Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) (MAP4K4)

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase belonging to the STE20 family, specifically the GCK-IV subfamily (UniProt P95631). It serves as a vital component of the c-Jun N-terminal kinase (JNK) signaling pathway, where it regulates cellular processes such as cytoskeletal rearrangement, cell motility, and apoptosis (PubMed: 15024005). MAP4K4 is frequently upregulated in various malignancies, including lung, pancreatic, and colorectal cancers, where it promotes tumor cell invasion and metastasis (PubMed: 24607834). In metabolic health, MAP4K4 acts as a negative regulator of insulin signaling by mediating TNF-alpha-induced insulin resistance in adipocytes and skeletal muscle (PubMed: 16415921). Consequently, it has emerged as a therapeutic target for type 2 diabetes and systemic inflammatory conditions. Small molecule inhibitors like PF-06260933 have been developed to target its kinase activity, showing promise in reducing inflammation and improving metabolic profiles in preclinical models (PubMed: 26830860). Additionally, MAP4K4 inhibition is being investigated for neuroprotective effects in Amyotrophic Lateral Sclerosis (ALS), as its reduction has been shown to enhance motor neuron survival (PubMed: 25063439).

Other names

NCK-interacting kinaseNIKHepatocyte progenitor kinase-like/germinal center kinase-like kinaseHGKFLJ10410

ATP-competitive inhibition of the kinase domain, preventing the phosphorylation of downstream substrates in the JNK signaling pathway (PubMed: 26830860).