Jianxun Li, Ph.D., Associate Professor
Department of Oral Biology
College of Dentistry
University of Illinois at Chicago
Tel: 312-996-3520
Email: jxli@uic.edu
The General Direction of Our Research
In the World of Integrin and Cytoskeleton
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Jianxun Li, Ph.D., Associate Professor
Department of Oral Biology College of Dentistry University of Illinois at Chicago Tel: 312-996-3520 Email: jxli@uic.edu |
|
The General Direction of Our Research |
The research focus of our laboratory is cell adhesion, a essential physiological event observed in every aspect of our lifes including immune cell activation, cell proliferation and differentiation, and tumor angiogenesis. We believed that cytoskeleton, membrane and membrane-bound receptors constitute a unified entity, such that a change in one element of the unit signals to other components of the units. However, solid evidence is needed to support this theory. Our research stresses the importance of cytoskeleton which not only functions as a structural support in these events, but also as part of the signaling and regulatory apparatus.
Understanding the activation mechanism of
b2 integrin
b2
integrin is the key adhesion molecule in the activation of leukocytes. The
activation of b2
integrin, i.e. its binding to various ligands, is essential for the activation
of leukocytes in immune defenses. While lacking
b2
integrin-mediated adhesion causes immune deficiency, excessive integrin-mediated
cell adhesion associates with autoimmunity.
In the case of b2
integrin, its ligand-binding activity on the extracellular surface of the plasma
membrane is tightly regulated by a number of intracellular signals originating
from other membrane receptors such as T cell receptors or chemokine receptors.
The question is how this signal transduction works?
Our laboratory and others have demonstrated that the b2 integrin molecules are maintained in an inactive form in resting leukocytes; the molecules are immobilized on the cell membrane in a diffused distribution by constraints from cytoskeletal complex. Activation signals cause the cytoskeletal complex to relax. Relaxation of the cytoskeletal constraint puts integrin in a free diffusion mode and facilitates the formation of clusters and conformational change that provide high avidity and affinity binding to the ligands. Thus, the cytoskeletal components controlling the inactive b2 integrin molecules are termed by our laboratory as “preactivation cytoskeletal complex”. Several proteins have been located into this complex including PKC, MacMARCKS, Dynamitin, Calmodulin, and talin.
In cardiovascular diseases:
Our research funded by American Heart Association is to investigate the b2 integrin activation during the minor inflammation in circulation. Activation of this adhesion molecule many contribute to the accumulation of “foam cells” and atherosclerosis. We are focusing on determining the activation status of b2 integrin in leukocytes and if they are activated, how to calm it down.
In bacterial infection:
In many cases of infections, the final killer is the overwhelm septic responses that proven to be fatal. Uncontrolled activation of leukocytes plays essential role in this case. Because b2 integrin is a key regulator of leukocytes, our laboratory is currently testing the inhibitors of integrin molecules in treating septic shocks.
In Cancer research:
One of main difficulties in fighting cancer is metastasis. Again, integrin plays very important roles in this process. In order for cancer cells to break away from the original sites, it is necessary to down regulate integrin adhesion. For these cancer cells to firmly adhere in a new location, however, the integrin molecules are then upregulated. Thus is a very fine tuned system. We are currently investigating how cytoskeleton is involved in the process.
Our specialized skills in addition to common cell biology and molecular biology techniques
Single
Particle Tracking:
The mobility of individual molecule on the cell membrane reflects its association with cytoskeleton underneath the membrane. Such mobility of b2 integrin can be monitored by coupling single molecules with microbeads under 200 nm through specific antibodies. The beads are small enough so that only one or two integrin molecules can bind to them. Using the contrast enhancement method, the beads can be seen by light microscope, although their size falls below the theoretical resolution of light microscopy. Therefore, by tracking the movement of the beads, we can track movement of the integrin molecules. By analyzing the track, we can calculate the mobility of integrin and obtain its diffusion coefficient (D), which in turn reflects the cytoskeletal constraint on the membrane receptors.
Fluorescent
Resonance Energy Transfer:
This method allows the detailed study of protein-protein interaction in living cells at real time to obtain temporal and spatial information. In this method, two interacting proteins are each labeled with different fluorophores. The emission wavelength of one (donor) fluorophore is the excitation wavelength of the other (acceptor). If the two proteins are close enough (50A), the excitation of the first fluorophore will result in the emission of the second fluorophore. This process, FRET, is highly sensitive to the distance (reciprocal to the R6, R = distance between two fluorophores) and orientation of two proteins (that carry the fluorophores). Therefore, FRET reflects the interaction of the two proteins.
