Amino acid signaling to mTOR/p70S6K in the heart : adding new and old pieces to the puzzle

Previous studies have been demonstrated that insulin and certain amino acids enhance protein synthesis and cell growth in different models including in the heart. A common and key signalling element in both processes is mTOR a Ser/Thr protein kinase which controls two downstream targets: p70S6K and 4EBP1. Together with other translation factors, both are important regulators of translation. Here, we study the molecular events leading to p70S6K activation by amino acids such as leucine and glutamine in the heart. Although it has been shown that under insulin stimulation the canonical PI3K∕PDK1∕PKB signalling pathway lead to p70S6K activation, little is known about how amino acids activate p70S6K. We hypothesized that leucine and glutamine known as anabolic regulators which activate p70S6K would integrate PDK1 in mediating their effects. Our results show that i) PDK1 usually considered to be dedicated to insulin signalling pathway is also a central kinase in the signal transduction pathway mediated by leucine in the heart, ii) PDK1 located downstream of a specific class 1 P13K contributes to the leucine mediated activation of mTOR via PRAS40, iii) insulin and leucine induces PRAS40∕mTOR∕p70S6K activation in a PDK1-dependent manner although by two different mechanisms, and iv) leucine and glutamine exert opposite effects on cardiac p70S6K regulation in adult heart. The multiple PDK1 involvement in hormonal (insulin) and nutrient (leucine) signalling transduction pathways would explain the cardiac-specific PDK1 -/- phenotype compared with other cardiac-specific knock outs of proximal insulin signalling elements. These findings points to PDK1 as a putative target to treat various cardiomyopathies.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL