Michael S. Marks, Ph.D.

faculty photo
Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine

Contact information
Children's Hospital of Philadelphia Research Institute
1107B Abramson Research Center
3615 Civic Center Blvd.
Philadelphia, PA 19104
Office: (215) 590-3664
Lab: (215) 590-3944
Education:
B.S. (Biological Sciences)
Cornell University, 1982.
Ph.D. (Immunology/Microbiology)
Duke University Durham, NC, 1989.
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Description of Research Expertise

Research Interests
Regulation and diseases of intracellular protein transport and organelle biogenesis.
Regulation of the formation of functional amyloid in organelle biogenesis.
Regulation of antigen processing and toll-like receptor signaling by endosomal trafficking pathways.

Key words: Melanosome, lysosome, melanoma, intracellular protein transport, vesicles, secretory lysosomes, Hermansky Pudlak syndrome, amyloid, protein sorting, platelets, antigen processing, major histocompatibility complex molecules, toll-like receptors.

Description of Research
Eukaryotic cells are 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, how sorting and assembly contribute to the biogenesis of specific organelles in several cell types, how these processes impact biological function in the pigmentary, blood clotting, and immune systems, and how they are thwarted by generally rare genetic diseases.

Our primary focus over the past 15 years has been on melanosomes of pigmented cells. Melanosomes are unique lysosome-related organelles present only in cells that make melanin, the major synthesized pigment in mammals. Genetic defects in melanosome constituents or in their delivery to nascent melanosomes result in ocular or oculocutaneous albinism, characterized by lack of pigmentation in the eyes and or skin and concomitant visual impairment and susceptibility to skin and ocular cancers. Melanosomes are among a number of tissue-specific lysosome-related organelles that are malformed and dysfunctional 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, we are dissecting the molecular mechanisms that regulate how different stage melanosomes are formed and integrated with the endosomal pathway. We use biochemical, morphological, and genetic approaches to follow the fates of melanosome-specific and ubiquitous endosomal and lysosomal proteins within pigment cells from normal individuals or mice and disease models. Using these approaches, we are (1) outlining protein transport pathways that lead to the formation of these unusual organelles, (2) dissecting biochemical pathways that lead to their morphogenesis, and (3) defining how these processes are subverted by genetic disease. Current efforts focus on how factors that are deficient in patients and mouse models of the genetic disease, Hermansky-Pudlak syndrome, impact melanosome biogenesis. We are particularly interested in how these factors contribute to the formation and dynamics of tubular connections between endosomes and maturing melanosomes that facilitate cargo transport.

Because genetic diseases like Hermansky-Pudlak syndrome affect multiple organ systems, we study how similar sorting processes involved in melanosome biogenesis influence other organelles in different cell types. The first involves lysosome-related organelles in platelets called dense granules and alpha granules. When platelets are activated at sites of blood vessel damage, the contents of these granules are released, leading to optimal blood clot formation and platelet activation. Like melanosomes, dense granules are malformed in Hermansky-Pudlak syndrome, and in collaboration with the Poncz, Stalker and French laboratories at CHOP and Penn we are studying how dense granule contents are delivered within platelets and their precursors (megakaryocytes). Studies in collaboration with the Poncz lab also address the contents and secretion of alpha granules and their disruption in human bleeding disorders.

The second cellular system is the dendritic cell, a master regulator of T cell-mediated immunity. Patients with Hermansky-Pudlak syndrome type 2 have recurrent bacterial infections, and we have found that this is at least in part due to defects in the way that dendritic cells sense bacterial infection. Normally, ingested bacteria trigger signaling by innate immune receptors present on the membrane enclosing the bacteria (the phagosome); this signaling is defective in dendritic cells from a mouse model of the disease due to impaired recruitment of the receptors and their signaling platforms. Ongoing studies aim to dissect how phagosome membrane dynamics normally lead to signaling and how this is altered in disease states.

Finally, melanosome precursors in pigment cells harbor intrernal fibrils upon which melanins deposit in later stages. The main component of these fibrils is a pigment cell-specific protein, PMEL. Fibrils formed by PMEL in vitro display features common with amyloid formed in disease states such as Alzheimer and Parkinson diseases. By dissecting how PMEL forms amyloid under physiological conditions, we hope to determine how the formation of "good" and "bad" amyloid differs and thus how the formation of "bad" amyloid might be controlled.




