ROCK I-mediated activation of NF-kappaB by RhoB.
RhoB is a short-lived protein whose expression is increased by a variety of extra-cellular stimuli including UV irradiation, epidermal growth factor (EGF) and transforming growth factor beta (TGF-beta). Whereas most Rho proteins are modified by the covalent attachment of a geranylgeranyl group, RhoB is unique in that it can exist in either a geranylgeranylated (RhoB-GG) or a farnesylated (RhoB-F) form. Although each form is proposed to have different cellular functions, the signaling events that underlie these differences are poorly understood. Here we show that RhoB can activate NF-kappaB signaling in multiple cell types. Whereas RhoB-F is a potent activator of NF-kappaB, much weaker activation is observed for RhoB-GG, RhoA, and RhoC. NF-kappaB activation by RhoB is not associated with increased nuclear translocation of RelA/p65, but rather, by modification of the RelA/p65 transactivation domain. Activation of NF-kappaB by RhoB is dependent upon ROCK I but not PRK I. Thus, ROCK I cooperates with RhoB to activate NF-kappaB, and suppression of ROCK I activity by genetic or pharmacological inhibitors blocks NF-kappaB activation. Suppression of RhoB activity by dominant-inhibitory mutants, or siRNA, blocks NF-kappaB activation by Bcr, and TSG101, but not by TNFalpha or oncogenic Ras. Collectively, these observations suggest the existence of an endosome-associated pathway for NF-kappaB activation that is preferentially regulated by the farnesylated form of RhoB.
Rodriguez
Pedro L
PL
Department of Microbiology and Molecular Genetics and New Jersey Medical School, University Hospital Cancer Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07101-1709, USA.
Sahay
Sutapa
S
Olabisi
Oyenike O
OO
Whitehead
Ian P
IP
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D017368:Protein Prenylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D054460:rho-Associated Kinases; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*; D000099177:Tsg101 Protein
D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D051562:Proto-Oncogene Proteins c-bcr; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D018631:ras Proteins; D054460:rho-Associated Kinases; D020743:rhoB GTP-Binding Protein; D000099177:Tsg101 Protein