Molecular and cell biology of Fc receptors: Mechanisms of function and role in phagocytosis and immune clearance.
Fc-gamma receptor, phagocytosis, endocytosis, immune clearance, Syk kinase.
Description of Research
The Schreiber laboratory has been a major contributor to understanding the molecular and cell biology of Fc-gamma receptors (receptors for immunoglobulin G) in human health and disease. The Fc-gamma receptors are part of the complex immune system that has evolved to enable cells to detect and destroy microbes during infection and antibody coated red blood cells and platelets and immune complexes in autoimmune disorders. Expression of Fc-gamma receptors on the surface of specialized cells such as macrophages enables these cells to ingest antibody-coated particles and bacteria (phagocytosis) and immune complexes (endocytosis).
For example, in addition to elucidating basic mechanisms involved in Fc-gamma receptor phagocytosis and endocytosis and the role of the Fc-gamma receptors, the research has demonstrated that the insertion of specific Fc-gamma receptors into non-phagocytic cells enables those cells to mediate phagocytosis and immune clearance. This finding has led to the concept that modification of non-phagocytic cells to express Fc-gamma receptors may enhance the ability of the body to defend itself against infection. Another therapeutic implication is in autoimmune disease. Modifying cells to express Fc-gamma receptors may enhance the clearance of harmful immune complexes from the circulation, thereby preventing their deposit in the tissues.
Studies in the Schreiber laboratory have had major implications for understanding the human immune-mediated thrombocytopenic disorders, where activating antibodies directed against the platelet surface can lead to thrombosis. In addition, studies are on-going on the role of Fc-gamma receptors in end stage kidney disease and in alcoholic cirrhosis and the molecular signaling apparatus responsible for such diseases as rheumatoid arthritis, systemic lupus erythematosus and serious infection.
Rotation Projects for 2006-2007
1. Pathways of Fc-gammaRIIA and Fc-gammaRI internalization and association with Syk kinase during phagosome formation and maturation.
2. Differences in phagosome fusion and its accompanying calcium signal among Fc-gamma receptors.
3. Clearance of IgG coated cells by Fc-gamma receptors.
4. Effect of PECAM-1 on Fc-gamma receptor signaling.
5. Role of Cbl and ubiquitination in Fc-gamma receptor function.
6. Identification of Fc-gammaRI gamma chain cytoplasmic domain sequences that modulate receptor mediated cytokine release.
Paul Chien, PhD - Research Specialist
Zena K. Indik, PhD - Senior Research Investigator
Sharon Hunter, PhD - Research Specialist
Moo-Kyung Kim, MD - Research Specialist
Xiao-Qing Pan, MD- Research Specialist
Zhen-Yu Huang, MD- Research Specialist
Brian Jones, BA - Graduate Group Student
Randall Worth, PhD - Postdoctoral Student
Hesamm Gharavi, MD - Postdoctoral Student
Jessica Billet, BA - Research Specialist
Tai-Hee Kim-Han, BA- Research Specialist
Booth JW, Kim MK, Jankowski A, Schreiber AD, Grinstein S: Contrasting requirements for ubiquitlylation during Fc receptor-mediated endocytosis and phagocytosis. EMBO J 21: 251-258, 2002.
Coppolino MG, Dierckman R, Loijens J, Collins RF, Pouladi M, Jongstra-Bilen J, Schreiber AD, Trimble WS, Anderson R, Grinstein S: Inhibition of phosphatidylinositol-4 phosphate 5-kinase la impairs localized actin remodeling and suppresses phagocytosis. J Biol Chem 2002 Notes: in press.
Edberg JC, Qin H, Gibson AW, Yee AM, Redecha PB, Indik ZK, Schreiber AD, Kimberly RP: The CY domain in the Fcƒ× Ria a-chain (CD64) alters ƒ×-chain tyrosine-based signaling and phagocytosis. J Biol Chem 2002 Notes: in press.
Coppolino MG, King C, Mohtashami M, Schreiber AD, Brumell JH, Finlay BB, Grinsteind S.and Trimble WS: Requirement for N-ethylmaleimide-sensitive factor activity at different stages of bacterial invasion and phagocytosis. J Biol Chem 276: 4772-4780, 2001.
Kim M-K, X-Q, Pan, Huang Z-Y, Hunter S, Hwang P-H, Indik ZK and Schreiber AD: Fcƒ× receptors differ in their structural requirements for interaction with the tyrosine kinase Syk in the initial steps of signaling for phagocytosis. Clin. Immunol 98: 125-32, 2001.
Worth RG, Mayo-Bond L, van de Winkel JGJ, Todd RF III, Schreiber AD and Petty HR: The cytoplasmic domain of Fcƒ×RIIA (CD32) participates in phagolysosome formation. Blood 98: 3429-34, 2001.
Marshall JG, Booth JW, Stambolic V, Mak T, Balla T, Schreiber AD, Meyer T and Grinstein S: Restricted accumulation of phosphatidylinositol3kinase products in a plasmalemmal subdomain during phagocytosis. J. Biol. Chem 153: 1369-80, 2001.
Huang Z-Y, Kim M-K, Indik ZK and Schreiber AD: Fcƒ×RIIA in endocytosis and phagocytosis: Role of ubiquitination during and Cbl. Blood 98: 699a, 2001.
Worth RG, Kim M-K and Schreiber AD: The novel Fcƒ×RIIA motif L-T-L provides a specific mechanism for phagolysosome fusion of IgG associated targets. Mol. Biol. of the Cell 12: 202a, 2001.
Worth RG, Kim M-K and Schreiber AD: The novel LTL motif of Fcƒ×RIIA
enhances phagolysosome fusion when transferred to other receptors. Interen'l Soc. for Exp. Hematol. Tokyo, Japan Aug 2001.
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Last updated: 03/30/2010
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