Research Interests: Biological networks that coordinate metabolism and growth
Lab: 7-154 MCB
Office: 7-132 MCB
We are interested in understanding the molecular networks that coordinate nutrient metabolism and cell growth. How cells assess nutrient- or energy states and relay this information into appropriate decisions on growth is poorly understood. Coordinate regulation of nutrient metabolism and cell growth is of fundamental importance, and many human diseases, such as cancer, diabetes, and developmental disorders, are affected by alterations in this process.
mTOR signaling network
Our research is focused on the mTOR signaling network that plays a crucial role in controlling cell growth in response to nutrient levels and growth factors. mTOR binds several proteins to form two distinct protein complexes. mTORC1 (mTOR complex 1) contains raptor (KOG1 ortholog), Gbl/mLst8, PRAS40 and DEPTOR, whereas mTORC2 (mTOR complex 2) conatins rapamycin insensitive companion of mTOR (rictor) (Avo3 ortholog), GbL/mLst8, Sin1 (Avo1 ortholog), PRR5/protor and DEPTOR. In spite of considerable efforts, it has not been possible to obtain a clear understanding of the molecular mechanisms by which the mTOR network is regulates by nutrient- and growth factor-signals. Utilizing novel molecular biology and biochemical tool as well as a variety of structural approaches, we identify novel components and connectivity in the network and determine biological functions and signaling specificity thereof. Our recent studies have led us to identify PRAS40 and PRR5 as key components of mTORC1 and mTORC2. We investigate the functions of these newly-identified components in the regulation of cell growth and metabolism with links to human diseases such as cancer and diabetes. We anticipate this study will advance our understanding of the molecular bases underlying the coordinate regulation between metabolism and growth during animal development and the pathogenesis of metabolic diseases such as cancer and diabetes.
As a crucial pathway downstream of mTOR, autophagy (cellular self-eating) plays an important role for metabolic homeostasis and cellular survival. Autophagy is an evolutionarily-conserved process through which cytoplasm, organelles, or long-lived proteins or protein aggregates are sequested in a double-membrane structures and subsequently degraded in lysosomes. Through destruction of cellular organelles and proteins, autophagy provides energy for starved cells or allows for balanced regulation between biogenesis and degradation of cellular structures, thereby playing important roles in growth, survival, differentiation, and development. Dys-regulation of autophagy is associated with many human diseases including cancer, myopathies, innate immunity, and neurodegenerative diseases such as Parkinson's and Huntington's diseases. Autophagy is induced when cells are starved of nutrients or mTOR is inhibited. Our recent study revealed that ULK1 and ULK1 protein kinases play key roles in autophagy induction in mammalian cells. We determined that mTORC1 phosphorylates ULK1 and ULK2 to inhibit the kinase functions. Later, studies from other groups identified that AMPK phosphorylates and positively regulates ULK1. We investigate how mTORC1 and AMPK regulate ULK functions with focus on its phosphorylation and its interaction with Atg13 and FIP200. We also study the shared and distinct functions of ULK1 and ULK2 in autophagy and non-autophagy processes.
mTOR-regulated Nuclear proteomics
Yun, Y.S., Kim, K.H., Tschida, B., Sachs, Z., Noble-Orcutt, K.E., Moriarity, B.S., Ai, T., Ding, R., Williams, J., Chen, L., Largaespada, D., Kim, D.-H. (2016). mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress. Molecular Cell 61, 625-39.
Park, JM., Jung, CH, Seo, M, Otto, NM, Grunwald, D, Kim, KH, Moriarity, B, Kim, YM, Starker, C, Nho, RS, Voytas, D, and Kim, D.-H. (2016) The ULK1 complex mediates mTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating Atg14. Autophagy 12, 547-564
Kim, Y.-M., Jung, C.H., Seo, M., Kim, E.K., Park, J.-M., Bae, S.S., and Kim, D.-H. (2015) mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Molecular Cell 57, 207-218. (PDF)
Ro, S.H., Jung, C.H., Hahn, W.S., Xu, X., Kim, Y.-M., Yun, Y.S., Park, J.-M., Kim, K.H., Seo, M., Ha, T.-Y., Arriaga, E.A., Bernlohr, D.A., & Kim, D.-H. (2013) Distinct functions of ULK1 and ULK2 in the regulation of lipid metabolism in adipocytes. Autophagy 9, 2103. (PDF)
Kim, Y.M., Stone, M., Hwang, T.H., Kim, Y.G., Dunlevy, J.R.,Griffin, T.J., and Kim, D.H. (2012) SH3BP4 is a negaive regulator of amino acid-Rag GTPase-mTORC1 signaling. Molecular Cell 46. (PDF)
Jung, C.H., Seo, M., Otto, N.M., and Kim, D.H. (2011) ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 7, 1212-1221.
Joo et al. (2011) Hsp90-Cdc37 Chaperone complex regulates Ulk1- and Atg13-mediated mitophagy. Molecular Cell 43, 572-585.
Kim, H.W., Ha, S.H., Lee, M.N., Huston, H., Houslay, M.D., Kim, D. H., Jang, S.K., Suh, P.G., and Ryu, S.H. (2010) Cyclic AMP controls mTOR through regulation of the dynamic interaction between Rheb and Phosphodiesterase 4D. Mol Cell Biol. 30, 5406-20. (PDF)
Bandhakavi, S.(*), Kim, Y. M. (*), Ro, S. H., Xie, H., Onsongo, G., Jun, C. B., Kim, D. H. (#) and Griffin, T. J. (#). Quantitative nuclear proteomics identifies mTOR regulation of DNA damage response. Molecular & Cellular Proteomics 9, 403-414. (PDF)
Jung, C. H., Ro, S. H., Cao, J., Otto, N. M. and Kim, D. H. (2010) mTOR regulation of autophagy. FEBS Letters 584, 1287-1295. (PDF)
Jung, C. H., Jun, C. B., Ro, S. H., Kim, Y. M., Otto, N. M., Cao, J., Kundu, M., and Kim, D. H. (2009) ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery. Mol. Biol. Cell 20, 1992-2003. (PDF)
Lee, M. N., Ha, S. H., Kim, J., Koh, A., Lee, C. S., Kim, J. H., Jeon, H., Kim, D. H., Suh, P. G., Ryu, S. H. (2009) Glycolytic flux signals to mTOR through GAPDH-mediated regulation of Rhed. Mol. Cell Biol. 29, 3991-4001. (PDF)
Bandhakavi, S., Xie, H., O'Callaghan, B., Sakurai, H., Kim, D. H., Griffin, T. J. (2008). Hsf1 activation inhibits rapamycin resistance and TOR signaling in yeast revealed by combined proteomic and genetic analysis. PLoS One 3, e1598. (PDF)
Kim, Y. L., Kim, J. E., Shin, K. J., Lee, S., Ahn, C., Chung, J., Kim, D. H., Seong, J. Y., Hwang, J. I. (2008). Gbl regulates INFa-induced NF-kB signaling by diretly inhibiting the activation of ikB kinase. Cellular Signaling 20, 2127-2133. (PDF)
Woo S. Y., Kim, D. H., Jun, C. B., Kim, Y. M., Haar, E. V., Lee, S. I., Hegg, J. W., Bandhakavi, S., Griffin, T. J., Kim, D. H. (2007) PRR5, a novel Component of mTOR Complex 2, Regulates Platelet-derived Growth Factor Receptor ß Expression and Signaling. J Biol Chem. 282, 25604-12. (PDF)
Vander Haar, E., Lee, S.I, Bandhakavi, S., Griffin, T. J., Kim, D. H. (2007) "Insulin Signaling to mTOR Mediated by Akt/PKB Substrate PRAS40." Nature Cell Biology 9, 316-23. (PDF)
Ha, S. H., Kim, D. H., Kim, I. S., Kim, J. H., Lee, M. N., Lee, H. J., Kim, J. H., Jang, S. K., Suh, P. G., Ryu, S. H. (2006) PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals. Cellular Signaling 18, 2283-91. (PDF)
Sarbassov, D. D., Ali, S. M., Kim, D.-H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D. M. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296-1302. (PDF).
Kim, D. H., Sarbassov, D., Ali, S. M., Latek, R. R., Guntur, K. V. P., Erdjument-Bromage, H., Tempst, P., and Sabatini, D. M. (2003) GbL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Molecular Cell 11, 895-904. (PDF)
Kim, D. H., Sarbassov, D., Ali, S. M., King, J. E., Latek, R. R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D. M. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163-175. (PDF)