Research Interests
A major emphasis in our laboratory is the study of a receptor protein tyrosine kinase, Mertk,that belongs to the Axl/Mer/Tyro3 family. This family has been implicated in a number of growth promoting processes and are highly expressed in certain tumor cells. A number of cancer-related attributes have been reported for these receptors and it suggests that this family is involved in cell survival, proliferation, adhesion, activation and gene regulation. Our focus is to understand the molecular and cellular function of these receptor tyrosine kinases on primary cells in normal and disease tissue.
At the time of our entry into these studies, two members Axl and Tyro3 had been discovered already and characterized considerably in cell lines; however, Mertk, both human and murine, was cloned soon afterwards by Doug Graham in Dr. Shelley Earps laboratory after it was found to be associated with a number of pediatric lymphomas. From an initial tissue distribution analysis, Mertk was expressed in a number of organs including brain, heart, kidney, reproductive, liver, spleen and bone marrow. Interestingly, part of this tissue distribution suggested an immune cell connection. Mertk was found on myeloid cells but not T cells or B cells. In collaboration with Doug Graham, we found Mertk was associated with T cell lymphomas, but was not expressed by resting or activated human primary T cells (Graham, Clin. Cancer Res 2006). This suggested that under normal conditions, Mertk was not expressed normally and appeared not to have a function in primary human T cells.
Todd Camenisch, who was a graudutate student in Dr. Shelley Earps lab, produced a mertkkd mouse in collaboration with Dr. Beverly Kohler. This mouse was targeted to express the extracellular domains of Mertk but disruption of the cytoplasmic kinase domain resulted in a null Mertk mouse as protein was not detected by Western blots or flow cytometry. Initial characterization also confirmed that Mertk was not expressed in murine T or B cells. However, it was shown to be expressed in macrophages and in spleen. When Todd entered my lab to further characterize the mertkkd mouse, we did not notice any increase in tumor formation in animals kept for greater than a year.
We have since worked on the hypothesis that Mertk may have biologic functions in normal cells. We set out to understand the function of Mertk in immune cells as Mertk had shown prominent expression in macrophages. Our intial work demonstrated Mertk regulates macrophage activation and immune function. Using a common macrophage stimulant, lipopolysaccharide (LPS) which is a component of Gram-negative bacteria, we found that Mertk was regulating transcription of cytokines such as tumor necrosis factor alpha (TNF-), partly through NFkB (Camenisch. J. Immunol. 1999) and AP-1 (in prep). There was an increased secretion of TNF- due to the absence of Mertk that made these mertkkd mice susceptible to endotoxic shock, a clinically important problem. Thus, Mertk receptor was shown to be biologically relevant serving to down regulate signal transduction, cellular activity, cytokine secretion, and prevention from death.
Subsequently, our lab discovered a second major function for Mertk on macrophages. We found that Mertk serves as a receptor that recognizes apoptotic cells. The clearance of apoptotic cells is critical for controlling immune activation and inflammation, tissue homeostasis and autoimmunity (Scott, Nature 2001). We demonstrated that Mertk regulates phagocytosis specifically as other mechanisms of phagocytosis such as Fc receptor-mediated or particle phagocytosis was unaffected. Furthermore, we corroborated the vital role Mertk plays in maintaining healthy retinal tissue through retinal pigment epithelial (RPE) cells (Scott, Nature 2001; Duncan, Invest. Ophthal. 2003). Mertk is critical for the RPE to remove shed apoptotic-like outer segments of rods and cones. Without this process, the retina degenerates and animals and humans become blind. We have recently shown that Mertk alone is the critical receptor on the RPE and mice with deletions of Axl or Tyro3 have normal eyes. Lastly, we demonstrated that a consequence of not clearing apoptotic cells results in autoimmune disease similar to systemic lupus erythematosus (Scott, Nature 2001; Cohen, J. Exp. Med. 2002). The production of autoantibodies likely results from the dysregulation of dendritic cells, a cell type important in cancer control. The function of Mertk on dendritic cells is currently under investigation in my lab with a recent submission of a manuscript under consideration (Seitz, J. Immunol., Submitted). The mertkkd mouse is one of the few phagocytic receptors associated with clearance of apoptotic cells that results in autoimmunity. Thus, Mertk appears to be a control point for a number of major biological processes and diseases.
Interestingly, we have now described differential usage of the Axl/Mertk/Tyro3 family dependent on the cell type. For instance, macrophages use primarily Mertk for the phagocytosis of apoptotic cells whereas dendritic cells use Axl and Tyro 3 but not Mertk (Seitz, J. Immunol. Submitted). Yet, in macrophages, Axl and Tyro3 are necessary for proper phosphorylation of Mertk, a process thought to be important for receptor activation and subsequent multiple cell signaling pathways. It is not clear why there is this preferential usage by each cell type; however, a complicated mechanism may be emerging that partitions phagocytic function from the regulation of signal transduction.
Our studies have been a platform for a number of major discoveries for this family of receptor tyrosine kinases. Mertk is now being investigated by a number of researchers here at UNC and elsewhere. It has been implicated either experimentally or clinically to affect retinitis pigmentosus (Scott, Nature 2001; Duncan, Invest. Ophthal. 2003), systemic lupus erythematosus (Scott, Nature 2001; Cohen, J. Exp. Med. 2002; Qian, Blood 2006), diabetes (Sen, Blood 2007; Wallet, J. Exper. Med, Submitted), reproduction (Lu, Nature 1999), inflammation and endotoxic shock (Camenisch, J. Immunol. 1999), atherosclerosis (Li, J. Biol. Chem. 2006), thrombosis (Angelill-Scherrer, J. Clin. Invest. 2005), NK hematopoesis, and to be involved in many different immune cell functions. Mertk is also important for natural killer cells and the role of Mertk in tumor immunity is currently being investigated in Dr. Earps laboratory. In my NIH biosketch, I have highlighted in bold the publications relevant to Mertk/Axl/Tyro3 and our current relevant funding from NIH is an RO1 AI50736 regarding the clearance of apoptotic cells. We have expanded our studies to include Axl and Tyro3 and together with Mertk, a more complicated interaction is emerging (Seitz, J. Immunol submitted). We continue to study signal transduction and the biological consequences of this important family of receptor tyrosine kinases, mindful that understanding the normal biological functions and signal transduction pathways regulated by Axl/Mertk/Tyro3 may provide insights into cancer biology and immune responses to cancer.

Recent Accomplishments and Honors
1989-1989 Postdoctoral Fellow, Department of Neurology, University of Southern Calif., Los Angeles, CA. Mentor: Dr. Stephen A. Stohlman
1990-1994 NIH Training and Arthritis Foundation Postdoctoral Fellow, Lineberger Comprehensive Cancer Center & Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC. Mentor: Dr. Jenny P.-Y. Ting
1995-2001 Assistant Professor, Department of Microbiology and Immunology
2001-current Associate Professor, Department of Microbiology and Immunology; UNC Neuroscience Center; Program in Molecular Biology & Biotechnology.
Faculty; member of Curriculum in Neurobiology; Curriculum of Oral Biology, Comprehensive Center of Inflammatory Disorders; Neurodevelopment Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Training
Degree: Ph.D.
Awarding Institution: University of Southern California
Los Angeles, CA ( Dr. Stephen A. Stohlman)
Date: 1984-1988
Specialty: Microbiology

Degree: M.S.
Awarding Institution: California State University, Los Angeles
Los Angeles, CA (Dr. Ken Andersen/Dr. Jeffrey A. Frelinger)
Date: 1980-1982
Specialty: Microbiology

Degree: B.S.
Awarding Institution: University of Southern California
Los Angeles, CA
Date: 1972-1977
Specialty: Biology

Publications
Woodward, J.G., MATSUSHIMA, G.K., Frelinger, J.A. and S.A. Stohlman. 1984. Fine specificity and genetic restriction of T cell clones specific for mouse hepatitis virus, strain JHM. J. Immunol. 133:1016-1021.
Stohlman, S.A., MATSUSHIMA, G.K., Casteel, N., and J.A. Frelinger. 1985. The defect in DTH in young adult SJL is due to a lack of functional antigen-presenting cells. Eur. J. Immunol. 15:913-916.
MATSUSHIMA, G.K., Harmon, R.C., and J.A. Frelinger. 1986. A new murine lymphocyte alloantigen, Ly-27.2. Immunogenetics 23:406-408.
Stohlman, S.A., MATSUSHIMA, G.K., Casteel, N., and L.P. Weiner. 1986. In vivo effects of coronavirus-specific T cell clones: DTH inducer cells prevent a lethal infection but do not inhibit virus replication. J. Immunol. 136:3052-3056.
Keck, J.G., MATSUSHIMA, G.K., Makino, S., Fleming, J.O., Vannier, D.M., Stohlman, S.A., and M.M.C. Lai. 1988. In vivo RNA-RNA recombination of coronavirus in mouse brain. J. Virol. 62:1810-1813.
MATSUSHIMA, G.K., and S.A. Stohlman. 1988. Maturation of the delayed-type hypersensitivity response in SJL mice: Absence of effector cell function. Eur. J. Immunol. 18:1411-1416.
Stohlman, S.A., Sussman, M.A., MATSUSHIMA, G.K., Shubin, R.A., and S.S. Erlich. 1988. Delayed-type hypersensitivity response in the central nervous system during JHM virus infection requires viral specificity for protection. J. Neuroimmunol. 19:255-268.
MATSUSHIMA, G.K., Gilmore, W., Casteel, N., Frelinger, J.A., and S.A. Stohlman. 1989. Evidence for a subpopulation of antigen-presenting cell specific for the induction of the delayed-type hypersensitivity response. Cell. Immunol. 119:171-181.
Erlich, S.S., MATSUSHIMA, G.K., and S.A. Stohlman. 1989. Studies on the mechanism of protection from acute viral encephalomyelitis by delayed-type hypersensitivity inducer T cell clones. J. Neurol. Sci 90:203-16.
MATSUSHIMA, G.K., and S.A. Stohlman. 1991. Distinct subsets of accessory cells activate Thy-1+ triple negative (CD3-, CD4-, CD8-) cells and the Th-1 delayed-type hypersensitivity effector T cells. J. Immunol. 146:3322-3331.
MATSUSHIMA, G.K., Itoh-Lindstrom, Y., and J. P.-Y. Ting. 1992. Activation of the HLA-DRA gene in primary human T lymphocytes: Novel usage of TATA and the X and Y promoter elements. Mol Cell Biol 12:5610-19.
MATSUSHIMA, G.K., Taniike, M., Suzuki, K., Grusby, M., Glimcher, L.H., Frelinger, J.A., and J.P.-Y. Ting. 1994. Absence of MHC class II genes reduces CNS demyelination, microglial/macrophage infiltration, and twitching in murine globoid cell leukodystrophy. Cell 78:645-656.
Hiremath, M.M., Saito, Y., Knapp, G.W., Ting, J.P.-Y., Suzuki, K., and MATSUSHIMA, G.K. 1998. Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice. J. Neuroimmunol. 92:38-49.
Morell, P., Barrett, C., Mason, J., Toews, A., Hostettler, J, and MATSUSHIMA, G.K. 1998. Gene expression in brain during cuprizone-induced demyelination and remyelination. Molec. Cell. Neurosci. 12:220-227.
Camenisch, T.D., Koller, B.H., Earp, H.S., and MATSUSHIMA, G.K. 1999. A novel tyrosine receptor kinase, Mer, inhibits TNF-a production and lipopolysaccharide-induced endotoxic shock. J. Immunol. 162:3498-03.
Lu, Q., Martin, G., Zhang, Q,. Camenisch, T. D., Boast, S., Casagranda, F., Lai, C., Skinner, M.K., Klein, R., MATSUSHIMA, G.K., Earp, H.S., Goff, S.P., and Lemke, G. 1999. Receptor tyrosine kinases of the Tyro 3 family are essential regulators of mammalian spermatogenesis. Nature 398:723-728.
Fu, K, Light, A.R., MATSUSHMA, G.K., and Maixner, W. 1999. Microglia reactions after subcutaneous formalin injection into the rat hind paw. Brain Res. 825:59-67.
Mason, J., Morell, P., Suzuki, K., and MATSUSHIMA, G.K. 2000. Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation. J. Neurosci. Res., 61:251-262.
Wu, Y.-P., McMahon, E., Kraine, M.R., Tisch, R., Meyers, A., Frelinger, J., MATSUSHIMA, G.K., and Suzuki, K. 2000. Distribution and characterization of GFP+ donor hematogenous cells in twitcher mice after bone marrow transplantation. Am. J. Pathol., 156:1849-1854.
Mason, J.L., Ye, P., Suzuki, K., DErcole, A.J., and MATSUSHIMA, G.K. 2000. Insulin-like growth factor inhibits mature oligodendrocyte apoptosis during primary demyelination. J. Neurosci. 201:5703-5708.
Gao, X., Gillig, T.A., Ye, P., DErcole, J., MATSUSHIMA, G.K., Popko, B. 2000. Interferon-gamma protects against cuprizone-induced demyelination. Molec. Cell. Neurosci. 16:338-349.
Muse, E.D., Jurevics, H., Toews, A.D., MATSUSHIMA, G.K., and Morell, P. 2000. Parameters related to lipid metabolism as markers of myelination in mouse brain. J. Neurochem. 76:1-11.
Serody, J.S., Burkett, S.E., Panoskaltsis-Mortari, A. Ng-Cashin, J., McMahon, E.J., MATSUSHIMA, G.K., Lira, S.A., Cook, D.N., and Blazar, B.R. 2000. T lymphocyte production of MIP-1a is critical to the recruitment of CD8+ T cells to the liver and lung during graft-versus-host disease. Blood 96:2973-2980.
MATSUSHIMA, G.K. and Morell, P. 2001. The neurointoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol. 11:107-116.
Mason, J.L., Langaman, C., Morell, P., Suzuki, K., and MATSUSHIMA, G.K. 2001. Episodic demyelination and subsequent remyelination within the murine central nervous system: Changes in axonal caliber. Neuropath. Appl. Neurobiol. 27:50-58.
Scott, R.S., McMahon, E.L., Pop, S.M., Reap, E.A., Carrichio, R., Cohen, P.L., Earp, H.S., and MATSUSHIMA, G.K. 2001. Phagocytosis and clearance of apoptotic cells is mediated by Mer. Nature 411:207-211.
Mason, J.L., Suzuki, K., Chaplin, D.D., and MATSUSHIMA, G.K. 2001. IL-1 promotes remyelination in the central nervous system. J. Neurosci. 21:7046-52.
McMahon, E.J., Cook, D.N., Suzuki, K., and MATSUSHIMA, G.K. 2001. Absence of MIP-1 delays CNS demyelination in the presence of an intact blood-brain barrier. J. Immunol. 167:2964-71.
Arnett, H.A., Mason, J.L., Marino, M., Old, L., Suzuki, K., MATSUSHIMA, G.K. and Ting, J.P.-Y. 2001. TNF- signaling through TNFR2 promotes proliferation of oligodendroctye progenitors and remyelination.
Nature Neuroscience 4:1-7.
Wu, Y.-P., McMahon, E.J., Matsuda, J., Suzuki, K., MATSUSHIMA, G.K., and Suzuki, K. 2001. Expression of immune-related molecules is down regulated in twitcher mice following bone marrow transplantation. J. Neuropathol. Exper. Neurol. 60:1062-1074.
Hellendall, R.P., Arnett, H.A., MATSUSHIMA, G.K., Suzuki, K., Laubach, V.E., Sherman, P., and Ting, J. P.-Y. 2002. The protective role of inducible nitric oxide synthetase (iNOS) in a neurotoxicant-induced demyelinating model. J. Immunol. 168:427-433.
Cohen, P.L., Caricchio, R., Abraham, V., Camenisch, T.D., Jennette, C., Roubey, R.A.S. Earp, H.S., MATSUSHIMA, G., and Reap, E.A. 2002. Delayed apoptotic cell clearance and Lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J. Exper. Med. 196:135-140.
McMahon, E.J., Suzuki, K., and MATSUSHIMA, G.K. 2002. Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact BBB. J. Neuroimmunol. 130:32-45.
Duncan, J.L., LaVail, M.M., Yasumura, D., Matthes, M.T., Yang, H., Trautmann, N., Chappelow, A.V., Feng, W., Earp, H.S., MATSUSHIMA, G.K., and Vollrath, D. 2003. An RCS-like retinal dystrophy phenotype in mer knockout mice. Invest Ophthalmol Vis Sci. 44:826-38.
Arnett H.A., Wang Y., MATSUSHIMA, G.K., Suzuki, K,, Ting, J.P. 2003. Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration. J Neurosci. 23:9824-32.
Yagi, T., McMahon, E.J., Takikita, S., Mohri, I., MATSUSHIMA, G.K., and Suzuki, K. 2004. Fate of donor hematopoietic cells in demyelinating mutant mouse, twitcher, following transplantation of GFP+ bone marrow cells. Neurobiolgy Disease 16: 98-109.
Mason JL, Toews A, Hostettler JD, Morell P, Suzuki K, Goldman JE, and MATSUSHIMA, G.K. 2004. Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. Am. J. Pathol. 164(5):1673-82.
Angelill-Scherrer, A., Burnier, L., Flores, N., Savi, P., DeMol, M., Schaeffer, P., Herbert, M., Lemke, G., Goff, S., MATSUSHIMA, G.K., Earp, S., Vesin, C., Hoylaerts, M.F., Plaisance, S., Collen, D., Conway, E.M., Werhle-Haller, B., and Cameliet, P. 2005. Role of Gas6 receptors in platelet signaling during thrombus stabilization: implications for anti-thrombotic therapy. J. Clin. Invest. 115:237-46.
Li, Y., Gerbod-Giannone, M-C, Seitz, H., Cui, D., Thorp, E., Tall, A.R., Matsushima, G.K., and Tabas, I. 2006. Cholesterol-induced apoptotic macrophages elicit an inflammatory response in phagocytes that is partially attenuated by the Mer receptor. J. Biol. Chem. 281:6707-6717.
Dupree, JL, Mason, JL, Marcus, JR, Stull, M, Levinson, R, MATSUSHIMA, GK, and Popko B. 2006. Oligodendrocytes assist in the maintenance of sodium channel clusters independent of the myelin sheath. Neuron Glia Biol. 1:1-14.
Qian Y, Conway KL, Lu X, Seitz HM, MATUSHIMA GK, and Clarke SH. 2006. Autoreactive MZ and B-1 B cell activation by Faslpr is coincident with an increased frequency of apoptotic lymphocytes and a defect in macrophage clearance. Blood 108:974-982.
Graham DK, Slazberg DB, Kurtzberg J, Sather S, MATSUSHIMA GK, Keating, AK, Liang X, Lovelll M, Williams SA, Dawson TL, Schell MJ, Anwar AA, Snodgrass, HR, and Earp HS. 2006. Ectopic expression of the proto-oncogene Mer in pediatric T cell acute lymphoblastic leukemia. Clin. Caner Res. 12:2662-2669.
Sen P, Wallet MA, Yi Z, Huang Y, Henderson M, Mathews CE, Earp HS, MATSUSHIMA G, Baldwin Jr AS, Tisch RM. 2007. Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-kB activation in dendritic cells. Blood 109:653-660.
Wallet, MA, Sen P, Flores R, Yi Z, Huang Y, Matthews CE, Earp HS, MATUSHIMA GK, Wang, Tisch R. 2007. Mertk is required for apoptotic cell-induced T cell tolerance. J. Exper. Med. (Submitted).
Seitz HM, Camenisch TD, Lemke G, Earp HS, and MATSUSHIMA GK. 2007. Macrophages and dendritic cells utilize different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J. Immunol. (Revisions Submitted).

E-mail: glenn_matsushima@med.unc.edu
Telephone: 966-0408
Address: UNC Neuroscience Center, NSRB 7109D Chapel Hill, NC 27599

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