Masahiro Morita, PhD

Assistant Professor

Education

Year	Degree	Discipline	Institution
2003	BS	Chemistry and Biotechnology	University of Tokyo Tokyo , Japan
2005	MS	Biophysics and Biochemistry	University of Tokyo Tokyo , Japan
2008	PhD	Biochemistry and Biophysics	University of Tokyo Tokyo , Japan
	Postdoctoral Training	Medical Sciences	University of Tokyo Tokyo , Japan
	Postdoctoral Training	Cancer Metabolism	McGill University Montreal, Quebec, Canada

Research

Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells change their metabolic programs to efficiently utilize the limited nutrients, ultimately driving macromolecule synthesis (e.g., protein, lipid and nucleotide synthesis) and cell growth and proliferation. Protein, the most abundant macromolecule in the cell, is aberrantly synthesized in malignant cells. Post-transcriptional regulation of gene expression, including mRNA translation and degradation, directly modulate protein synthesis, and are dysregulated in a variety of metabolic diseases including cancer. However, the mechanisms that underpin the role of post-transcriptional regulation in controlling cancer and metabolism remain largely unknown. The focus on our research is to determine how mutually dependent changes in protein synthesis and cellular metabolism contribute to the development of cancer and metabolic diseases. To this end, we will investigate the role of one of the central energy-sensing signaling pathways known to regulate both cellular energetics and protein synthesis: the mammalian/mechanistic target of rapamycin (mTOR) pathway in cancer and metabolic diseases.

The mTOR complex 1 (mTORC1) pathway is one of the major oncogenic signaling pathways that stimulates anabolism (e.g., protein synthesis) and suppresses catabolism (e.g., autophagy) in response to nutrient availability through multiple downstream effectors (in the Figure below). Prominent ones include translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and ribosomal protein S6 kinases (S6Ks). 4E-BPs are translation initiation repressors, which bind to the mRNA 5’cap-binding protein eIF4E and prevent the assembly of the eIF4F complex, consisting of eIF4E, that facilitates ribosome recruitment to the mRNA. Phosphorylation of 4E-BPs by mTORC1 results in their dissociation from eIF4E, thus allowing assembly of the eIF4F complex and promoting protein synthesis and cell proliferation. The oncogenic activity of the mTORC1 pathway is mediated through 4E-BP-dependent translational activation of mRNAs encoding tumor-promoting proteins, such as cell cycle regulators and metabolic enzymes.

Our laboratory focuses on mTORC1-depenedent control of mRNA translation and degradation in cancer and metabolic diseases. We have developed a genome-wide analyses of mRNA translation and degradation to find the target mRNAs. Our genome-wide analysis reveals that the oncogenic mTORC1 signaling pathway stimulates not only global protein synthesis, but also translation of a subset of mRNAs that encode pivotal regulators of mitochondrial dynamics. Our group demonstrates that mTORC1 coordinates energy consumption by translation machinery, and energy production by bolstering mitochondrial functions and dynamics via regulation of 4E-BPs. Furthermore, we show that the CCR4-NOT poly(A) nuclease (deadenylase) controls susceptibility to metabolic disorders, which is a cancer-predisposing state, by selectively regulating turnover of mRNAs encoding hormone-like proteins. Dissecting the mechanistic underpinnings of these translational and metabolic signatures should provide a molecular basis to improve the efficacy of existing drugs and devise more effective therapies to treat poor outcome cancer patients. Taken together, our laboratory is currently highlighting the pathways that relate the post-transcriptional regulation to metabolic perturbations in cancer, which in long term will provide novel therapeutic avenues to target cancer energetics.

