Summary An efficient immune response relies on the presence of T-cells expressing a functional T-cell receptor (TCR). While the mechanisms generating TCR diversity for antigenic recognition are well defined, what controls its surface expression is less known. Here we found that deletion of the mTORC2 component rictor at early stages of T-cell development led to aberrant maturation and increased proteasomal degradation of nascent TCR. While CD127 expression became elevated, the levels of TCR as well as CD4, CD8, CD69, Notch and CD147 were significantly attenuated on the surface of rictor-deficient thymocytes. Diminished expression of these receptors led to suboptimal signaling, partial DN4 proliferation and DP activation as well as developmental blocks at the double-negative 3 and CD8-ISP stages. Since CD147 glycosylation was also defective in SIN1-deficient fibroblasts, our findings suggest that mTORC2 is involved in the co/post-translational processing of membrane receptors. Thus, mTORC2 impacts development via regulation of the quantity and quality of receptors important for cell differentiation.

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Cell surface proteins transduce extracellular signals into the cell to control metabolism and growth. In turn, their expression is linked to nutrient availability and other growth signals by mechanisms that are poorly understood. The mammalian target of rapamycin (mTOR) regulates cell growth and metabolism and is part of two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. We found that mTORC2 is involved in the processing and maturation of cell surface receptors such as CD147. CD147 is a highly glycosylated receptor that has been linked to tumor progression via its role in activating matrix metalloproteinases and maturation of lactate transporters. In breast cancer cells, CD147 glycosylation is highly sensitive to glucose starvation and mTOR inhibition. In mTORC2-disrupted cells CD147 is misprocessed and occurs predominantly in a low glycosylated form. CD147 misprocessing can be partly rescued by addition of exogenous UDP-GlcNAc, the end product of the hexosamine biosynthetic pathway (HBP). However, UDP-GlcNAc cannot restore the abnormal growth and metabolism in mTORC2-disrupted cells due to defects in expression of other key metabolic enzymes in these cells. Our findings define a role for mTORC2 in regulating receptor glycosylation via the HBP and reveal a broader role for mTORC2 in controlling other biosynthetic pathways that become deregulated in cancer. Citation Format: Chang-Chih Wu, Thomas Lynch, Joseph Moloughney, Aixa Navia, Olufunmilola Ibironke, Po-Chien Chou, Nicole M. Vega-Cotto, Sisi Zhang, Joshua Rabinowitz, Guy Werlen, Estela Jacinto. mTOR complex 2 modulates glycosylation of CD147 via the hexosamine biosynthetic pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2441. doi:10.1158/1538-7445.AM2014-2441