 |
 |
 |
 |
 |
 |
 |
Member Information
Michael S. Marks, PhD
Associate Professor, Department of Pathology and Laboratory Medicine
Office Phone:
Office Fax:
Email:
Website(s): http://www.med.upenn.edu/immun/Faculty/marks.html; http://www.med.upenn.edu/camb/faculty/cbp/marks.html
Education: PhD 1989, Duke University
Keywords: protein transport, multivesicular body formation, organelle biogenesis
Research and/or Clinical Interests:
Characterizing the role of multivesicular bodies in the formation of tissue-specific organelles and the mechanisms by which proteins are targeted to them.
Summary:
Our laboratory studies the mechanisms by which proteins are sorted among endocytic organelles within mammalian cells, with particular emphasis on cell-type specific organelles such as melanosomes of pigment cells and major histocompatibility complex class II compartments in antigen presenting cells. Like late endosomes of all cells, these cell-type specific organelles evolve from multivesicular intermediates in which intralumenal vesicles are formed by invagination of the endosomal limiting membrane. A major focus of our studies is therefore to decipher how the formation of these intralumenal vesicles and the sorting of cargo into them contribute to the formation of specialized organelles. Among the known components of the intralumenal vesicle forming machinery are highly conserved proteins that perform similar functions in yeast, such as Hrs, ESCRT-1, and hVps4, and others that seem to be functionally required only in specialized mammalian cells, such as the products of the genes that are disrupted in patients with Hermansky Pudlak Syndrome.
Interestingly, many of these same components are recruited by HIV to allow for virus budding either from the plasma membrane, as in infected cultured fibroblasts, or into multivesicular endosomes, as in infected macrophages. For example, the ESCRT-1 component Tsg101, via its Hrs binding site, binds directly to HIV Gag protein. This interaction results in recruitment of the ESCRT complexes, which are normally recruited to Hrs-enriched membranes through the Hrs-Tsg101 interaction, to Gag-enriched membranes in infected cells. Virus budding ensues in a manner that is topologically identical to the formation of intralumenal vesicles of multivesicular endosomes. Work in press by other labs implicate additional components of the multivesicular body forming machinery in direct interactions with other virus components. Thus, a deeper understanding of the machinery that drives intralumenal vesicle formation in various cell types will provide us with a more thorough understanding of the potential mechanisms of HIV virus formation. By characterizing multivesicular body formation and protein sorting in specialized cell types, we expect to uncover new avenues for virus budding that may contribute to the infectious cycle of HIV and other pathogenic viruses.
Representative Publications:
Calvo , PA , DW Frank, BM Bieler, JF Berson and MS Marks (1999). A cytoplasmic sequence in human tyrosinase defines a second class of di-leucine-based sorting signals for late endosomal and lysosomal delivery. J. Biol. Chem. 274: 12780-12789.
Berson, JF, DW Frank , PA Calvo, BM Bieler and MS Marks (2000). A common temperature-sensitive allelic form of human tyrosinase is retained in the endoplasmic reticulum at the non-permissive temperature. J. Biol. Chem. 275: 12281-12289.
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.
Berson, JF , DC Harper, D Tenza, G Raposo and MS Marks (2001). Pmel17 initiates premelanosomal morphogenesis within multivesicular bodies. Mol. Biol. Cell 12: 3451-3464.
Marks, MS and MC Seabra (2001). The melanosome: membrane dynamics in black and white. Nature Rev. Mol. Cell Biol. 2: 738-748.
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.
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.
Setty, SRG, ME Shin, A Yoshino, MS Marks and C 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.
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.
Nichols, S, DC Harper, JF Berson and MS Marks (2003). A novel splice variant of Pmel17 expressed by human melanocytes and melanoma cells lacking some of the internal repeats. J. Invest. Dermatol ., in press.
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.