Publications

1.	Pearl, D., Katsumura, S., Amiri, M., Tabatabaei, N., Zhang, X., Vinette, V., Pang, X., Beug, S. T., Kim, S. H., Jones, L. M., Robichaud, N., Ong, S. G., Jia, J. J., Ali, H., Tremblay, M. L., Jaramillo, M., Alain, T., Morita, M., Sonenberg, N., & Tahmasebi, S. (2020). 4E-BP-dependent translational control of Irf8 mediates adipose tissue macrophage inflammatory response. Journal of Immunology, 204(9), 2392-2400. https://doi.org/10.4049/jimmunol.1900538
2.	O’Dwyer, C., Yaworski, R., Katsumura, S., Ghorbani, P., Gobeil Odai, K., Nunes, J. R. C., LeBlond, N. D., Sanjana, S., Smith, T. T. K., Han, S., Margison, K. D., Alain, T., Morita, M., & Fullerton, M. D. (2020). Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity. Hepatology Communications, 4(6), 876-889. https://doi.org/10.1002/hep4.1516
3.	Chou, C. W., Tan, X., Hung, C. N., Lieberman, B., Chen, M., Kusi, M., Mitsuya, K., Lin, C. L., Morita, M., Liu, Z., Chen, C. L., & Huang, T. H. M. (2020). Menin and menin-associated proteins coregulate cancer energy metabolism. Cancers, 12(9), 1-21. [2715]. https://doi.org/10.3390/cancers12092715
4.	Ito-Kureha, T., Miyao, T., Nishijima, S., Suzuki, T., Koizumi, S. I., Villar-Briones, A., Takahashi, A., Akiyama, N., Morita, M., Naguro, I., Ishikawa, H., Ichijo, H., Akiyama, T., & Yamamoto, T. (2020). The CCR4–NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression. Nature communications, 11(1), [6169]. https://doi.org/10.1038/s41467-020-19975-4
5.	Morita, M., Siddiqui, N., Katsumura, S., Rouya, C., Larsson, O., Nagashima, T., Hekmatnejad, B., Takahashi, A., Kiyonari, H., Zang, M., St-Arnaud, R., Oike, Y., Giguère, V., Topisirovic, I., Okada-Hatakeyama, M., Yamamoto, T., & Sonenberg, N. (2019). Hepatic posttranscriptional network comprised of CCR4–NOT deadenylase and FGF21 maintains systemic metabolic homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 116(16), 7973-7981. https://doi.org/10.1073/pnas.1816023116
6.	Hulea, L., Gravel, S. P., Morita, M., Cargnello, M., Uchenunu, O., Im, Y. K., Lehuédé, C., Ma, E. H., Leibovitch, M., McLaughlan, S., Blouin, M. J., Parisotto, M., Papavasiliou, V., Lavoie, C., Larsson, O., Ohh, M., Ferreira, T., Greenwood, C., Bridon, G., ... Topisirovic, I. (2018). Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides. Cell Metabolism, 28(6), 817-832.e8. https://doi.org/10.1016/j.cmet.2018.09.001
7.	Jafarnejad, S. M., Chapat, C., Matta-Camacho, E., Gelbart, I. A., Hesketh, G. G., Arguello, M., Garzia, A., Kim, S. H., Attig, J., Shapiro, M., Morita, M., Khoutorsky, A., Alain, T., Christos, G. G., Stern-Ginossar, N., Tuschl, T., Gingras, A. C., Duchaine, T. F., & Sonenberg, N. (2018). Translational control of ERK signaling through miRNA/4EHP-directed silencing. eLife, 7, [e35034]. https://doi.org/10.7554/eLife.35034
8.	Li, X., Morita, M., Kikuguchi, C., Takahashi, A., Suzuki, T., & Yamamoto, T. (2017). Adipocyte-specific disruption of mouse Cnot3 causes lipodystrophy. FEBS Letters, 591(2), 358-368. https://doi.org/10.1002/1873-3468.12550
9.	Bhat, M., Yanagiya, A., Graber, T., Razumilava, N., Bronk, S., Zammit, D., Zhao, Y., Zakaria, C., Metrakos, P., Pollak, M., Sonenberg, N., Gores, G., Jaramillo, M., Morita, M., & Alain, T. (2017). Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells. Oncotarget, 8(31), 50542-50556. https://doi.org/10.18632/oncotarget.10671
