[5][6] MAP4K4 is involved in a wide array of physiological processes including cell migration, proliferation and adhesion;[7] its activity has been implicated in systemic inflammation,[8] metabolic disorders,[9] cardiovascular disease[9] and cancer.

Mammalian MAP4K4 was initially identified in mice as a kinase activator for a protein called Nck[10] followed shortly by identification and cloning of the human orthologue encoded by the MAP4K4 gene.

[5] Secondary sites also require phosphorylation for the enzyme to assume full activation and is achieved via autophosphorylation or by upstream kinases.

[14] Evidence from mammalian and fly studies indicate that MAP4K4 is involved with tumour necrosis factor alpha (TNF-α) and its c-jun N-terminal kinase (JNK) signaling pathway.

The activation of the JNK signal transduction pathway by MAP4K4 has been implicated in apoptotic regulation of many different cell types,[17] tumorigenesis and/or inflammation.

There is increasing evidence suggesting cytokines such as TNF-α mediate biological effects antagonistic to insulin action and induce inflammation observed in obesity.

[21] Additionally, miRNA silencing of MAP4K4 in pancreatic beta-cells conferred protection against TNF-α repression of insulin transcription and secretion,[24] further confirming that MAP4K4 targeting is a potential strategy for diabetes prevention and treatment.

The biggest causes of death for patients with cancer are tumour invasion and metastasis – processes that are highly correlated with cell migration and motility.

[28][30] Poor prognosis and clinical progression of hepatocellular carcinoma,[30] pancreatic adenocarcinoma,[31] and colorectal cancer[32] are all closely correlated with MAP4K4 expression levels.