Pharmacological inhibition of the MAP2K7 kinase in human disease

Abstract

The MAP2K7 signaling pathway activates the c-Jun NH2-terminal protein kinase (JNK) in response to stress signals, such as inflammatory cytokines, osmotic stress, or genomic damage. While there has been interest in inhibiting JNK due to its involvement in inflammatory processes and cancer, there is increasing focus on developing MAP2K7 inhibitors to enhance specificity when MAP2K7 activation is associated with disease progression. Despite some progress, further research is needed to fully comprehend the role of MAP2K7 in cancer and assess the potential use of kinase inhibitors in cancer therapy. This review examines the role of MAP2K7 in cancer and the development of small-molecule inhibitors.

Keywords: MAP2K7; T-ALL; cancer; kinase inhibitors; leukemia; mitogen-activated protein kinase kinase 7.

Figure 1

The MAP2K7-JNK pathway. (A) Extracellular (LPS, growth factors, TNFα, IL1) and intracellular (metabolism, DNA damage) stress signals activate the MAP3K-MAP2K7-JNK pathway. This is a three-tier kinase cascade stabilized by the scaffolding protein JIP-1. NF𝜅B activates the inhibitor GADD45β. (B) Structural domains of MAP2K7 proteins, D domains, kinase domain with Ser 271 (S271) and Thr 275 (T275) phosphorylated by MAP3K, and DVD domains. (C) Phosphorylation of S271 and T275 induces a conformation change, increasing accessibility to the ATP binding domain. (D) Phosphomimetic mutation activates MAP2K7. The phosphomimetic mutant S271D and T275D mimic the active form of MAP2K7.

Figure 2

Aberrant MAP2K7 activation in pediatric T-ALL. Samples from pediatric T-ALL patients showed epigenetic silencing of KLF4 via CpG methylation with elevated activation of the MAP2K7-JNK pathway. The conditional deletion of the Klf4 gene in the NOTCH1-induced T-ALL model recapitulates the findings in human samples showing upregulation of MAP2K7 and activation of the MAP2K7-JNK pathway that drives the proliferation of leukemia-initiating cells and leukemic T-ALL cells.