Browse > Article
http://dx.doi.org/10.14348/molcells.2020.0089

Mislocalization of TORC1 to Lysosomes Caused by KIF11 Inhibition Leads to Aberrant TORC1 Activity  

Jang, Yoon-Gu (Institute of Molecular Biology and Genetics, Seoul National University)
Choi, Yujin (Institute of Molecular Biology and Genetics, Seoul National University)
Jun, Kyoungho (Institute of Molecular Biology and Genetics, Seoul National University)
Chung, Jongkyeong (Institute of Molecular Biology and Genetics, Seoul National University)
Publication Information
Molecules and Cells / v.43, no.8, 2020 , pp. 705-717 More about this Journal
Abstract
While the growth factors like insulin initiate a signaling cascade to induce conformational changes in the mechanistic target of rapamycin complex 1 (mTORC1), amino acids cause the complex to localize to the site of activation, the lysosome. The precise mechanism of how mTORC1 moves in and out of the lysosome is yet to be elucidated in detail. Here we report that microtubules and the motor protein KIF11 are required for the proper dissociation of mTORC1 from the lysosome upon amino acid scarcity. When microtubules are disrupted or KIF11 is knocked down, we observe that mTORC1 localizes to the lysosome even in the amino acid-starved situation where it should be dispersed in the cytosol, causing an elevated mTORC1 activity. Moreover, in the mechanistic perspective, we discover that mTORC1 interacts with KIF11 on the motor domain of KIF11, enabling the complex to move out of the lysosome along microtubules. Our results suggest not only a novel way of the regulation regarding amino acid availability for mTORC1, but also a new role of KIF11 and microtubules in mTOR signaling.
Keywords
Drosophila; KIF11; lysosome; microtubule; mTORC1;
Citations & Related Records
Times Cited By KSCI : 4  (Citation Analysis)
연도 인용수 순위
1 Middleton, K. and Carbon, J. (1994). KAR3-encoded kinesin is a minusend-directed motor that functions with centromere binding proteins (CBF3) on an in vitro yeast kinetochore. Proc. Natl. Acad. Sci. U. S. A. 91, 7212-7216.   DOI
2 Nguyen, T.P., Frank, A.R., and Jewell, J.L. (2017). Amino acid and small GTPase regulation of mTORC1. Cell. Logist. 7, e1378794.   DOI
3 Nithianantham, S., Le, S., Seto, E., Jia, W., Leary, J., Corbett, K.D., Moore, J.K., and Al-Bassam, J. (2015). Tubulin cofactors and Arl2 are cage-like chaperones that regulate the soluble ${\alpha}$${\beta}$-tubulin pool for microtubule dynamics. Elife 4, e08811.   DOI
4 Noda, Y., Okada, Y., Saito, N., Setou, M., Xu, Y., Zhang, Z., and Hirokawa, N. (2001). KIFC3, a microtubule minus end-directed motor for the apical transport of annexin XIIIb-associated Triton-insoluble membranes. J. Cell Biol. 155, 77-88.   DOI
5 Panchaud, N., Peli-Gulli, M.P., and De Virgilio, C. (2013). Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci. Signal. 6, ra42.   DOI
6 Paschal, B.M. and Vallee, R.B. (1987). Retrograde transport by the microtubule-associated protein MAP 1C. Nature 330, 181-183.   DOI
7 Peng, M., Yin, N., and Li, M.O. (2017). SZT2 dictates GATOR control of mTORC1 signalling. Nature 543, 433-437.   DOI
8 Porter, M.E., Scholey, J.M., Stemple, D.L., Vigers, G.P., Vale, R.D., Sheetz, M.P., and McIntosh, J.R. (1987). Characterization of the microtubule movement produced by sea urchin egg kinesin. J. Biol. Chem. 262, 2794-2802.   DOI
9 Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A.L., Nada, S., and Sabatini, D.M. (2010). Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290-303.   DOI
