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Actin-based motility of Mycobacterium marinum. Mm are red, actin blue 
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Interaction of IAP (CD47) with integrins and heterotrimeric G proteins depends on cholesterol, which also regulates IAP conformation  |
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Bone marrow-derived macrophages. Actin is red, phosphotyrosine green
| The cartoon shows PLIC domains. The arrowheads point to phagosomes in a macrophage stained with anti-PLIC  |
Locomotion, phagocytosis, and adhesion are highly regulated processes in leukocytes. We study the molecular mechanisms underlying these processes and their regulation. We have been particularly interested in integrins, which are molecules involved in cell-cell recognition and cell attachment to extracellular matrix for virtually every cell in the body. Leukocyte integrins are required for the migration of cells to sites of inflammation and infection and for optimal cell function at these extravascular sites. Many of our studies have focused on leukocyte beta2 and beta3 integrins and the functionally and physically associated molecule Integrin-Associated Protein (IAP or CD47). Current efforts in the laboratory are directed at developing a more detailed molecular understanding of CD47 and integrin function in inflammation and leukocyte integrin cooperation with other host defense receptors. Two relatively new projects have arisen from this work. We have shown that the actin-bundling protein L-plastin (LPL, plastin-2) regulates beta2 integrin dependent signal transduction in leukocytes, and current studies are directed toward understanding molecular mechanism. In a second set of experiments, we have shown that a ubiquitin-related protein family that we call PLICs (for proteins linking IAP to the cytoskeleton) are cytosolic binders to CD47. Our work has shown involvement of PLICs in signaling, endocytosis, and phagocytosis, and current studies are directed toward understanding how this protein mediates crosstalk among these various cellular activities.
References on the lab's work on integrins, CD47, cytoskeleton and inflammation from PubMed (NCBI)
About half the laboratory studies the pathogenesis of Mycobacterial infections using the Mycobacterium marinum model. M. marinum causes a tuberculosis-like disease in fish and is genetically closely related to the human pathogen, M. tuberculosis. It also causes a peripheral granulomatous infection in humans, called fish tank granuloma. We have used transposon mutagenesis to isolate M. marinum mutants that lack specific pathogenic features. Ongoing work is directed at determining the roles for these genes in pathogenesis of mycobacterial infections and their potential as novel therapeutic targets in prevention or therapy of disease. A recent surprising observation is that M. marinum escape from phagosomes and polymerize host cell actin by a mechanism that requires the Arp2/3 complex and WASP family proteins. This is so far unique among Mycobacteria, and we are investigating how M. marinum do this and whether it is relevant to pathogenesis of other Mycobacterial infections.
References on our Mycobacterial work from PubMed (NCBI)
Last modified
by Eric Brown on 6 June 2005