Dianqing (Dan) Wu
Professor
Joined Yale in 2006

Education:

1981-85	B.S. Biochemistry, Nanjing University
1987-91	Ph.D. Biochemistry, Clarkson University and W. Alton Jones Cell Science Center
1991-94	Postdoc, California Institute of Technology

Research Interests:
Our long-term goal is to understand the molecular basis and function of signal transduction pathways, with the emphasis on those initiated by seven-transmembrane receptors. These receptors can be divided into two groups: one couples to heterotrimeric GTP-binding proteins; and the other binds to ligands including hedgehog proteins and Wnt proteins. Currently, we are focusing on chemoattractant and Wnt-activated signaling.

Chemoattractants, including the superfamily of chemotactic cytokines, chemokines, play an important role in host defense by attracting and activating leukocytes at sites of injury and infection. However, their unchecked activities contribute to may inflammation-related diseases, including atherosclerosis, arthritis, tumorigenesis, and various allergies. Work in my lab has made significant contributions to the understanding of signaling mechanisms and functions of a number of chemoattractant-activated pathways. These include pathways linked by PLC β, PI3Kγ, PIXα/Pak/Cdc42, PTEN, P-Rex1, and Myo1f. We are continuing to use a combination of molecular and cell biological, biochemical, transgenic, functional genomic, and proteomic approaches to characterize novel chemoattractant signaling mechanisms and study their functions in cell migration and inflammation-related paradigms.

The Wnt family of secretory glycoproteins participates in a wide variety of developmental events including, control of cell growth, generation of cell polarity, and specification of cell fate. Wnt pathways have been also closely linked to tumorigenesis and bone formation. Most notable contributions from my is the discovery of the interaction between Wnt coreceptor LRP-5 and Axin, which provides the first connection from a Wnt receptor to a intracellular signaling component and the characterization of the role of Dkk2 in regulation of osteogenic differentiation. We are continuing to work on the elucidation of fundamental mechanisms of Wnt signaling and characterization of their role in pathophysiological processes, including osteoporosis, metabolic syndrome, diabetes, and tumorigenesis, using computation-based virtual screening and chemical genomic approaches, in addition to the aforementioned ones.

Selected References:
1. Li, Z., Jiang, H., Xie, W., Zhang, Z., Smrcka, A., and Wu, D. (2000). Significant Roles Of PLC beta2/3 And PI3Kgamma In Chemoattractant-Mediated Signal Transduction. Science, 287: 1046-1049. [This Week in Science, Science 287;929; Perspective, Science 287;982-985; News and Views, Nature 404; 135-136].

2. Mao, J., Wang, J. Liu, B, Pan, W., Farr, G. H III, Flint, C., Yuan, H., Takada, S., Kimelman, D., Li, L., and Wu, D (2001) Low-Density Lipoprotein Receptor-Related Protein-5 Binds To Axin And Regulates The Canonical Wnt Signaling Pathway. Mol. Cell, 7, 801-809. [News and Views, Nature 411, 255-256]

3. Li, L., Mao, J., Sun, L., Liu, W., and Wu, D. (2002). Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. J Biol Chem 277, 5977-5981.

4. Boyden, L. M., Mao, J., Belsky, J., Mitzner, L., Farhi, A., Mitnick, M. A., Wu, D., Insogna, K., and Lifton, R. P. (2002). High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346, 1513-1521.

5. Li, Z., Hannigan, H, Mo, Z., Liu. B, Lu, W., Wu, Y., Smrcka, A.V., Wu, G., Liu, M., Huang, C-H., and Wu, D. (2003) Directional Sensing Requires G-Mediated PAK1 and PIX-Dependent Activation of Cdc42. Cell 114,215-227. [Mini-review, Cell 114; 153-156]

6. Zhang, Y., Wang, Y., Li, X, Zhang, J., Mao, J., Li, Z., Insogna, K., Zheng, J., Li, L., Harris, S., and Wu, D. (2004) LRP5 HBM G171V Mutation Disrupts LRP5 Interaction with Mesd. Mol. Cell. Biol. 24;4677-4684.

7. . Li, Z., X. Dong, Z. Wang, W. Liu, N. Deng, Y. Ding, L. Tang, T. Hla, R. Zeng, L. Li and D. Wu., (2005) Regulation of PTEN by small GTPases. Nat. Cell Biol., 7;399-404. (News & Views, Nat Cell Biol 7;334; Editors’ Choice, Science 308;327)

8. Li, X., Zhang, Y., Liu, W., Liu, P., Zhang, J., Harris, E.H., and Wu, D., (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem, 280, 19883-19887.

9. Li, X., Liu, P., Liu, W., Zhang, J., Boskey, A., Harris, E. S., Rowe, D., Ke, HuaZhu, and Wu, D. (2005). Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet, 37, 945-952.

10. Dong, X,. Mo, Z,. Guo, C,. Li, Z., and Wu, D. (2005) P-Rex1 Is a Primary Rac2 Guanine Nucleotide Exchange Factor in Mouse Neutrophils. Curr. Biol. 15, 1874-1879.

11. Pan, WJ., Jia, Y., Wang, J., Gan, X., Tsiokas, L., Wu, D., and Li, L. (2005) B-catenin regulates myogenesis by relieving I-mfa-mediated suppression of myogenic regulatory factors in P19 cells. Proc. Natl. Acad. Sci. USA 102, 17378-83.

12. Kim, S. V., W. Z. Mehal, X. Dong, V. Heinrich, M. Dembo, M. S. Mooseker, D. Wu, and R. A. Flavell, Modulation of cell adhesion and motility in the immune system by Myosin 1f. Science. 2006 in press.

13. Mani, A., J. Radhakrishnan, H. Wang, A. Mani, M.A. Mani, C. Nelson-Williams, K.S. Carew, S. Mane, H. Najmabadi, D. Wu, and R.P. Lifton, LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science, 2007. 315: 1278-82

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