Mitogen-activated protein kinase kinase 4 and 7 (MKK4/7)

Mitogen-activated protein kinase kinase 4 (MKK4) and Mitogen-activated protein kinase kinase 7 (MKK7) are dual-specificity kinases that function as the essential upstream activators of the c-Jun N-terminal kinase (JNK) signaling pathway [1, 2]. These gatekeeper kinases integrate a wide array of stress-related stimuli, including proinflammatory cytokines (e.g., TNF-alpha, IL-1beta), ultraviolet radiation, and oxidative stress, to regulate critical cellular processes such as apoptosis, proliferation, and the immune response [3, 4]. While MKK7 is a specific activator of JNK, MKK4 also possesses the capacity to activate the p38 MAPK pathway, reflecting their non-redundant roles in signal transduction [5, 6]. In oncology, dual MKK4/7 inhibition is being explored to suppress tumor growth and metastasis in aggressive cancers, such as triple-negative breast cancer and prostate cancer, where the JNK pathway is often hyperactivated [7, 8]. Conversely, selective MKK4 inhibition has emerged as a promising strategy in regenerative medicine to unlock the liver's regenerative capacity by rerouting stress signaling through the MKK7-JNK1 axis, which promotes hepatocyte proliferation [9, 10]. Small molecule inhibitors like HRX215 and BSJ-04-122 are currently being developed to target these kinases for liver regeneration and cancer therapy, respectively [11, 12].

Other names

MAP2K4MAP2K7MEK4MEK7JNKK1JNKK2SEK1SEK2SAPKK1SAPKK4Mitogen-activated protein kinase kinase 4Mitogen-activated protein kinase kinase 7

Inhibition of the dual-specificity phosphorylation of the Thr-Pro-Tyr motif in JNK (by MKK4 and MKK7) and the Thr-Gly-Tyr motif in p38 MAPK (by MKK4), thereby modulating downstream stress-activated signaling cascades [7, 8, 11].