Department Affiliation: Primary: Molecular Biology and Genetics; Secondary: Pharmacology and Molecular Sciences; Oncology
Degree: Ph.D., University of California, Los Angeles
Telephone Number: 410-502-3179
E-mail address: firstname.lastname@example.org
School of Medicine Address: 714-A Preclinical Teaching Bldg., 725 N. Wolfe Street, Baltimore, MD 21205
Growth control in normal development and cancer; signal transduction; animal models of cancer
During animal development, growth and patterning must be intimately coordinated to generate organs of reproducible size and shape. Compared to our understanding of pattern formation, much less is known about how the size of an organ is determined. My laboratory is using Drosophila and mice as model systems to investigate size-control mechanisms in normal development and their pathological roles in cancer growth. Our general approach is to use Drosophila as a genetic tool to discover size-control genes. We then use a combination of genetics and biochemistry to place these genes into signaling networks. Finally, we use mouse genetics to investigate how the size-control mechanisms we have uncovered in Drosophila regulate tissue homeostasis in mammals. With these concerted efforts, we aim to decipher the universal rules that govern the control of organ size in metazoan animals. Our research has focused on the following two areas.
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.
Wu, S., Huang, J., Dong, J. and Pan, D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114:445-456, 2003. Pub Med Reference
- Huang, J., Wu, S., Barrera, J., Matthews, K. and Pan, D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell 122:421-434, 2005. Pub Med Reference
- Dong, J., Feldman, G., Huang, J., Wu, S., Zhang, N., Comerford, S. A., Gayyed, M. F., Anders, R. A., Maitra, A., and Pan, D. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130:1120-1133, 2007. Pub Med Reference
- Wu, S., Liu, Y., Zheng, Y., Dong, J., and Pan, D. The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev. Cell, 14: 388-398, 2008. Pub Med Reference
- Yu, J., Zheng, Y., Dong, J., Klusza, S., Deng, W-M., and Pan, D. Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev. Cell 18:288-299, 2010. Pub Med Reference
- Ling, C., Zheng, Y., Yin, F., Yu, J., Huang, J., Hong, Y., Wu, S., and Pan, D. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc. Natl. Acad. Sci. USA 107:10532-10537, 2010. Pub Med Reference
- Zhang, N., Bai, H., David, K.K., Dong, J., Zheng Y., Cai, J., Giovannini, M., Liu, P., Anders, A.A., and Pan, D. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell, 19: 27-38, 2010. Pub Med Reference
- Cai, J., Zhang, N., Zheng, Y., de Wilde, R.F., Maitra, A., and Pan, D. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24:2383-2388, 2010. Pub Med Reference
Other graduate programs in which Dr. Pan participates: