Duojia (D.J.) Pan, Ph.D.
Professor of Molecular Biology and Genetics
714A Preclinical Teaching Building
Link to Dr. Pan's webpage
Growth Control in Normal Development and Cancer
1. Control of cell size by hormones and nutrients.
Studies from my laboratory have revealed two evolutionarily conserved pathways that act in concert to regulate cell size. These include the insulin and the Tsc1/Tsc2/TOR pathways. Tsc1 and Tsc2 are tumor suppressors mutated in the human tumor syndrome tuberous sclerosis complex (TSC), but their molecular mechanisms had been unclear. Our studies showed that the insulin and the Tsc1/Tsc2/TOR pathways converge on the same translation initiation factors, and activation of either pathway leads to a similar increase in cell size. We demonstrated that the Tsc1/Tsc2/TOR pathway functions as a checkpoint that couples cell growth with nutrient availability. These studies provided a new paradigm for how proteins involved in nutrient sensing could function as tumor suppressors. We further demonstrated that the Tsc1/Tsc2 protein complex functions as GTPase Activating Protein (GAP) towards the small GTPase Rheb, thereby revealing the long sought-after direct target of the Tsc tumor suppressors. The revelation of TOR as downstream target of Tsc1/Tsc2 has led to clinical trials employing rapamycin, a specific inhibitor of TOR, for the treatment of TSC patients.
2. An intrinsic mechanism that stops organ growth.
While environmental cues such as nutrients play an important role in determining organ size, intrinsic counting mechanisms must exist that stop growth when an organ reaches its final size. My laboratory has elucidated a novel kinase cascade (called the Hippo pathway) that plays a critical role in stopping organ growth as cells enter the differentiation phase of organogenesis. The core of the Hippo kinase cascade comprises the Ste20-like kinase Hpo, the NDR family kinase Wts/Lats, and the transcriptional coactivator Yki. Hpo phosphorylates and activates Wts/Lats, which in turn, inactivates Yki by phosphorylating the latter at a critical residue (S168). We showed that the Hippo pathway is required to stop organ growth, and it does so by simultaneously promoting cell death and restricting cell proliferation through the transcriptional regulation of target genes such as the cell cycle regulator cyclin E and the cell death inhibitor diap1. We further delineated a mammalian Hippo pathway that links the mammalian homologues of Hpo (MST1/2), Wts (Lats1/2) and Yki (YAP) in a kinase cascade. Using a conditional YAP transgenic mouse model, we demonstrated that the mammalian Hippo pathway is a potent regulator of organ size and that its dysregulation leads to tumorigenesis in mammals. Very recently, we identified the TEAD/TEF family protein Scalloped as a DNA-binding transcription factor that partners with Yki to mediate the transcriptional output of the Hippo pathway. Our current efforts are focused on identifying additional components of the Hippo pathway, including the elusive signal that triggers its activation.