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.

Inflammatory Responses Induced by Lipopolysaccharide Are Amplified in Primary Human Monocytes but Suppressed in Macrophages by Complement Protein C5a

“…However, only high concentrations of LPS triggered delayed ERK1/2 activation (20 min after stimulation) by comparison with the C5a response, which occurs within 5 min. The MAP3K tumor progression locus 2 is essential for activation of ERK1/2 by multiple TLRs, including TLR4, in macrophages (44). Consistent with this, we observed that LPS triggered MEK1 phosphorylation in macrophages independently of activation of another MAP3K, c-Raf.…”

Intestinal myofibroblast-specific Tpl2-Cox-2-PGE 2 pathway links innate sensing to epithelial homeostasis

“…Tpl2 is currently considered a well-established inflammatory mediator, with significant pharmacological interest for IBD (3). We have shown a relevant pathogenic implication of Tpl2 in Tnf ΔARE mice which spontaneously develop a chronic T-cell-mediated Crohn's-like IBD pathology in the ileum (7) without involvement of epithelial barrier disruption and restoration processes in which IMFs could play an important homeostatic role.…”

“…S1 A and B). Molecularly, Tpl2 is known to bind to NF-ĸB1-p105 in a stabilized but inactive form (3) and, when activated, is released to phosphorylate the major immediate targets MEK1/2 activating mainly the ERK pathway and downstream inflammatory mediators (3). The NFKB1 gene is also genetically associated with IBD in GWAS (2), highlighting the relevance of this pathway to human disease.…”

“…Tpl2 also mediates pathogenesis in the TNF-driven and T-cell-mediated Tnf ΔARE mouse model of Crohn's-like IBD, indicating a potential pathogenic relevance of this pathway in specific contexts (7). Due to these proinflammatory functions, established mainly in cells of hematopoietic origin, Tpl2 is considered to be an appealing pharmacological target for the treatment of IBD and other inflammatory diseases (3,8).…”

B-cell Expansion and Lymphomagenesis Induced by Chronic CD40 Signaling Is Strictly Dependent on CD19

“…Because sorafenib treatment rather resulted in increased Erk activation, it is unlikely that Raf kinases are involved in activation of this signaling pathway. It might be that PI3K/Akt is acting through the IKK complex to activate Mek and Erk because links between PI3K and NF-kB as well as NF-kB and MAPK-signaling have already been described (27,29).…”