10 Sarbassov, D.D., Guertin, D.A., Ali, S.M., and Sabatini, D.M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098-1101.   DOI
11 Saxton, R.A., Chantranupong, L., Knockenhauer, K.E., Schwartz, T.U., and Sabatini, D.M. (2016). Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature 536, 229-233.   DOI
12 Scholey, J.E., Nithianantham, S., Scholey, J.M., and Al-Bassam, J. (2014). Structural basis for the assembly of the mitotic motor Kinesin-5 into bipolar tetramers. Elife 3, e02217.   DOI
13 Sharp, D.J., McDonald, K.L., Brown, H.M., Matthies, H.J., Walczak, C., Vale, R.D., Mitchison, T.J., and Scholey, J.M. (1999). The bipolar kinesin, KLP61F, cross-links microtubules within interpolar microtubule bundles of Drosophila embryonic mitotic spindles. J. Cell Biol. 144, 125-138.   DOI
14 Slangy, A., Lane, H.A., d'Herin, P., Harper, M., Kress, M., and Niggt, E.A. (1995). Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83, 1159-1169.   DOI
15 Tseng, K.F., Wang, P., Lee, Y.J., Bowen, J., Gicking, A.M., Guo, L., Liu, B., and Qiu, W. (2018). The preprophase band-associated kinesin-14 OsKCH2 is a processive minus-end-directed microtubule motor. Nat. Commun. 9, 1067.   DOI
16 Wang, X., Campbell, L.E., Miller, C.M., and Proud, C.G. (1998). Amino acid availability regulates p70 S6 kinase and multiple translation factors. Biochem. J. 334(Pt 1), 261-267.   DOI
17 Vale, R.D., Reese, T.S., and Sheetz, M.P. (1985). Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility. Cell 42, 39-50.   DOI
18 Wakana, Y., Villeneuve, J., van Galen, J., Cruz-Garcia, D., Tagaya, M., and Malhotra, V. (2013). Kinesin-5/Eg5 is important for transport of CARTS from the trans-Golgi network to the cell surface. J. Cell Biol. 202, 241-250.   DOI
19 Walker, R.A., Salmon, E.D., and Endow, S.A. (1990). The Drosophila claret segregation protein is a minus-end directed motor molecule. Nature 347, 780-782.   DOI
20 Wolfson, R.L., Chantranupong, L., Saxton, R.A., Shen, K., Scaria, S.M., Cantor, J.R., and Sabatini, D.M. (2016). Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351, 43-48.   DOI
21 Wolfson, R.L., Chantranupong, L., Wyant, G.A., Gu, X., Orozco, J.M., Shen, K., Condon, K.J., Petri, S., Kedir, J., Scaria, S.M., et al. (2017). KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543, 438-442.   DOI
22 Yang, H., Jiang, X., Li, B., Yang, H.J., Miller, M., Yang, A., Dhar, A., and Pavletich, N.P. (2017). Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 552, 368-373.   DOI
23 Chung, J., Kuo, C.J., Crabtree, G.R., and Blenis, J. (1992). Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 69, 1227-1236.   DOI
24 Bar-Peled, L., Chantranupong, L., Cherniack, A.D., Chen, W.W., Ottina, K.A., Grabiner, B.C., Spear, E.D., Carter, S.L., Meyerson, M., and Sabatini, D.M. (2013). A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100-1106.   DOI
25 Burnett, P.E., Barrow, R.K., Cohen, N.A., Snyder, S.H., and Sabatini, D.M. (1998). RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl. Acad. Sci. U. S. A. 95, 1432-1437.   DOI
26 Chantranupong, L., Scaria, S.M., Saxton, R.A., Gygi, M.P., Shen, K., Wyant, G.A., Wang, T., Harper, J.W., Gygi, S.P., and Sabatini, D.M. (2016). The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165, 153-164.   DOI
27 Cole, D.G., Saxton, W.M., Sheehan, K.B., and Scholey, J.M. (1994). A "slow" homotetrameric kinesin-related motor protein purified from Drosophila embryos. J. Biol. Chem. 269, 22913-22916.   DOI
