Key words: signal transduction, pattern formation and growth control, tumor suppressor gene, control of adult stem cell proliferation, tissue regeneration
Cell-cell communication (cell signaling) is a fundamental and prevalent mechanism that controls cell growth, cell fate determination and pattern formation of multicellular organisms. We are interesting in studying how inductive signals are generated and interpreted by cells, and how misregulation of cell signaling may cause diseases such as cancer.
Cell-cell communication is often mediated by conserved signaling pathways, such as Hedgehog (Hh) and Wingless (Wg)/Wnt pathways. Mutations in genes of Hh and Wg/Wnt pathways have been linked to several types of cancers including basal cell carcinomas, the most common cancer afflicting some 750,000 people every year in the United States alone. The Hh and Wg/Wnt pathways are operating in a similar way among organisms as different as Drosophila and human, which means that we can use animal models to study these important pathways.
We have been carrying out systematic genetic screens to identify genes controlling pattern formation and growth of Drosophila adult organs. Toward this end, we have identified many novel components in the Hh, Wg and other signaling pathways. For example, our genetic screen has led to an unexpected and important discovery that the cAMP dependent protein kinase, PKA, plays a pivotal role in regulating Hh signal transduction. We found that PKA acts in concert with GSK3, CK1 and an E3 ubiquitin ligase SCFSlimb to control the proteolytic processing and activity of Cubitus interruptus (Ci), a member of Gli family of zinc-finger transcription factor that transduces Hh signal into the nuclei. Ci forms protein complexes with the kinesin-like protein Costal2 (Cos2), the Ser/Thr kinase Fused (Fu), and the tumor suppressor protein Su(fu). We found that this complex regulates subcellular localization and proteolytic processing of Ci. We are investigating the biochemical mechanisms by which complex formation regulates different aspects of Ci.
Hh transduces signal by binding to the multi-span transmembrane protein Patched (Ptc), leading to the activation of the seven-transmembrane protein Smoothened (Smo). We discovered that Smo transduces Hh signal by physically interacting Cos2/Fu/Ci complexes. In response to Hh, Smo is phosphorylation by PKA and CK1, leading to its cell surface accumulation and active conformation. We are investigating how Smo phosphorylation and trafficking are regulated and how different levels of Hh signal are transduced by Smo to activate Ci. In addition, we apply similar genetic, molecular and biochemical approaches to tackle other new components in the Hh and related pathways.
We are also interested in understanding how cell growth and organ size are regulated and how growth and patterning are coordinated. Toward this end, we have identified a new tumor suppressor pathway, called Hippo (Hpo) signaling pathway, which controls organ size by restricting cell proliferation and promoting apoptosis in both Drosophila and mammals. We found that KO of mammalian homologues of Hpo (MST1/2) leads to liver cancer. We are exploring the upstream regulators and downstream effectors of Hpo tumor suppressor pathway.
Finally, we are interested in the mechanisms that control adult stem cell proliferation, tissue homeostasis and regeneration. We found that Drosophila adult intestine stem cells undergo excessive proliferation and differentiation to replenish lost cells in response to tissue damage. We are studying how tissue injury leads to changes in stem cell behaviors.
Awards & Honors
- CPRIT Individual investigator award
- Eugene Mc Dermott Scholar in Biomedical Research, UT Southwestern
- Leukemia & Lymphoma Society Scholar Award
- Searle Scholars, The Chicago Community Trust