1985-1990 Ph.D. Biochemistry
Department of Biochemistry
City University of New York, New York
1985-1990 M.S Biochemistry
Department of Biochemistry
City University of New York, New York
1985-1988 M.A. Biochemistry
Department of Chemistry
City College of New York, New York
1982-1985 M.S. Biochemistry:
Department of Endocrinology
Shanghai Institute of Biochemistry, Academia, Sinica
1978-1982 B.S. Biology
Department of Biology
Wuhan University, China
2000-Present Tenured Associate Professor, Department of Oral Biology, College of Dentistry, University of Illinois at Chicago
1998-Present Associate Professor, Department of Oral Biology, College of Dentistry, University of Illinois at Chicago
1998-Present Faculty of the Graduate College of the University of Illinois at Chicago
1994 - 1997 Assistant Professor, Department of Microbiology and Immunology, University of Tennessee, Memphis, College of Medicine
1994 - 1997 Faculty of the Graduate School of the University of Tennessee
1992 - 1994 Postdoctoral Fellow, Laboratory of Signal Transduction, The Rockefeller University.
1990 - 1992 Postdoctoral Associate, Laboratory of Cellular Physiology and Immunology, The Rockefeller University.
Recipient of Cancer Research Institute postdoctoral fellowship.
Recipient of the Established Investigator Award, American Heart Association
NIH Grant:
1996-2001 NIGMS RO1 P.I.
Protein Kinase C-mediated Integrin activation
2001-2006 NIGMS RO1 P.I.
Protein Kinase C-mediated Integrin activation
2001-2005 American Heart Association Established Investigator P.I.
Microtubule and Motor Proteins in
Integrin Activation
1996-2005 The Council of Tobacco Research Grant P.I.
Role of a C Kinase Substrate in
Macrophage phagocytosis.
1994-1995 American Cancer Society Grant P.I.
PKC substrates in the membrane
trafficking
1994-1995 UT Medical Group Foundation Grant P.I.
Macrophage Phagocytosis
1991-1994 Cancer Research Institute Fellowship
Macrophage Activation
1997-2000 American Heart Association Grant P.I.
Protein Kinase C-mediated
Integrin Activation
(Declined in favor of CTR grant)
Jianxun Li and Horst Schulz. 1988. 4-Bromo-2-octenoic acid specifically inactivates 3-ketoacyl-CoA thiolase and thereby fatty acid oxidation in rat liver mitochondria. Biochemistry 27:5995-6000.
Tor Smeland, Jianxun Li, Chinhong Chu, Dean Cubas and Horst Schulz. 1989. The 3-hydroxyacyl-CoA epimerase activity of rat liver peroxisomes is due to the combined action of two enoyl-CoA hydratases. Biochem. Biophys. Res. Commun. 160:988-992.
Jianxun Li, Tor E. Smeland and Horst Schulz. 1990. D-3-Hydroxyacyl coenzyme A dehydratase from rat liver peroxisomes. J. Biol. Chem. 265:13629-13634.
Jianxun Li, Daniel L. Norwood and Horst Schulz. 1990. Mitochondrial metabolism of valproic acid. Biochemistry 30:388-394.
Tor Smeland, Jianxun Li, Dean Cubas and Horst Schulz. 1991. New Development in Fatty Acid Oxidation. P.M. Coatf and K. Tanaka (eds). Wiley-Liss.
Jianxun Li and Alan Aderem. 1992. MacMARCKS, a novel member of the MARCKS family of protein kinase C substrates. Cell. 70:791-801.
Zixin Zhu, Zhihua Bao and Jianxun Li 1995. MacMARCKS mutation blocks macrophage phagocytosis of zymosan. J. Biol.Chem. 270:17652-17655
Jianxun Li, Zixin Zhu and Zhihua Bao 1996. Role of MacMARCKS in integrin-dependent macrophage spreading and tyrosine phosphorylation of paxillin. J. Biol.Chem. 271: 12985-12990
Lili Yue, Zhihua Bao and Jianxun Li. 1999. MacMARCKS is an essential component in LFA-1 and ICAM-1 mediated leukocyte aggregation. J. Cell. Physiol. 181, 355-360.
Lili Yue, Zhihua Bao and Jianxun Li. 2000. MacMARCKS restores the adhesion of Wehi 274.1.7 cells to the ICAM-1-coated surface. Cell Adhesion and Communication, 7(5). p355-366.
Lili Yue, Shijiang Lu, Jorge Garces, Tianquan Jin and Jianxun Li, 2000. Protein Kinase C-regulated Dynamitin-MacMARCKS interaction is Involved in Macrophage Cell Spreading. J. Biol. Chem. 275(31), p23948-23956
Tianquan Jin, Lili Yue and Jianxun Li 2001. In Vivo Interaction between Dynamitin and MacMARCKS Detected by the Fluorescent Resonance Energy Transfer Method. J. Biol. Chem. 276(16), p12879-12884
Ximing Zhou and Jianxun Li, 2002. The microtubule cytoskeleton participates in control of beta(2) integrin avidity. J. Biol. Chem. 276 (48): 44762-44769
Ximing Zhou, Tianquan Jin and Jianxun Li, 2002. The Signal Transduction Pathways Regulating the Cytoskeletal constraint on b2 Integrin through Ca2+, PKC and Calmodulin.
Hongying Zhen, Lili Yue and Jianxun Li, 2002. Biochemical Characterization of the ATPase Activity of Dynamitin.