivate YAP/TAZ transcriptional co-activators . YAP/TAZ regulate target gene expression mainly through interaction with TEAD transcription factors. The Hippo pathway is regulated by upstream components (such as NF2, KIBRA, and AMOT) or diverse physical/biochemical signals (such as cell polarity, cell-cell contact, cell-ECM interaction, mechanical cues, and diffusible signals including a variety of G-protein-coupled receptor ligands ). We are particularly interested to know how these upstream signals transmit to downstream kinases and effectors.
Hippo Pathway In Tissue Regeneration
The Hippo pathway is involved in the regeneration of several organs, such as intestine, liver, and skin. Following tissue damage, the activity of YAP, the major effector of the Hippo pathway, is transiently induced, which in turn promotes expansion of tissue-resident progenitors and facilitates tissue regeneration. However, how the Hippo pathway activity is dynamically regulated remains mysterious. Moreover, given the importance of the Hippo pathway in cell plasticity, novel and specific activators of YAP may be a powerful tool for promoting tissue regeneration. We are interested to develop new strategies to facilitate tissue regeneration by targeting the Hippo pathway.
Hippo Pathway In Cancer
YAP and TAZ, the major effectors of the Hippo pathway, are two homologous oncoproteins, and they are inhibited by upstream regulators with tumor suppressor function. YAP and TAZ are frequently activated or highly expressed in various cancer specimens. Moreover, their activity has been linked to resistance to some widely used anti-cancer drugs, and YAP activation is responsible for relapse in some cancers. Thus the Hippo pathway represent an ideal target for anti-cancer therapies. We are interested in the mechanisms underlying YAP and TAZ activation in cancer, and the function of YAP and TAZ in cancer initiation and development.