Francis Ka-Ming Chan

Overview:

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.

Positions:

Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1996

University of California - Berkeley

Grants:

Necroptosis signaling adaptors in inflammatory diseases

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Viral mechanisms of necroptosis evasion

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Viral inhibition of cell death in host immune responses

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Viral inhibition of cell death in host immune responses

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Non-apoptotic signaling through Fas activates Akt and promotes T cell differentiation through Caspase-8

Authors
Yi, F; Ouyang, C; Yamamoto, T; Cruz, A; Chan, FK; Frazzette, N; Thomas, S; Restifo, NP; Siegel, RM
MLA Citation
Yi, Fei, et al. “Non-apoptotic signaling through Fas activates Akt and promotes T cell differentiation through Caspase-8.” Journal of Immunology, vol. 198, no. 1, 2017.
URI
https://scholars.duke.edu/individual/pub1489401
Source
wos-lite
Published In
The Journal of Immunology
Volume
198
Published Date

Measurement of molecular interactions in living cells by fluorescence resonance energy transfer between variants of the green fluorescent protein.

Many signal transduction pathways operate through oligomerization of proteins into multi-subunit complexes. Although biochemical assays can identify potential protein-protein interactions, studying these interactions in living cells is more challenging. Fluorescence resonance energy transfer (FRET) has been used as a "spectroscopic ruler" to measure molecular proximity, but these methods have been limited by the need for chemical labeling of target proteins or labeled antibodies. We present methods for examining interactions between target proteins molecularly fused to cyan and yellow variants of the green fluorescent protein (GFP) by FRET in living cells. Flow cytometric and microscope-based methods are described that have been applied to a variety of interacting proteins.
Authors
Siegel, RM; Chan, FK; Zacharias, DA; Swofford, R; Holmes, KL; Tsien, RY; Lenardo, MJ
MLA Citation
Siegel, R. M., et al. “Measurement of molecular interactions in living cells by fluorescence resonance energy transfer between variants of the green fluorescent protein.Sci Stke, vol. 2000, no. 38, June 2000, p. pl1. Pubmed, doi:10.1126/stke.2000.38.pl1.
URI
https://scholars.duke.edu/individual/pub1498615
PMID
11752595
Source
pubmed
Published In
Science'S Stke : Signal Transduction Knowledge Environment
Volume
2000
Published Date
Start Page
pl1
DOI
10.1126/stke.2000.38.pl1

The scaffold-dependent function of RIPK1 in dendritic cells promotes injury-induced colitis.

Receptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death. While RIPK1 promotes cell death through its kinase activity, it also functions as a scaffold protein to promote cell survival by inhibiting FADD-caspase 8-dependent apoptosis and RIPK3-MLKL-dependent necroptosis. This pro-survival function is highlighted by excess cell death and perinatal lethality in Ripk1-/- mice. Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. Hematopoietic stem cell transplantation restored not only immunodeficiency but also intestinal inflammatory pathology, indicating that RIPK1 in hematopoietic cells is critical to maintain intestinal immune homeostasis. Here, we generated dendritic cell (DC)-specific Ripk1-/- mice in a genetic background with loss of RIPK1 kinase activity and found that the mice developed spontaneous colonic inflammation characterized by increased neutrophil and Ly6C+ monocytes. In addition, these mice were highly resistant to injury-induced colitis. The increased colonic inflammation and the resistance to colitis were restored by dual inactivation of RIPK3 and FADD, but not by inhibition of RIPK3, MLKL, or ZBP1 alone. Altogether, these results reveal a scaffold activity-dependent role of RIPK1 in DC-mediated maintenance of colonic immune homeostasis.
Authors
Moriwaki, K; Park, C; Koyama, K; Balaji, S; Kita, K; Yagi, R; Komazawa-Sakon, S; Semba, M; Asuka, T; Nakano, H; Kamada, Y; Miyoshi, E; Chan, FKM
MLA Citation
Moriwaki, Kenta, et al. “The scaffold-dependent function of RIPK1 in dendritic cells promotes injury-induced colitis.Mucosal Immunol, Aug. 2021. Pubmed, doi:10.1038/s41385-021-00446-y.
URI
https://scholars.duke.edu/individual/pub1496451
PMID
34462571
Source
pubmed
Published In
Mucosal Immunol
Published Date
DOI
10.1038/s41385-021-00446-y

Identifying Fas/CD95 non-apoptotic signaling pathways associated with T cell differentiation

Authors
Thomas, SK; Ouyang, C; Cruz, AC; Klebanoff, CA; Yamamoto, TN; Chan, FK; Mocarski, ES; Roback, L; Restifo, NP; Siegei, RM
MLA Citation
Thomas, Stacy K., et al. “Identifying Fas/CD95 non-apoptotic signaling pathways associated with T cell differentiation.” Journal of Immunology, vol. 196, 2016.
URI
https://scholars.duke.edu/individual/pub1489402
Source
wos-lite
Published In
The Journal of Immunology
Volume
196
Published Date

Detection of Protein-Protein Interactions in vivo Using Cyan and Yellow Fluorescent Proteins

This article describes a technique for detecting protein?protein interactions in vivo using cyan and yellow fluorescent proteins. The phenomenon of fluorescence resonance energy transfer (FRET) describes the transfer of energy from one fluorophore to another through dipole-dipole interaction. The use of GFP variants such as CFP (cyan) and YFP (yellow) in FRET analysis has the additional advantage of allowing detection of intracellular associations in living cells. While most of the applications of FRET have employed fluorescence microscopic imaging methods, it has recently become feasible to perform FRET analysis using flow cytometry. One needs to perform electronic compensation to remove CFP emission from the FRET channel (P5-P6). One then should perform interlaser compensation between CFP and YFP using Omnicomp circuitry to remove YFP excitation from the 413-nm laser. Analyze collected data using Flowjo software. Control samples transfected with non-interacting FRET pairs should be used as negative controls to determine the baseline FRET signal. © 2006 Copyright © 2006 Elsevier Inc. All rights reserved.
Authors
MLA Citation
Chan, F. K. M. “Detection of Protein-Protein Interactions in vivo Using Cyan and Yellow Fluorescent Proteins.” Cell Biology, Four-Volume Set, vol. 2, 2006, pp. 355–58. Scopus, doi:10.1016/B978-012164730-8/50117-9.
URI
https://scholars.duke.edu/individual/pub1498612
Source
scopus
Volume
2
Published Date
Start Page
355
End Page
358
DOI
10.1016/B978-012164730-8/50117-9