title: Activation of the small GTPase Cdc42 by the inflammatory cytokines TNF(alpha) and IL-1, and by the Epstein-Barr virus transforming protein LMP1.
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.
authors.affiliation: MRC Laboratory for Molecular Cell Biology, CRC Oncogene and Signal Transduction Group, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: A
authors.initials: A
authors.lastname: Puls
authors.forename: A G
authors.initials: AG
authors.lastname: Eliopoulos
authors.forename: C D
authors.initials: CD
authors.lastname: Nobes
authors.forename: T
authors.initials: T
authors.lastname: Bridges
authors.forename: L S
authors.initials: LS
authors.lastname: Young
authors.forename: A
authors.initials: A
authors.lastname: Hall
mesh_terms: D016475:3T3 Cells / Q000187:drug effects; D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D000077214:Becaplermin; D001704:Biopolymers; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects* / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000502:physiology; D007249:Inflammation; D007375:Interleukin-1 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008845:Microinjections; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D011554:Pseudopodia / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein; D047990:TNF Receptor-Associated Factor 1; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014763:Viral Matrix Proteins / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000199:Actins; D001426:Bacterial Proteins; D001704:Biopolymers; D016895:Culture Media, Serum-Free; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007375:Interleukin-1; D016328:NF-kappa B; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D053199:TNF Receptor-Associated Death Domain Protein; D047990:TNF Receptor-Associated Factor 1; C481226:Tradd protein, mouse; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins; D000077214:Becaplermin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein