| ErbB2 receptor tyrosine kinase signaling mediates early demyelination induced by leprosy bacilli. | |
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MedLine Citation:
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PMID: 16892039 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Demyelination is a common pathologic feature in many neurodegenerative diseases including infection with leprosy-causing Mycobacterium leprae. Because of the long incubation time and highly complex disease pathogenesis, the management of nerve damage in leprosy, as in other demyelinating diseases, is extremely difficult. Therefore, an important challenge in therapeutic interventions is to identify the molecular events that occur in the early phase before the progression of the disease. Here we provide evidence that M. leprae-induced demyelination is a result of direct bacterial ligation to and activation of ErbB2 receptor tyrosine kinase (RTK) signaling without ErbB2-ErbB3 heterodimerization, a previously unknown mechanism that bypasses the neuregulin-ErbB3-mediated ErbB2 phosphorylation. MEK-dependent Erk1 and Erk2 (hereafter referred to as Erk1/2) signaling is identified as a downstream target of M. leprae-induced ErbB2 activation that mediates demyelination. Herceptin (trastuzumab), a therapeutic humanized ErbB2-specific antibody, inhibits M. leprae binding to and activation of ErbB2 and Erk1/2 in human primary Schwann cells, and the blockade of ErbB2 activity by the small molecule dual ErbB1-ErbB2 kinase inhibitor PKI-166 (ref. 11) effectively abrogates M. leprae-induced myelin damage in in vitro and in vivo models. These results may have implications for the design of ErbB2 RTK-based therapies for both leprosy nerve damage and other demyelinating neurodegenerative diseases. |
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Authors:
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Nikos Tapinos; Makoto Ohnishi; Anura Rambukkana |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural Date: 2006-07-30 |
Journal Detail:
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Title: Nature medicine Volume: 12 ISSN: 1078-8956 ISO Abbreviation: Nat. Med. Publication Date: 2006 Aug |
Date Detail:
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Created Date: 2006-08-07 Completed Date: 2006-09-21 Revised Date: 2013-05-08 |
Medline Journal Info:
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Nlm Unique ID: 9502015 Medline TA: Nat Med Country: United States |
Other Details:
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Languages: eng Pagination: 961-6 Citation Subset: IM |
Affiliation:
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The Rockefeller University, Bronk Building, Room 501, Box 172, 1230 York Avenue, New York, New York 10021, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Monoclonal / pharmacology Antibodies, Monoclonal, Humanized Butadienes / pharmacology COS Cells Cells, Cultured Cercopithecus aethiops Coculture Techniques Demyelinating Diseases / metabolism*, pathology Enzyme Activation / drug effects Enzyme Inhibitors / pharmacology HeLa Cells Humans Leprosy / metabolism*, microbiology Mice Mice, Knockout Mice, Nude Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / metabolism Mycobacterium leprae / genetics, metabolism* Nitriles / pharmacology Pyrimidines / pharmacology Pyrroles / pharmacology Rats Receptor, erbB-2 / metabolism* Schwann Cells / enzymology, metabolism Sciatic Nerve / metabolism, microbiology, ultrastructure Signal Transduction* |
| Grant Support | |
ID/Acronym/Agency:
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R01 A145816//PHS HHS; R01 NS45187/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Butadienes; 0/Enzyme Inhibitors; 0/Nitriles; 0/PKI 166; 0/Pyrimidines; 0/Pyrroles; 0/U 0126; EC 2.7.10.1/Receptor, erbB-2; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; P188ANX8CK/trastuzumab |
| Comments/Corrections | |
Comment In:
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Nat Med. 2006 Aug;12(8):889-90
[PMID:
16892032
]
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Erratum In:
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Nat Med. 2006 Sep;12(9):1100 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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