Map4k3 and the Posttranscriptional Control of Gene Expression: A closer look at the MAP kinase control over the tumour promoting mTOR pathway

Abstract

A tight balance between growth and apoptosis is essential to a functional non-malignant cell. Cell growth is determined by one of its major regulators, mTOR, and is dependent on a number of nutrient- and energy-sensing input signals. These converge onto mTOR which controls protein synthesis and cell growth. Deregulation of this pathway is known to contribute to tumourigenesis and it is being investigated as a therapeutic target. Apoptosis, on the other hand, is an orderly choreography that comes together in causing the serene demise of a cell. Bcl-2 family members establish a tightly controlled balance over pro- and anti-apoptotic signals. Evasion from apoptosis is thought to be one of the hallmarks of cancer. MAP4K3 is a high order signal transducer that was recently found to both positively regulate mTOR through nutrient signalling and induce apoptosis through the intrinsic and extrinsic pathways. Recently, MAP4K3 was shown to activate mTORC1 targets in an amino aciddependent way and to cause cell growth. In another study, it was found to cause apoptosis through the JNK pathway and by upregulating pro-apoptotic Bcl-2 members through the mTORC1 pathway. These findings make it interesting to investigate its targeted translation changes. In addition to its role in apoptosis, MAP4K3 was found to be involved in a number of other pathways and diseases. In the present study, I focus on the contribution of MAP4K3 to the translation initiation-inducing mTORC1 pathway and investigate the translational changes it causes. MAP4K3 induces cell growth and increases protein synthesis rates. It also causes an increase in the number of highly translated mRNAs in polysome profiling experiments. Put together, these observations led me to identify the genes modulated byMAP4K3 with the aim of establishing new leads in the paths paved by this high order signal transducer. I pinpoint the most interesting and most likely MAP4K3-modulated genes at the translational level, and propose new paths worth validating and pursuing