10.	Morita, M., Prudent, J., Basu, K., Goyon, V., Katsumura, S., Hulea, L., Pearl, D., Siddiqui, N., Strack, S., McGuirk, S., St-Pierre, J., Larsson, O., Topisirovic, I., Vali, H., McBride, H. M., Bergeron, J. J., & Sonenberg, N. (2017). mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1. Molecular Cell, 67(6), 922-935.e5. https://doi.org/10.1016/j.molcel.2017.08.013
11.	Araki, K., Morita, M., Bederman, A. G., Konieczny, B. T., Kissick, H. T., Sonenberg, N., & Ahmed, R. (2017). Translation is actively regulated during the differentiation of CD8 + effector T cells. Nature Immunology, 18(9), 1046-1057. https://doi.org/10.1038/ni.3795
12.	Gandin, V., Masvidal, L., Cargnello, M., Gyenis, L., McLaughlan, S., Cai, Y., Tenkerian, C., Morita, M., Balanathan, P., Jean-Jean, O., Stambolic, V., Trost, M., Furic, L., Larose, L., Koromilas, A. E., Asano, K., Litchfield, D., Larsson, O., & Topisirovic, I. (2016). MTORC1 and CK2 coordinate ternary and eIF4F complex assembly. Nature communications, 7, [11127]. https://doi.org/10.1038/ncomms11127
13.	Gandin, V., Masvidal, L., Hulea, L., Gravel, S. P., Cargnello, M., McLaughlan, S., Cai, Y., Balanathan, P., Morita, M., Rajakumar, A., Furic, L., Pollak, M., Porco, J. A., St-Pierre, J., Pelletier, J., Larsson, O., & Topisirovic, I. (2016). NanoCAGE reveals 5' UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs. Genome Research, 26(5), 636-648. https://doi.org/10.1101/gr.197566.115
14.	Inoue, T., Morita, M., Hijikata, A., Yoko Fukuda-Yuzawa, F-Y., Adachi, S., Isono, K., Ikawa, T., Kawamoto, H., Koseki, H., Natsume, T., Fukao, T., Ohara, O., Yamamoto, T., & Kurosaki, T. (2015). CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability. Journal of Experimental Medicine, 212(9), 1465-1479. https://doi.org/10.1084/jem.20150384
15.	El-Assaad, W., El-Kouhen, K., Mohammad, A. H., Yang, J., Morita, M., Gamache, I., Mamer, O., Avizonis, D., Hermance, N., Kersten, S., Tremblay, M. L., Kelliher, M. A., & Teodoro, J. G. (2015). Deletion of the gene encoding G0/G1 switch protein 2 (G0s2) alleviates high-fat-diet-induced weight gain and insulin resistance, and promotes browning of white adipose tissue in mice. Diabetologia, 58(1), 149-157. https://doi.org/10.1007/s00125-014-3429-z
16.	Fonseca, B. D., Zakaria, C., Jia, J. J., Graber, T. E., Svitkin, Y., Tahmasebi, S., Healy, D., Hoang, H. D., Jensen, J. M., Diao, I. T., Lussier, A., Dajadian, C., Padmanabhan, N., Wang, W., Matta-Camacho, E., Hearnden, J., Smith, E. M., Tsukumo, Y., Yanagiya, A., Morita, M., Petroulakis, E., González, J. L., Hernández, G., Alain, T. & Damgaard, C. K. (2015). La-related protein 1 (LARP1) represses terminal oligopyrimidine (TOP) mRNA translation downstream of mTOR complex 1 (mTORC1). Journal of Biological Chemistry, 290(26), 15996-16020. https://doi.org/10.1074/jbc.M114.621730
17.	Morita, M., Gravel, S. P., Hulea, L., Larsson, O., Pollak, M., St-Pierre, J., & Topisirovic, I. (2015). MTOR coordinates protein synthesis, mitochondrial activity. Cell Cycle, 14(4), 473-480. https://doi.org/10.4161/15384101.2014.991572
18.	Takahashi, A., Adachi, S., Morita, M., Tokumasu, M., Natsume, T., Suzuki, T., & Yamamoto, T. (2015). Post-transcriptional Stabilization of Ucp1 mRNA Protects Mice from Diet-Induced Obesity. Cell Reports, 13(12), 2756-2767. https://doi.org/10.1016/j.celrep.2015.11.056
19.	Rouya, C., Siddiqui, N., Morita, M., Duchaine, T. F., Fabian, M. R., & Sonenberg, N. (2014). Human DDX6 effects miRNA-mediated gene silencing via direct binding to CNOT1. RNA, 20(9), 1398-1409. https://doi.org/10.1261/rna.045302.114
20.	Shirai, Y. T., Suzuki, T., Morita, M., Takahashi, A., & Yamamoto, T. (2014). Multifunctional roles of the mammalian CCR4-NOT complex in physiological phenomena. Frontiers in Genetics, 5(AUG), [Article 286]. https://doi.org/10.3389/fgene.2014.00286Shirai, Y. T., Suzuki, T., Morita, M., Takahashi, A., & Yamamoto, T. (2014). Multifunctional roles of the mammalian CCR4-NOT complex in physiological phenomena. Frontiers in Genetics, 5(AUG), [Article 286]. https://doi.org/10.3389/fgene.2014.00286
21.	Gandin, V., Sikström, K., Alain, T., Morita, M., McLaughlan, S., Larsson, O., & Topisirovic, I. (2014). Polysome fractionation and analysis of mammalian translatomes on a genome-wide scale. Journal of Visualized Experiments, (87). https://doi.org/10.3791/51455
22.	Watanabe, C., Morita, M., Hayata, T., Nakamoto, T., Kikuguchi, C., Li, X., Kobayashi, Y., Takahashi, N., Notomi, T., Moriyama, K., Yamamoto, T., Ezura, Y., & Noda, M. (2014). Stability of mRNA influences osteoporotic bone mass via CNOT3. Proceedings of the National Academy of Sciences of the United States of America, 111(7), 2692-2697. https://doi.org/10.1073/pnas.1316932111
23.	Morita, M., Gravel, S. P., Chénard, V., Sikström, K., Zheng, L., Alain, T., Gandin, V., Avizonis, D., Arguello, M., Zakaria, C., McLaughlan, S., Nouet, Y., Pause, A., Pollak, M., Gottlieb, E., Larsson, O., St-Pierre, J., Topisirovic, I., & Sonenberg, N. (2013). MTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metabolism, 18(5), 698-711. https://doi.org/10.1016/j.cmet.2013.10.001
24.	Morita, M., Ler, L. W., Fabian, M. R., Siddiqui, N., Mullin, M., Henderson, V. C., Alain, T., Fonseca, B. D., Karashchuk, G., Bennett, C. F., Kabuta, T., Higashi, S., Larsson, O., Topisirovic, I., Smith, R. J., Gingras, A. C., & Sonenberg, N. (2012). A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. Molecular and cellular biology, 32(17), 3585-3593. https://doi.org/10.1128/MCB.00455-12
25.	Larsson, O., Morita, M., Topisirovic, I., Alain, T., Blouin, M. J., Pollak, M., & Sonenberg, N. (2012). Distinct perturbation of the translatome by the antidiabetic drug metformin. Proceedings of the National Academy of Sciences of the United States of America, 109(23), 8977-8982. https://doi.org/10.1073/pnas.1201689109
26.	Alain, T., Morita, M., Fonseca, B. D., Yanagiya, A., Siddiqui, N., Bhat, M., Zammit, D., Marcus, V., Metrakos, P., Voyer, L. A., Gandin, V., Liu, Y., Topisirovic, I., & Sonenberg, N. (2012). eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. Cancer Research, 72(24), 6468-6476. https://doi.org/10.1158/0008-5472.CAN-12-2395
27.	Fabian, M. R., Cieplak, M. K., Frank, F., Morita, M., Green, J., Srikumar, T., Nagar, B., Yamamoto, T., Raught, B., Duchaine, T. F., & Sonenberg, N. (2012). Erratum: miRNA-mediated deadenylation is orchestrated by GW182 through two conserved motifs that interact with CCR4-NOT (Nature Structural and Molecular Biology (2011) 18 (1211-1217)). Nature Structural and Molecular Biology, 19(3), 364. https://doi.org/10.1038/nsmb0312-364c
