Dr. Duojia Pan
Size-control mechanisms in development and cancer
Professor, Molecular Biology and Genetics and Oncology
Investigator, Howard Hughes Medical Institute
Ph.D., University of California, Los Angeles, School of Medicine
University of California at Berkeley
Growth control in normal development and cancer
The Pan laboratory uses the fruit fly Drosophila melanogaster as a genetic model to investigate size-control mechanisms in development and their implications for human diseases. Drosophila offers the richest collection of tools for manipulating gene function, and its genome shows the highest degree of conservation to humans among all the invertebrate model organisms.
Using a combination of genetic and biochemical approaches, research from the Pan laboratory has provided critical insights into the molecular underpinning of several growth-control pathways. Another important goal of the Pan laboratory is to take molecules and pathways uncovered in Drosophila and apply this information to the study of growth control in vertebrates.
These studies not only shed light on basic developmental mechanisms, but also provide insights into various human diseases including cancer.
Dr. Pan's research has been focused on the following two areas:
Control of Cell Size by Hormones and Nutrients:
Studies from the Pan 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). 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. The Pan laboratory 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.
They further showed that the Tsc1/Tsc2 protein complex functions as GTPase Activating Protein (GAP) toward 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.
An Intrinsic Mechanism That Stops Organ Growth When it Reaches its Final
A long-standing question in developmental biology is how an organ stops growing when it reaches its final size. The Pan laboratory has discovered a novel kinase cascade (called the Hippo pathway) that plays a critical role in this process. In Drosophila, 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, which in turn, inactivates Yki by phosphorylating the latter at a critical residue
(S168) and excluding it from the nucleus, where it normally functions as a coactivator for the TEAD/TEF family transcription factor Scalloped (Sd). The Pan laboratory showed that the Hippo pathway is required to stop organ growth, and it does so by simultaneously promoting cell death and restricting cell proliferation. Very recently, the Pan laboratory 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, they demonstrated that the mammalian Hippo pathway is a potent regulator of organ size and that its dysregulation leads to tumorigenesis in mammals. The Pan laboratory continues to identify additional components of the Hippo pathway and to investigate the role of Hippo signaling in normal development and cancer.
Cai, J.; Zhang, N.; Zheng, Y.; de Wilde, R.F.; Maitra, A.; Pan, D. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 2010 Nov 1;24(21):2383-2388.
Ling, C.; Zheng, Y.; Yin, F.; Yu, J.; Huang, J.; Hong, Y.; Wu, S.; Pan, D. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10532-10537.
Pan, D. The hippo signaling pathway in development and cancer. Dev Cell. 2010 Oct 19;19(4):491-505
Tian, W.; Yu, J.; Tomchick, D.R.; Pan, D.; Luo, X. Structural and functional analysis of the YAP-binding domain of human TEAD2. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7293-7298.
Yu, J.; Zheng, Y.; Dong, J.; Klusza, S.; Deng, W.M.; Pan, D. Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell. 2010 Feb 16;18(2):288-299.
Zhang, N.; Bai, H.; David, K.K.; Dong, J.; Zheng, Y.; Cai, J.; Giovannini, M.; Liu, P.; Anders, R.A.; Pan, D. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell. 2010 Jul 20;19(1):27-38.