The Ser/Thr Kinase MAP4K4 Controls Pro-Metastatic Cell Functions

Abstract

The search for novel targeted therapies for major human conditions such as diabetes, cardiovascular diseases and cancer is a slow and costly process. Progress is often hampered by poor drug efficaciousness in the patients, low selectivity/specificity of the compounds and cellular evasion mechanism that are rather common in anti-cancer therapies. This is particularly true also for compounds inhibiting kinases, which in theory are optimal targets thanks to their druggable enzymatic activity. Novel targeting strategies are needed to reduce side effects and treatment failure caused by non-specific drug function and target resistance, respectively. An ideal compound will repress the relevant kinase effector function, while leaving kinase functions that are not disease-relevant unaltered. To achieve function-specific inhibition, the molecular mechanism of the drug target that governs the pathological process, must be identified. The Ser/Thr kinase MAP4K4 is implicated in inflammatory and metabolic disorders and cancer progression. In this review, we describe the molecular effector functions of MAP4K4 that exert those activities and how they have been identified and characterized both in invertebrate organisms and mammals. We discuss how the modulation of the cellular cytoskeleton by MAP4K4 may be connected to pathological conditions such as aberrant angiogenesis and cancer metastasis, and we describe the molecular mechanisms that are so far known to be mechanistically involved in these processes.