28.	Takahashi, A., Kikuguchi, C., Morita, M., Shimodaira, T., Tokai-Nishizumi, N., Yokoyama, K., Ohsugi, M., Suzuki, T., & Yamamoto, T. (2012). Involvement of CNOT3 in mitotic progression through inhibition of MAD1 expression. Biochemical and Biophysical Research Communications, 419(2), 268-273. https://doi.org/10.1016/j.bbrc.2012.02.007
29.	Takahashi, A., Morita, M., Yokoyama, K., Suzuki, T., & Yamamoto, T. (2012). Tob2 inhibits peroxisome proliferator-activated receptor γ2 expression by sequestering smads and C/EBPα during adipocyte differentiation. Molecular and cellular biology, 32(24), 5067-5077. https://doi.org/10.1128/MCB.00610-12
30.	Ito, K., Inoue, T., Yokoyama, K., Morita, M., Suzuki, T., & Yamamoto, T. (2011). CNOT2 depletion disrupts and inhibits the CCR4-NOT deadenylase complex and induces apoptotic cell death. Genes to Cells, 16(4), 368-379. https://doi.org/10.1111/j.1365-2443.2011.01492.x
31.	Fabian, M. R., Cieplak, M. K., Frank, F., Morita, M., Green, J., Srikumar, T., Nagar, B., Yamamoto, T., Raught, B., Duchaine, T. F., & Sonenberg, N. (2011). MiRNA-mediated deadenylation is orchestrated by GW182 through two conserved motifs that interact with CCR4-NOT. Nature Structural and Molecular Biology, 18(11), 1211-1217. https://doi.org/10.1038/nsmb.2149
32.	Morita, M., Oike, Y., Nagashima, T., Kadomatsu, T., Tabata, M., Suzuki, T., Nakamura, T., Yoshida, N., Okada, M., & Yamamoto, T. (2011). Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3 +/- mice. EMBO Journal, 30(22), 4678-4691. https://doi.org/10.1038/emboj.2011.320
33.	Ito, K., Takahashi, A., Morita, M., Suzuki, T., & Yamamoto, T. (2011). The role of the CNOT1 subunit of the CCR4-NOT complex in mRNA deadenylation and cell viability. Protein and Cell, 2(9), 755-763. https://doi.org/10.1007/s13238-011-1092-4
34.	Wang, H., Morita, M., Yang, X., Suzuki, T., Yang, W., Wang, J., Ito, K., Wang, Q., Zhao, C., Bartlam, M., Yamamoto, T., & Rao, Z. (2010). Crystal structure of the human CNOT6L nuclease domain reveals strict poly(A) substrate specificity. EMBO Journal, 29(15), 2566-2576. https://doi.org/10.1038/emboj.2010.152
35.	Yang, X., Morita, M., Wang, H., Suzuki, T., Yang, W., Luo, Y., Zhao, C., Yu, Y., Bartlam, M., Yamamoto, T., & Rao, Z. (2008). Crystal structures of human BTG2 and mouse TIS21 involved in suppression of CAF1 deadenylase activity. Nucleic acids research, 36(21), 6872-6881. https://doi.org/10.1093/nar/gkn825
36.	Miyasaka, T., Morita, M., Ito, K., Suzuki, T., Fukuda, H., Takeda, S., Inoue, J. I., Semba, K., & Yamamoto, T. (2008). Interaction of antiproliferative protein Tob with the CCR4-NOT deadenylase complex. Cancer Science, 99(4), 755-761. https://doi.org/10.1111/j.1349-7006.2008.00746.x
37.	Morita, M., Suzuki, T., Nakamura, T., Yokoyama, K., Miyasaka, T., & Yamamoto, T. (2007). Depletion of mammalian CCR4b deadenylase triggers elevation of the p27 Kip1 mRNA level and impairs cell growth. Molecular and cellular biology, 27(13), 4980-4990. https://doi.org/10.1128/MCB.02304-06

https://scholars.uthscsa.edu/en/persons/masahiro-morita