Coordinated control of mRNA translation and proper folding of nascent polypeptides is critical for normal cell function. Deregulation of protein synthesis and misfolding underlie a number of pathological conditions such as cancer. The mechanisms that couple translation to protein folding are poorly understood particularly in higher eukaryotes. Most studies have focused on either translation or protein folding processes but signaling mechanisms that link these two events, particularly in response to extracellular conditions, remain to be elucidated. The mammalian target of rapamycin (mTOR) plays a central role in cell growth by promoting protein synthesis in response to nutrients, growth factors and energy status. Aberrant mTOR signaling can trigger oncogenesis;hence, mTOR inhibitors are currently under clinical trials for cancer therapy. mTOR functions in protein synthesis by controlling translation initiation and ribosome biogenesis. These processes can be inhibited by the clinically important drug, rapamycin, and are mediated by mTOR, as part of mTOR complex 1 (mTORC1). mTOR also forms a second complex (mTORC2) consisting of mTOR, rictor, SIN1, and mLST8 that is not directly targeted by rapamycin. This complex plays a pivotal role in the phosphorylation and activation of Akt, a protein kinase that is often deregulated in cancer. Because inhibiting Akt promotes cell death, drugs that can specifically inhibit mTORC2 could be more effective in preventing cancer. However, the cellular functions of mTORC2 are less characterized. We recently discovered that mTORC2 associates with translating ribosomes and couples translation with the processing of nascent Akt. This novel function of mTORC2 is critical for proper folding and stability of Akt to prevent premature degradation during translation. Thus, inhibition of mTORC2 would not only prevent Akt activation but also diminish its expression. Our research proposal will elucidate how mTORC2 functions in cotranslational processing of nascent polypeptides using both cellular and animal models. Because of the central role of mTOR in cell growth and metabolism, our studies will have significant implications in the understanding of how growth stimuli can be integrated by mTOR to control the quality and quantity of newly synthesized proteins.
The mammalian target of rapamycin (mTOR) is an important target for cancer therapy because of its central role in protein synthesis during cell growth and proliferation. We will now elucidate how it can link protein synthesis with cotranslational protein processing and thereby control not only the activity but the stability and turnover of proteins. Drugs that can target the novel cotranslational mTOR functions could be more effective in inhibiting tumor growth.