28 Enos, A.P. and Morris, N.R. (1990). Mutation of a gene that encodes a kinesin-like protein blocks nuclear division in A. nidulans. Cell 60, 1019-1027.   DOI
29 Hara, K., Yonezawa, K., Weng, Q.P., Kozlowski, M.T., Belham, C., and Avruch, J. (1998). Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273, 14484-14494.   DOI
30 Gross, S.P. (2004). Hither and yon: a review of bi-directional microtubulebased transport. Phys. Biol. 1, R1-R11.   DOI
31 Heitman, J., Movva, N.R., and Hall, M.N. (1991). Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905-909.   DOI
32 Hirokawa, N., Noda, Y., Tanaka, Y., and Niwa, S. (2009). Kinesin superfamily motor proteins and intracellular transport. Nat. Rev. Mol. Cell Biol. 10, 682-696.   DOI
33 Inoki, K., Li, Y., Xu, T., and Guan, K.L. (2003). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829-1834.   DOI
34 Inoki, K., Li, Y., Zhu, T., Wu, J., and Guan, K.L. (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648-657.   DOI
35 Kapitein, L.C., Peterman, E.J., Kwok, B.H., Kim, J.H., Kapoor, T.M., and Schmidt, C.F. (2005). The bipolar mitotic kinesin Eg5 moves on both microtubules that it crosslinks. Nature 435, 114.   DOI
36 Kashlna, A., Baskin, R., Cole, D., Wedaman, K., Saxton, W., and Scholey, J. (1996). A bipolar kinesin. Nature 379, 270.   DOI
37 Kim, M.Y., Kruger., A.J., Jeong, J.Y., Kim, J., Shin, P.K., Kim, S.Y., Cho, J.Y., Hahm, K.B., and Hong, S.P. (2019). Combination therapy with a PI3K/mTOR dual inhibitor and chloroquine enhances synergistic apoptotic cell death in Epstein-Barr virus-infected gastric cancer cells. Mol. Cells 42, 448-459.   DOI
38 Lee, J., Yi, S., Chang, J.Y., Kim, J.T., Sul, H.J., Park, K.C., Zhu, X., Cheng, S.Y., Kero, J., Kim, J., et al. (2019). Loss of primary cilia results in the development of cancer in the murine thyroid gland. Mol. Cells 42, 113-122.   DOI
39 Kim, W., Jang, Y.G., Yang, J., and Chung, J. (2017). Spatial activation of TORC1 is regulated by Hedgehog and E2F1 signaling in the Drosophila eye. Dev. Cell 42, 363-375.e4.   DOI
40 Lawrence, C.J., Dawe, R.K., Christie, K.R., Cleveland, D.W., Dawson, S.C., Endow, S.A., Goldstein, L.S., Goodson, H.V., Hirokawa, N., Howard, J., et al. (2004). A standardized kinesin nomenclature. J. Cell Biol. 167, 19-22.   DOI
41 Li, L., Khan, N., Hurd, T., Ghosh, A.K., Cheng, C., Molday, R., Heckenlively, J.R., Swaroop, A., and Khanna, H. (2013). Ablation of the X-linked retinitis pigmentosa 2 (Rp2) gene in mice results in opsin mislocalization and photoreceptor degeneration. Invest. Ophthalmol. Vis. Sci. 54, 4503-4511.   DOI
42 Manifava, M., Smith, M., Rotondo, S., Walker, S., Niewczas, I., Zoncu, R., Clark, J., and Ktistakis, N.T. (2016). Dynamics of mTORC1 activation in response to amino acids. Elife 5, e19960.   DOI
43 Mann, B.J. and Wadsworth, P. (2019). Kinesin-5 regulation and function in mitosis. Trends Cell Biol. 29, 66-79.   DOI
44 McDonald, H.B., Stewart, R.J., and Goldstein, L.S. (1990). The kinesin-like ncd protein of Drosophila is a minus end-directed microtubule motor. Cell 63, 1159-1165.   DOI
45 Menon, S., Dibble, C.C., Talbott, G., Hoxhaj, G., Valvezan, A.J., Takahashi, H., Cantley, L.C., and Manning, B.D. (2014). Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156, 771-785.   DOI
46 Kim, S.G., Buel, G.R., and Blenis, J. (2013). Nutrient regulation of the mTOR complex 1 signaling pathway. Mol. Cells 35, 463-473.   DOI