Francis Ka-Ming Chan, PhD
Our lab is interested in how cell death impacts innate inflammation and immune responses. We have a long-standing interest in the biology and signaling mechanism of tumor necrosis factor (TNF), a key cytokine that regulates many inflammatory diseases (e.g. rheumatoid arthritis, inflammatory bowel diseases etc), pathogen infections, and cancer. Several key discoveries made by the PI during his graduate school and postdoctoral training include identification of one of the first cell cycle inhibitors, INK4d-p19 (Mol Cell Biol. 1995, cited over 300 times), and the discovery of the "pre-ligand assembly domain (PLAD)" that mediates TNF receptors signal transduction (Science 2000, cited over 800 times).
In recent years, we have focused our effort on elucidating the signaling mechanism of a novel form of inflammatory cell death termed necroptosis. In 2009, our group identified Receptor Interacting Protein kinase 3 (RIPK3) as a central mediator of necroptosis (Cell, 2009, cited over 1000 times). Current projects include (1) deciphering the signaling mechanisms of necroptosis, (2) interrogation of the biology of RIPK3 and related necroptosis signaling molecules in intestinal wound healing and inflammation, (3) elucidation of the role of necroptosis in pathogen infections, and many others.
We aim to take the knowledge we gain from basic pathway discovery to better understand the principles of immune regulation. We believe our endeavor will pave the way for more efficacious therapeutic intervention in auto-inflammatory diseases, cancers and pathogen infections.
Current research projects in the lab include the following broad areas. Interested students and postdoctoral candidates are encouraged to contact Dr. Chan for more information on rotation projects and research opportunities.
1. The role of necroptosis signal adaptors in inflammatory diseases
We are interested in how the kinases RIPK1 and RIPK3, both of which have critical functions in cell death, contribute to injury-induced inflammation and tissue repair. Currently, we are using mouse models of intestinal injury and inflammation to study the function of these signal adaptors in intestinal homeostasis.
2. The role of cell death in anti-viral immune responses
We have discovered that necroptosis is an important innate immune defense mechanism against certain viruses. We are interested in how host cell death during pathogen infections can alter the course of the host immune response. On the other hand, we are also interested in exploring the mechanisms employed by different viral pathogens in combating the host cell death machinery.
3. Signaling mechanism of RIP kinases in cell death and inflammation
We found that the RIP kinases can promote inflammation through cell death-dependent and independent mechanisms. What are the molecular events that regulate the diverse functions of the RIP kinases? We are using biochemical, cell biological, and genetic tools to dissect the molecular regulation of these important immune signaling molecules.
Education and Training
- Ph.D., University of California at Berkeley, 1996
Selected Grants and Awards
Luz, Nivea F., Ricardo Khouri, Johan Van Weyenbergh, Dalila L. Zanette, Paloma P. Fiuza, Almerio Noronha, Aldina Barral, et al. “Leishmania braziliensis Subverts Necroptosis by Modulating RIPK3 Expression..” Frontiers in Microbiology 9 (January 2018). https://doi.org/10.3389/fmicb.2018.02283.
Moriwaki, Kenta, Sakthi Balaji, John Bertin, Peter J. Gough, and Francis Ka-Ming Chan. “Distinct Kinase-Independent Role of RIPK3 in CD11c+ Mononuclear Phagocytes in Cytokine-Induced Tissue Repair..” Cell Rep 18, no. 10 (March 7, 2017): 2441–51. https://doi.org/10.1016/j.celrep.2017.02.015.
Moriwaki, Kenta, Nivea Farias Luz, Sakthi Balaji, Maria Jose De Rosa, Carey L. O’Donnell, Peter J. Gough, John Bertin, Raymond M. Welsh, and Francis Ka-Ming Chan. “The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages..” J Immunol 196, no. 1 (January 1, 2016): 407–15. https://doi.org/10.4049/jimmunol.1501662.
Moriwaki, Kenta, Sakthi Balaji, Thomas McQuade, Nidhi Malhotra, Joonsoo Kang, and Francis Ka-Ming Chan. “The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair..” Immunity 41, no. 4 (October 16, 2014): 567–78. https://doi.org/10.1016/j.immuni.2014.09.016.
Li, Jixi, Thomas McQuade, Ansgar B. Siemer, Johanna Napetschnig, Kenta Moriwaki, Yu-Shan Hsiao, Ermelinda Damko, et al. “The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis..” Cell 150, no. 2 (July 20, 2012): 339–50. https://doi.org/10.1016/j.cell.2012.06.019.
Cho, Young Sik, Sreerupa Challa, David Moquin, Ryan Genga, Tathagat Dutta Ray, Melissa Guildford, and Francis Ka-Ming Chan. “Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation..” Cell 137, no. 6 (June 12, 2009): 1112–23. https://doi.org/10.1016/j.cell.2009.05.037.
Chan, Francis Ka-Ming, Joanna Shisler, Jacqueline G. Bixby, Martin Felices, Lixin Zheng, Michael Appel, Jan Orenstein, Bernard Moss, and Michael J. Lenardo. “A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses..” J Biol Chem 278, no. 51 (December 19, 2003): 51613–21. https://doi.org/10.1074/jbc.M305633200.
Wang, J., L. Zheng, A. Lobito, F. K. Chan, J. Dale, M. Sneller, X. Yao, J. M. Puck, S. E. Straus, and M. J. Lenardo. “Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II..” Cell 98, no. 1 (July 9, 1999): 47–58. https://doi.org/10.1016/S0092-8674(00)80605-4.