Mitogen-activated protein kinase kinase kinase 21 (MLK4) (MLK4)

Mitogen-activated protein kinase kinase kinase 21 (MLK4), also known as Mixed-lineage kinase 4, is a serine/threonine protein kinase that serves as a critical component of the mitogen-activated protein kinase (MAPK) signaling architecture. It functions as a MAP3K, phosphorylating and activating downstream kinases such as MKK4 and MKK7, which in turn activate the JNK, p38, and ERK pathways to regulate cell growth, migration, and survival (UniProt Q5TCX8; Martini et al., 2013). MLK4 is frequently overexpressed or mutated in several aggressive cancers, including triple-negative breast cancer and microsatellite stable colorectal cancer, where it often cooperates with oncogenic RAS or BRAF signaling to drive tumorigenesis and metastasis (Martini et al., 2013; Das et al., 2025). Beyond oncology, MLK4 has been identified as a negative regulator of TLR4-mediated inflammatory signaling and is implicated in the pathogenesis of neurodegenerative diseases through its role in stress-induced neuronal apoptosis (GeneCards; Marker et al., 2013). While specific MLK4 inhibitors are not yet clinically approved, pan-MLK inhibitors like CEP-1347 and URMC-099 have demonstrated the potential to modulate these pathways in preclinical models of cancer and neuroinflammation (Maroney et al., 2001; Marker et al., 2013). Targeting MLK4 represents a promising strategy for treating chemoresistant tumors and managing neuroinflammatory conditions by disrupting aberrant kinase-driven signaling networks.

Other names

MAP3K21Mixed lineage kinase 4KIAA1804Mitogen-activated protein kinase kinase kinase MLK4

Inhibition of kinase activity, blocking the phosphorylation of downstream mitogen-activated protein kinase kinases (MKK4, MKK7) and subsequent activation of MAPK signaling cascades (JNK, p38, ERK).