Rotation Projects for 2015-2016
1. Define metal import defects in melanocytes from mouse models of Hermansky-Pudlak syndrome types 7-9.
2. Assess role of Sec1/Munc18 family members in regulating melanosome biogenesis.
3. Define targeting signals for incorporation of transmembrane cargo proteins in megakaryocyte dense granules or lung epithelial cell lamellar bodies.
4. Assess phosphoinositide distribution during phagosome maturation in dendritic cells.
5. Test for anterograde and retrograde trafficking defects in dendritic cells and macrophages from Hermansky-Pudlak syndrome model mice.

Lab personnel:
Adriana Mantegazza - Senior Scientist
Megan Dennis - Post-doctoral fellow
Jialing Bao - Post-doctoral fellow
Tina Ho – BGS Graduate Student (CAMB)
Hayley Hanby - BGS Graduate Student (CAMB)
Dawn Harper - Research Associate
Amanda Acosta - Undergraduate researcher
Alexis Borden - Undergraduate researcher

Selected Publications

Meng R, Wu J, Harper DC, Wang Y, Kowalska MA, Abrams CS, Brass LF, Poncz M, Stalker TJ, and Marks MS: Defective release of alpha-granule and lysosome contents from platelets in mouse Hermansky-Pudlak syndrome models. Blood 125(10): 1623-1632, March 2015.

Bellono N, Escobar IE, Lefkovith AJ, Marks MS and Oancea EV: An intracellular anion channel critical for pigmentation. eLife 3: e04543, December 2014.

Mantegazza AR, Zajac AL, Twelvetrees A, Holzbaur EL, Amigorena S and Marks MS: TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation. Proc. Natl. Acad. Sci. U.S.A. 111(43): 15508-15513, October 2014.

Delevoye C, Miserey-Lenkei S, Montagnac G, Gilles-Marsens F, Paul-Gilloteaux P, Giordano F, Waharte F, Marks MS, Goud B and Raposo G: Recycling endosome tubule morphogenesis from sorting endosomes requires the kinesin motor KIF13A. Cell Rep. 6(3): 445-454, February 2014.

Marks MS, Heijnen HFG and Raposo G: Lysosome-related organelles: Unusual compartments become mainstream. Curr. Opin. Cell Biol. 25(4): 495-505, August 2013.

Watt B, van Niel G, Raposo G and Marks MS: PMEL: A pigment cell-specific model for functional amyloid formation. Pigment Cell and Melanoma Res. 26(3): 300-315, May 2013.

Sitaram A, Dennis MK, Chaudhuri R, De Jesus-Rojas W, Tenza D, Setty SRG, Wood CS, Sviderskaya EV, Bennett DC, Raposo G, Bonifacino JS and Marks MS: Differential recognition of a dileucine-based sorting signal by AP-1 and AP-3 reveals a requirement for both BLOC-1 and AP-3 in delivery of OCA2 to melanosomes. Mol. Biol. Cell 23(16): 3178-3192, August 2012.

Meng R, Wang Y, Yao Y, Zhang Z, Harper DC, Heijnen HFG, Sitaram A, Li W, Raposo G, Weiss MJ, Poncz M and Marks MS: SLC35D3 delivery from megakaryocyte early endosomes is required for platelet dense granule biogenesis and differentially defective in Hermansky-Pudlak syndrome models. Blood 120(2): 404-414, July 2012.

Mantegazza AR, Guttentag SH, El-Benna J, Sasai M, Iwasaki A, Shen H, Laufer TM and Marks MS: Adaptor protein-3 in dendritic cells facilitates phagosomal Toll-like receptor signaling and antigen presentation to CD4+ T cells. Immunity 36(5): 782-794, May 2012.

Sitaram A and Marks MS: Mechanisms of protein delivery to melanosomes in pigment cells. Physiology 27(2): 85-99, April 2012.

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Last updated: 03/26/2015
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