title: IκB kinase regulation of the TPL-2/ERK MAPK pathway.
abstract: Nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) activation play central roles in the induction of gene expression in innate immune cells following pathogen recognition. TPL-2 (tumor progression locus 2) is the MAP 3-kinase component of an ERK-1/2 (extracellular signal-regulated kinase 1/2) MAPK pathway activated by Toll-like receptor and tumor necrosis factor receptor family stimulation. In this review, we discuss results obtained from our laboratory and others that show that TPL-2 signaling function is directly controlled by the inhibitor of NF-κB (IκB) kinase (IKK) complex. Significantly, this means that IKK controls both NF-κB and ERK activation. TPL-2 is stoichiometrically complexed with the NF-κB inhibitory protein, NF-κB1 p105, and the ubiquitin-binding protein ABIN-2, both of which are required to maintain TPL-2 protein stability. Binding to p105 also prevents TPL-2 from phosphorylating MEK (MAPK/ERK kinase), its downstream target. Agonist stimulation releases TPL-2 from p105-inhibition by IKK-mediated phosphorylation of p105, which triggers degradation of p105 by the proteasome. This facilitates TPL-2 phosphorylation of MEK, in addition to liberating p105-associated Rel subunits to translocate into the nucleus. We also examine evidence that TPL-2 is critical for the induction of inflammation and may play a role in development and/or progression of certain types of cancer. Finally, we consider the potential of TPL-2 as an anti-inflammatory drug target for treatment of certain types of inflammatory disease and cancer.
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research, Mill Hill, London, UK.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Gantke
authors.forename: Srividya
authors.initials: S
authors.lastname: Sriskantharajah
authors.forename: Michael
authors.initials: M
authors.lastname: Sadowski
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009369:Neoplasms / Q000150:complications / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011518:Proto-Oncogene Proteins; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases