Mickey Marks

Cell Biology and Physiology Program

Address

513 Stellar-Chance Labs/ 6100 (office)
515 Stellar- Chance Labs/ 6100 (lab)
422 Curie Boulevard
Philadelphia PA 19104-6100

Office tel.: 215 898-3204
Lab tel.: 215 898-2925
Fax: 215 573-4345
E-mail: marksm@mail.med.upenn.edu

Link(s)

Dr. Marks's Immunology Graduate Group page

EDUCATION

Cornell University: BS (Biological Sciences), 1982.

Duke University: PhD (Immunology/Microbiology), 1989.

RESEARCH INTERESTS

• Regulation and diseases of intracellular protein transport and organelle biogenesis.
• Regulation of the formation of functional amyloid in organelle biogenesis.

Key words: Melanosome, lysosome, golgi, melanoma, intracellular protein transport, vesicles, secretory lysosomes, Hermansky Pudlak syndrome, amyloid, protein sorting.

Search PubMed for articles

DESCRIPTION OF RESEARCH

The central vacuolar system of eukaryotic cells is compartmentalized into distinct membrane-bound organelles and vesicular structures, each with its own characteristic function and set of protein constituents. Work in my laboratory is focused on understanding how integral membrane protein complexes are assembled and sorted to the appropriate compartments within the late secretory and endocytic pathways, and how sorting and assembly contributes to the biogenesis of specific organelles.

Our current efforts are mainly focused on melanosomes of pigmented cells. Melanosomes are unique lysosome-related organelles present only in cells that make melanin, the major synthesized pigment in mammals. Melanosomes are among a number of tissue-specific lysosome-related organelles that are disrupted in a group of rare heritable disorders, including Hermansky-Pudlak and Chediak-Higashi syndromes, and pigment cell-specific proteins that localize to melanosomes are targets for the immune system in patients with melanoma. In an effort to understand the molecular basis of these diseases and of presentation of melanosomal proteins to the immune system, we are trying to understand how different stage melanosomes are formed and integrated with the endosomal pathway. We use biochemical and morphological approaches to follow the fates of melanosome-specific and ubiquitous endosomal and lysosomal proteins within pigment cells from normal individuals/ mice and disease models. Using these approaches, we are (1) outlining protein transport pathways that lead to the formation of these unusual organelles and (2) dissecting biochemical pathways that lead to their morphogenesis. Current efforts focus on (1) the role of cytoplasmic factors in mediating melanosome protein transport and biogenesis, including factors deficient in patients and mouse models of Hermansky-Pudlak syndrome, and (2) the regulation of fibril formation by one of the melanosome proteins, Pmel17, which physiologically displays features common with amyloid formed in disease states such as Alzheimer's disease and the prion diseases. We hope that by dissecting how Pmel17 forms amyloid like fibrils under physiological conditions, we may not only understand melanosome biogenesis but also the formation of amyloid under pathological conditions.

One of the main pathologic features of Hermansky-Pudlak syndrome is excessive bleeding, due to a failure to generate another lysosome-related organelle, the dense granule, in megakaryocytes and platelets. We are thus beginning to extend our studies of organelle biogenesis into megakaryocytes by comparing protein sorting to distinct stages of melanosomes in pigment cells to what we believe will be related sorting processes to dense granules and other platelet lysosome-related organelles.

A major finding in our lab has been that multivesicular endosomes play an important intermediary role in melanosome biogenesis, and that different melanosome cargoes are sorted to internal membranes within these endosomes by different - and non-tissue-specific - mechanisms. We are trying to understand the molecular basis for these mechanisms and whether heterogeneity among the internal membranes plays an important biological role in processes other than organelle biogenesis. For example, the immune system hijacks secreted forms of these internal membranes to stimulate or anergize specific T lymphocytes, and the source of membrane might influence the outcome of anti-melanoma immune responses.

RECENT PUBLICATIONS

Raposo, G. and M.S. Marks. (2007). Melanosomes - dark organelles enlighten endosomal membrane transport. Nature Rev. Mol. Cell Biol., in press.

Setty, SRG, D Tenza, ST Truschel, EM Chou, EV Sviderskaya, AC Theos, ML Lamoreux, SM Di Pietro, M Starcevic, DC Bennett, EC Dell'Angelica, G Raposo and MS Marks. (2007). BLOC-1 is required for cargo-specific sorting from vacuolar early endosomes toward lysosome-related organelles. Mol. Biol. Cell 18, 768-780.

Theos, AC, JF Berson, SB Cromer, DC Harper, KE Herman, EV Sviderskaya, ML Lamoreux, DC Bennett, G Raposo and MS Marks. (2006). Dual loss of ER export and endocytic signals with altered melanosome morphology in the silver mutation of Pmel17. Mol. Biol. Cell. 17, 3598-3612.

Theos, AC, ST Truschel, DC Harper, JF Berson, D Tenza, PC Thomas, G Raposo and MS Marks .(2006). A novel pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis. Dev. Cell. 10, 343-354.

Fowler, DM, AV Koulov, C Alory-Jost, MS Marks, WE Balch and JW Kelly. (2006). Functional amyloid formation within mammalian tissue. PLoS Biol. 4: e6.

LAB

Rotation Projects

1. Use an in vitro assay to dissect factors required for incorporation of Pmel17 in internal vesicles of multivesicular bodies.
2. Use an in vitro assay to define the trigger for fibril formation by the Pmel17 lumenal domain.
3. Define how SNARE proteins interact functionally and biochemically with the products of genes deficient in Hermansky-Pudlak syndrome types 3, 5, 6, 7 and 8.
4. Identify the melanosome sorting defects in melanocytes from Hermansky-Pudlak syndrome types 3, 5 and 6.
5. Define SNARE components present in megakaryocyte/ platelet dense granules and alpha granules.

Personnel:

Subba Rao Gangi Setty – Senior Research Investigator (Post-doc)
Brenda Watt – Graduate Student (CAMB)
Anand Sitaram – Graduate Student (CAMB)
Dawn Harper Maholik - Research Specialist
Wilfredo de Jesús Rojas - Undergraduate Researcher