Abstract
Latent membrane protein 1 (LMP1) acts like a permanently activated receptor of the tumor necrosis factor (TNF)-receptor superfamily and is absolutely required for B cell immortalization by Epstein-Barr virus. Molecular and biochemical approaches demonstrated that LMP1 usurps cellular signaling pathways resulting in the induction of NF-kappaB and AP-1 via two C-terminal activating regions. We demonstrate here that a third region encompassing a proline rich sequence within the 33 bp repetitive stretch of LMP1's C-terminus is required for the activation of Janus kinase 3 (JAK3). The interaction of LMP1 and JAK3 leads to the enhanced tyrosine auto/transphosphorylation of JAK3 within minutes after crosslinking of a conditional NGF-R:LMP1 chimera and is a prerequisite for the activation of STAT transcription factors. These results reveal a novel activating region in the LMP1 C-terminus and identify the JAK/STAT pathway as a target of this viral integral membrane protein in B cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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B-Lymphocytes / enzymology
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B-Lymphocytes / metabolism
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Cell Line
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Consensus Sequence / genetics
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DNA / genetics
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DNA / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enzyme Activation
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Herpesvirus 4, Human / genetics
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Herpesvirus 4, Human / metabolism*
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Humans
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Janus Kinase 3
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Mice
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Molecular Sequence Data
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Phosphorylation
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Phosphotyrosine / metabolism
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Proline / genetics
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Proline / metabolism
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Protein Binding
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Receptors, Nerve Growth Factor / genetics
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Receptors, Nerve Growth Factor / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Repetitive Sequences, Amino Acid
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STAT1 Transcription Factor
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Sequence Deletion
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Signal Transduction*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Viral Matrix Proteins / chemistry
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Viral Matrix Proteins / genetics
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Viral Matrix Proteins / metabolism*
Substances
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DNA-Binding Proteins
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EBV-associated membrane antigen, Epstein-Barr virus
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Receptors, Nerve Growth Factor
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Recombinant Fusion Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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Stat1 protein, mouse
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Trans-Activators
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Viral Matrix Proteins
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Phosphotyrosine
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DNA
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Proline
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Protein-Tyrosine Kinases
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JAK3 protein, human
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Jak3 protein, mouse
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Janus Kinase 3