Role of Mitogen-activated protein kinase kinase kinase kinase 4 signaling in liver and metabolic diseases.

MAP4K4 is a serine/threonine protein kinase belonging to the germinal center kinase (GCK) sub-group of sterile 20 protein (Ste20p) family of kinases. MAP4K4 has been involved in regulating multiple biological processes and a plethora of pathologies, including systemic inflammation, cardiovascular diseases, cancers, metabolic and hepatic diseases. Recently, multiple reports have indicated the upregulation of MAP4K4 expression and signaling in hyperglycemia and liver diseases. This review summarizes our current understanding of MAP4K4 structure, expression, as well as its regulation and signaling, specifically in metabolic and hepatic diseases. Reviewing these promising studies will enrich our understanding of MAP4K4 signaling which will help us design innovative therapeutic interventions against metabolic and liver diseases using MAP4K4 as a target. Significance Statement Although most studies on the involvement of MAP4K4 in human pathologies are related to cancers, only recently its role in liver and other metabolic diseases is beginning to unravel. This mini review discusses recent advancements in MAP4K4 signaling and comprehensively characterizes MAP4K4 as a clinically relevant therapeutic target against liver diseases.