MAP4K4: an emerging therapeutic target in cancer

Abstract

The serine/threonine kinase MAP4K4 is a member of the Ste20p (sterile 20 protein) family. MAP4K4 was initially discovered in 1995 as a key kinase in the mating pathway in Saccharomyces cerevisiae and was later found to be involved in many aspects of cell functions and many biological and pathological processes. The role of MAP4K4 in immunity, inflammation, metabolic and cardiovascular disease has been recognized. Information regarding MAP4K4 in cancers is extremely limited, but increasing evidence suggests that MAP4K4 also plays an important role in cancer and MAP4K4 may represent a novel actionable cancer therapeutic target. This review summarizes our current understanding of MAP4K4 regulation and MAP4K4 in cancer. MAP4K4-specific inhibitors have been recently developed. We hope that this review article would advocate more basic and preclinical research on MAP4K4 in cancer, which could ultimately provide biological and mechanistic justifications for preclinical and clinical test of MAP4K4 inhibitor in cancer patients.

Keywords: Cancer; MAP4K4; Signaling pathways; Therapeutic target.

Fig. 1

Schematic diagram of MAP4K4 structure. Both human and mouse MAP4K4 are composed of an N-terminal kinase domain and a C-terminal citron-homology domain. Mouse MAP4K4 contains proline-rich motifs. Sites involved in regulation of kinase activity and potential phosphorylation sites are indicated

Fig. 2

Schematic diagram of suggested MAP4K4 downstream effectors and biological outcomes in cancer. Studies on MAP4K4 in cancer have shown that MAP4K4 regulates different biological outcomes (red boxes) trough different cell signaling pathways (boxes with different colors), implicating that MAP4K4 exerts its role in regulation of tumorigenesis and tumor progression in a biological context-dependent manner