Abstract
Unraveling the molecular mechanisms by which filarial nematodes, major human pathogens in the tropics, evade the host immune system remains an elusive goal. We have previously shown that excretory-secretory product-62 (ES-62), a homologue of phosphorylcholine-containing molecules that are secreted by human parasites and which is active in rodent models of filarial infection, is able to polyclonally activate certain protein tyrosine kinase and mitogen-activating protein kinase signal transduction elements in B lymphocytes. Such activation mediates desensitization of subsequent B cell Ag receptor (BCR) ligation-induced activation of extracellular signal-regulated kinase-mitogen-activated protein (ErkMAP) kinase and ultimately B cell proliferation. We now show that the desensitization is due to ES-62 targeting two major regulatory sites of B cell activation. Firstly, pre-exposure to ES-62 primes subsequent BCR-mediated recruitment of SHP-1 tyrosine phosphatase to abolish recruitment of the RasErkMAP kinase cascade via the Igalphabeta-ShcGrb2Sos adaptor complex interactions. Secondly, any ongoing ErkMAP kinase signaling in ES-62-primed B cells is terminated by the MAP kinase phosphatase, Pac-1 that is activated consequently to challenge via the BCR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / metabolism
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Antigens, Helminth / immunology
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CD79 Antigens
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Dipetalonema / immunology*
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Dual Specificity Phosphatase 2
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Enzyme Activation / immunology
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Glycoproteins / immunology*
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Glycoproteins / metabolism
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Helminth Proteins / immunology
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Intracellular Signaling Peptides and Proteins
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MAP Kinase Signaling System / immunology
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Mice
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Mice, Inbred BALB C
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Mitogen-Activated Protein Kinases / metabolism*
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Phosphorylation
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Phosphorylcholine / immunology*
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Protein Phosphatase 1
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Protein Phosphatase 2
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / metabolism*
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Receptors, Antigen, B-Cell / metabolism*
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Receptors, Antigen, B-Cell / physiology*
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Tyrosine / metabolism
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src Homology Domains / immunology
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src-Family Kinases / metabolism
Substances
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Antigens, CD
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Antigens, Helminth
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CD79 Antigens
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Cd79b protein, mouse
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Glycoproteins
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Helminth Proteins
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Intracellular Signaling Peptides and Proteins
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Receptors, Antigen, B-Cell
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Phosphorylcholine
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Tyrosine
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lyn protein-tyrosine kinase
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src-Family Kinases
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Mitogen-Activated Protein Kinases
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Protein Phosphatase 1
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Protein Phosphatase 2
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DUSP2 protein, human
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Dual Specificity Phosphatase 2
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Dusp2 protein, mouse
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn6 protein, mouse