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Department Affiliation: Primary: Molecular Biology and Genetics/Howard Hughes Medical Institute; Secondary: Pharmacology and Molecular Sciences
Degree: Ph.D., University of California, Los Angeles
Rank: Adjunct Professor
E-mail address: email@example.com
Address: Dept. of Physiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 95390
Growth control in normal development and cancer; signal transduction; animal models of cancer
The control of organ size is a long-standing puzzle in developmental biology. My laboratory uses Drosophila and mice as model systems to investigate size-control mechanisms in normal development and their pathological roles in cancer. 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 general mechanisms underlying control of organ size in animals.
To discover size-control genes, we conducted genetic screens in Drosophila for mutations that result in overgrowth of adult structures. These overgrowth mutants can be broadly divided into two classes: those associated with an increase in cell size and those associated with an increase in cell number. Earlier studies from my laboratory focused on the cell-size mutants, which led to the discovery of a cell size-controlling pathway that involves the tuberous sclerosis tumor suppressors Tsc1 and Tsc2, the small GTPase Rheb, and the protein kinase TOR. The functional link between Tsc1 and Tsc2 and TOR uncovered in Drosophila paved the way for the clinical development of mTOR inhibitor everolimus in the treatment of subependymal giant cell astrocytoma associated with tuberous sclerosis.
Much of our recent work focused on the overgrowth mutants associated with an increase in cell number. These studies led us to elucidate the Hippo signaling pathway, which plays a critical role in stopping organ growth by simultaneously promoting cell death and cell cycle exit as cells enter the differentiation phase of organogenesis. In Drosophila, the Ste20-like kinase Hippo (Hpo) phosphorylates and activates the NDR family kinase Warts (Wts). Wts, in turn, phosphorylates and inactivates the oncoprotein Yorkie (Yki) by excluding it from the nucleus, where it normally functions as a coactivator for the DNA-binding transcription factor Scalloped (Sd). Building on insights from Drosophila, we further delineated a mammalian Hippo pathway that links the mammalian homologues of Hpo (Mst1/2), Wts (Lats1/2), Yki (YAP), and Sd (TEAD/TEF family members) in an analogous signaling cascade. Using a conditional YAP transgenic mouse model, we showed that the mammalian Hippo pathway is a potent regulator of organ size and that its dysregulation leads to tumorigenesis in mammals.
Our current and future research directions include: 1) elucidating the composition, mechanism and regulation of Hippo signaling using Drosophila as a model; 2) understanding the role of Hippo signaling in mammalian development, regeneration and tumorigenesis using mouse genetics; 3) investigating the ancestral role of Hippo signaling in unicellular organisms; 4) developing small-molecule modulators of the Hippo pathway for cancer and regenerative medicine.
- Zheng, Y., Wang, W., Liu, B., Deng, H., Uster, E., and Pan, D. Identification of Happyhour/MAP4K as alternative Hpo/Mst-like kinases in the Hippo kinase cascade. Dev. Cell, 34: 642-655, 2015. Pub Med Reference
- Cai, J., Maitra, A., Anders, R.A., Taketo, M.M., and Pan, D. beta-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis. Genes Dev., 29: 1493-1506, 2015. Pub Med Reference
- Chen, Q., Zhang, N., Xie, R., Wang, W., Cai, J., Choi, K.S., David, K.K., Huang, B., Yabuta, N., Nojima, H., and Pan, D. Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. Genes Dev., 29: 1285-1297, 2015. Pub Med Reference
- Deng, H., Wang, W., Yu, J., Zheng, Y., Qing, Y., and Pan, D. Spectrin regulates Hippo signaling by modulating cortical actomyosin activity. eLife, Mar 31:e06567, 2015. doi: 10.7554/eLife.06567. Pub Med Reference
Qing, Y., Yin, F., Wang, W., Zheng, Y., Guo, P., Schozer, F., Deng, H., and Pan, D. The Hippo effector Yorkie activates transcription by interacting with a histone methyltransferase complex through Ncoa6. eLife, Jul 15:e02564, 2014. doi: 10.7554/eLife.02564. Pub Med Reference
- Chen, Q., Zhang, N., Gray, R.S., Li, H., Ewald, A.J., Zahnow, C.A., and Pan, D. A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis. Genes Dev., 28: 432-437, 2014. Pub Med Reference
- Yin, F., Yu, J., Zheng, Y., Chen, Q., Zhang, N., and Pan, D. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell, 154: 1342-1355, 2013. Pub Med Reference
- Koontz, L.M., Liu-Chittenden, Y., Yin, F., Zheng, Z., Yu, J., Huang, B., Chen, Q., and Pan, D. The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression. Dev. Cell, 25: 388-401, 2013. Pub Med Reference
- Liu-Chittenden, Y., Huang, B., Shim, J.S., Chen, Q., Lee, S-J, Anders, R.A., Liu, J.O. and Pan, D. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 26: 1300-1305, 2012. Pub Med Reference
- Sebé-Pedrós, A., Zheng, Y., Ruiz-Trillo, I., and Pan, D. Premetazoan origin of the Hippo signaling pathway. Cell Reports, 1: 13-20, 2012. 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
- 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
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
- 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
- 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
- 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
- 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
- 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
Other graduate programs in which Dr. Pan participates: