Immunology Graduate Group

Michael S. Marks, Ph.D.
Associate Professor, Pathology & Laboratory Medicine

Address: 230 John Morgan Bldg./ 6082
Office Phone: (215) 898-3204
Lab Phone: (215) 898-2925
Fax: (215) 573-4345
Email:  marksm@mail.med.upenn.edu

Dr. Marks' Cell & Molecular Biology page

Education:
Ph.D., Duke University
B.S., Cornell University, Ithaca, NY

Research Interests

Intracellular protein transport, organelle biogenesis, diseases of organelle biogenesis, tumor antigen processing.

Research Summary

Our laboratory is interested in understanding how proteins are delivered to endosomal compartments within cells and how specialized sorting and delivery mechanisms are utilized to generate tissue-specific endosomal organelles. Our work stems from our interests in antigen processing by major histocompatibility complex (MHC) class II molecules. MHC class II molecules are specialized to present CD4+ T cells with peptides that are derived from antigens encountered in late endocytic organelles of antigen presenting cells. To do this, the antigens, class II molecules, and accessory proteins must be specifically targeted to endosomes. We are trying to understand the basic molecular processes that govern endosomal protein sorting and how it may be applicable to presentation of tumor-associated antigens, particularly those associated with melanoma. We are also trying to understand how sets of tumor-associated antigens are trafficked within melanoma cells. These tumor-associated antigens elicit CD4+ T cell responses in some melanoma patients, and we hope to understand how intracellular trafficking and localization contribute to these responses. Furthermore, the trafficking of these antigens, of some antigen presenting molecules, and of residents of cytotoxic granules within cytotoxic T cells is disturbed in a number of genetic diseases, such as Hermansky-Pudlak and Chediak-Higashi syndromes. We are trying to understand how the products of the genes affected in these diseases contribute to the trafficking of the relevant proteins.

We use a combination of molecular biology, cell biology, microscopy, and biochemistry to study the fate of selected "cargo" proteins within cells and to manipulate the protein sorting machinery. Through mutagenesis and chimeric protein approaches, we are trying to understand how various signals impart specificity for localization to distinct compartments. Through the use of dominant negative molecular approaches, biochemical techniques, and genetic tools provided by mouse models of Hermansky-Pudlak syndrome, we are also trying to better define the pathways taken by melanoma-associated antigens and class II molecules to their appropriate compartments. Finally, we are beginning to introduce cell-free assays to better assess the role of components of the sorting machinery in discrete trafficking step.

Immunofluorescence microscopy analysis of the intracellular localization of two melanoma-associated antigens, Tyrp1 and Pmel17, relative to Lamp1 in a melanoma cell line. Tyrp1 and Pmel17 are normal constituents of melanocytes and function in melanin synthesis and storage; they are also targets of CD4+ and CD8+ T lymphocytes in patients with malignant melanoma. This figure shows that within melanoma cells, the compartments that contain these proteins are largely distinct from those that contain an ubiquitous integral membrane protein of late endosomes and lysosomes, Lamp1. They are also distinct from each other. We are dissecting the transport pathways involved in segregating these proteins and assessing how these transport pathways contribute to eliciting MHC class II-restricted T cell responses.

Recent Publications

Yoshino, A, BM Bieler, DC Harper, DA Cowan, S Sutterwala, DM Gay, NB Cole, JM McCaffery and MS Marks (2003). A role for GRIP domain proteins and/or their ligands in structure and function of the trans Golgi network. J. Cell Sci, in press.

*Nichols, S, *DC Harper, JF Berson and MS Marks (2003). An alternatively spliced form of Pmel17 expressed in melanocytes and melanoma cells lacking some of the internal repeats. J. Invest. Dermatol, in press.

Berson, JF, AC Theos, DC Harper, D Tenza, G Raposo and MS Marks (2003). Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis. J. Cell Biol. 161: 521-533.

Marks, MS, A Theos and G Raposo (2003). Melanosomes and MHC class II antigen processing compartments: a tinted view of intracellular trafficking and immunity. Immunol. Res. 27: 409-426.

Setty, SRG, ME Shin, A Yoshino, MS Marks and CG Burd (2003). Golgi recruitment of GRIP domain proteins by Arf-like GTPase 1 (Arl1p) is regulated by Arf-like GTPase 3 (Arl3p). Curr. Biol. 13: 401-404.

Raposo, G, B Fevrier, W Stoorvogel and MS Marks (2002). Lysosome related organelles in antigen presenting cells and melanocytes. Cell Struct. Function 27, 443-456.

Raposo, G and MS Marks (2002). The dark side of lysosome-related organelles: specialization of the endosomal pathway for melanosome biogenesis. Traffic 3: 237-248.

Cowan, D, D Gay, BM Bieler, H Zhao, A Yoshino, JG Davis, MM Tomayko, R Murali, MI Greene and MS Marks (2002). Characterization of mouse tGolgin-1 (golgin-245/ trans golgi p230/ 256kD golgin) and its upregulation during oligodendrocyte development. DNA and Cell Biol., 21: 505-517.

Marks, MS and MC Seabra (2001). The melanosome: membrane dynamics in black and white. Nature Rev. Mol. Cell Biol. 2: 738-748.

Berson, JF, DC Harper, D Tenza, G Raposo and MS Marks (2001). Pmel17 initiates premelanosome morphogenesis within multivesicular bodies. Mol. Biol. Cell 12: 3451-3464.

Raposo, G, D Tenza, DM Murphy, JF Berson and MS Marks (2001). Distinct protein sorting and localization to premelanosomes, melanosomes, and lysosomes in pigmented melanocytic cells. J. Cell Biol. 152: 809-823.

 

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