Abstract
Cdc42, a Rho-family GTPase, has been implicated in several signal transduction pathways, including organization of the actin cytoskeleton, activation of the c-Jun N-terminal MAP kinase (JNK) and stimulation of the nuclear transcription factor kappa B (NF(kappa)B). We report here that exposure of fibroblasts to the inflammatory cytokines tumor necrosis factor (alpha) (TNF(alpha)) and interleukin-1 (IL-1) triggers the activation of Cdc42 leading first to filopodia formation and subsequently to Rac and Rho activation. Inhibition of Cdc42 completely suppresses cytokine-induced actin polymerization, but not activation of JNK or NF(kappa)B. The latent membrane protein 1 of Epstein-Barr virus, LMP1, is thought to mimic constitutively activated TNF family receptors. When expressed in fibroblasts, LMP1 stimulates Cdc42-dependent filopodia formation as well as JNK and NF(kappa)B activation. Using LMP1 mutants, we show that activation of Cdc42 and JNK/NF(kappa)B occur through distinct pathways and that Cdc42 activation is independent of LMP1's interaction with TRADD and TRAF proteins.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells / drug effects
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Actin Cytoskeleton / metabolism
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Actins / metabolism
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Animals
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Bacterial Proteins / metabolism
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Becaplermin
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Biopolymers
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Culture Media, Serum-Free / pharmacology
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Cytoskeleton / drug effects*
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Cytoskeleton / ultrastructure
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Enzyme Activation / drug effects
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Fibroblasts / drug effects
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Herpesvirus 4, Human / physiology
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Inflammation
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Interleukin-1 / pharmacology*
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JNK Mitogen-Activated Protein Kinases
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Mice
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Microinjections
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Microscopy, Fluorescence
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / metabolism
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Platelet-Derived Growth Factor / pharmacology
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Proteins / metabolism
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Proto-Oncogene Proteins c-sis
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Pseudopodia / drug effects
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Recombinant Proteins / pharmacology
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Signal Transduction
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TNF Receptor-Associated Death Domain Protein
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TNF Receptor-Associated Factor 1
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins*
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Tumor Necrosis Factor-alpha / pharmacology*
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Viral Matrix Proteins / pharmacology*
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cdc42 GTP-Binding Protein / antagonists & inhibitors
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cdc42 GTP-Binding Protein / metabolism*
Substances
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Actins
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Bacterial Proteins
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Biopolymers
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Culture Media, Serum-Free
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EBV-associated membrane antigen, Epstein-Barr virus
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Interleukin-1
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NF-kappa B
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Platelet-Derived Growth Factor
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Proteins
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Proto-Oncogene Proteins c-sis
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Recombinant Proteins
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TNF Receptor-Associated Death Domain Protein
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TNF Receptor-Associated Factor 1
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Tradd protein, mouse
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
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Tumor Necrosis Factor-alpha
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Viral Matrix Proteins
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Becaplermin
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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cdc42 GTP-Binding Protein