mTOR signalling hyperphosphorylation of 4E-BP1 and translational control during myogenic differentiation

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During muscle cell regeneration or following injury, critical information stored in the gene sequences of the genetic material (DNA) has to be decoded by the cell to produce a wide variety of essential proteins of the right type and in the right amount to allow for this process. The general transfer of information from DNA to protein is carried out by the messenger RNA (mRNA), which is a copy of the DNA sequence. This mRNA has to be decoded into protein by a complex, highly regulated machine termed a ribosome, in a process known as translation. To work efficiently, accurately, and to allow the ribosome to function in the best interests of the cell, this machinery requires helper proteins (translation initiation factors; eIF) that interact with each other, and also make sure that the mRNA and the ribosome come together into a highly regulated, large initiation complex to make the proteins required. So how does the cell control this? The interaction of the initiation factors themselves is a major site for regulation in mammalian cells. One protein, 4E-binding protein 1 (4E-BP1) prevents the interaction of eIF4E with the scaffold protein, eIF4G, and stops the recruitment of mRNA to the ribosome and halts protein synthesis. When protein synthesis is needed, the cell signals to 4E-BP1 to release the eIF4E/mRNA from the 4E-BP1/eIF4E/mRNA complex to let it work. The cell does this by marking the 4E-BP1 with phosphate groups in a process known as phosphorylation. This modification promotes its release from eIF4E/mRNA which can subsequently bind to eIF4G and form the multi-protein initiation complex required to make the correct types and amounts of protein needed for muscle cell regeneration. In the work described here we want to investigate the signals required to bring about the phosphorylation of 4E-BP1 and identify the tagged sites which are important for controlling this process during muscle cell regeneration. We also want to understand more about what other cellular components are required to assemble the stored forms of mRNA in the 4E-BP1/eIF4E/mRNA complex.