Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A
Open accessAbstract
Autophagy is a cellular catabolic process critical for cell viability and homoeostasis. Inhibition of mammalian target of rapamycin (mTOR) complex-1 (mTORC1) activates autophagy. A puzzling observation is that amino acid starvation triggers more rapid autophagy than pharmacological inhibition of mTORC1, although they both block mTORC1 activity with similar kinetics. Here we find that in addition to mTORC1 inactivation, starvation also causes an increase in phosphatase activity towards ULK1, an mTORC1 substrate whose dephosphorylation is required for autophagy induction. We identify the starvation-stimulated phosphatase for ULK1 as the PP2A-B55α complex. Treatment of cells with starvation but not mTORC1 inhibitors triggers dissociation of PP2A from its inhibitor Alpha4. Furthermore, pancreatic ductal adenocarcinoma cells, whose growth depends on high basal autophagy, possess stronger basal phosphatase activity towards ULK1 and require ULK1 for sustained anchorage-independent growth. Taken together, concurrent mTORC1 inactivation and PP2A-B55α stimulation fuel ULK1-dependent autophagy.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
During amino acid starvation, PP2A is activated by α4 dissociation from PP2A/C and increased PP2A/B55α formation, leading to ULK1 dephosphorylation and autophagy induction.
“It has been reported that during amino acid starvation, PP2A is activated due to dissociation of α4 from PP2A/C and increased formation of PP2A/B55α, leading to dephosphorylation of the mTORC1 substrate ULK1 and activation, which promotes the induction of autophagy (Wong et al., 2015).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Wong et al., 2015
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351 · see citing works
The protein kinase complement of the human genome
Manning, G., Whyte, D. B., Martinez, R., Hunter, T., & Sudarsanam, S. (2002) · Science · doi:10.1126/science.1075762 · Cited by 8,145 · see citing works
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Kim, J., Kundu, M., Viollet, B., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2152 · Cited by 7,227 · see citing works
Autophagy: Renovation of Cells and Tissues
Mizushima, N., & Komatsu, M. (2011) · Cell · doi:10.1016/j.cell.2011.10.026 · Cited by 6,467 · see citing works
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083 · see citing works
The Role of Atg Proteins in Autophagosome Formation
Mizushima, N., Yoshimori, T., & Ohsumi, Y. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154005 · Cited by 2,978 · see citing works
The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
Sancak, Y., Peterson, T. R., Shaul, Y. D., Lindquist, R. A., Thoreen, C. C., Bar-Peled, L., & Sabatini, D. M. (2008) · Science · doi:10.1126/science.1157535 · Cited by 2,773 · see citing works
Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy
Egan, D. F., Shackelford, D. B., Mihaylova, M. M., Gelino, S., Kohnz, R. A., Mair, W., Vasquez, D. S., Joshi, A., Gwinn, D. M., Taylor, R., et al. (2011) · Science · doi:10.1126/science.1196371 · Cited by 2,600 · see citing works
Autophagy in Human Health and Disease
Choi, A. M. K., Ryter, S. W., & Levine, B. (2013) · New England Journal of Medicine · doi:10.1056/nejmra1205406 · Cited by 2,583 · see citing works
Autophagy in Health and Disease: A Double-Edged Sword
Shintani, T., & Klionsky, D. J. (2004) · Science · doi:10.1126/science.1099993 · Cited by 2,531 · see citing works
Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S., & Sabatini, D. M. (2010) · Cell · doi:10.1016/j.cell.2010.02.024 · Cited by 2,464 · see citing works
Nutrient-dependent mTORC1 Association with the ULK1–Atg13–FIP200 Complex Required for Autophagy
Hosokawa, N., Hara, T., Kaizuka, T., Kishi, C., Takamura, A., Miura, Y., Iemura, S.-I., Natsume, T., Takehana, K., Yamada, N., et al. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e08-12-1248 · Cited by 2,076 · see citing works
ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery
Jung, C. H., Jun, C. B., Ro, S.-H., Kim, Y.-M., Otto, N. M., Cao, J., Kundu, M., & Kim, D.-H. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e08-12-1249 · Cited by 2,025 · see citing works
Mammalian autophagy: core molecular machinery and signaling regulation
Yang, Z., & Klionsky, D. J. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.11.014 · Cited by 1,956 · see citing works
Thoreen, C. C., Kang, S. A., Chang, J. W., Liu, Q., Zhang, J., Gao, Y., Reichling, L. J., Sim, T., Sabatini, D. M., & Gray, N. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900301200 · Cited by 1,803 · see citing works
ULK1·ATG13·FIP200 Complex Mediates mTOR Signaling and Is Essential for Autophagy
Ganley, I. G., Lam, D., Wang, J., Ding, X., Chen, S., & Jiang, X. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900573200 · Cited by 1,559 · see citing works
Self-citationPancreatic cancers require autophagy for tumor growth
Yang, S., Wang, X., Contino, G., Liesa, M., Sahin, E., Ying, H., Bause, A., Li, Y., Stommel, J. M., Dell'Antonio, G., et al. (2011) · Genes & Development · doi:10.1101/gad.2016111 · Cited by 1,498 · see citing works
Serine/threonine phosphatases: mechanism through structure
Shi, Y. (2009) · Cell · doi:10.1016/j.cell.2009.10.006 · Cited by 1,488 · see citing works
Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis
Guo, J. Y., Chen, H.-Y., Mathew, R., Fan, J., Strohecker, A. M., Karsli-Uzunbas, G., Kamphorst, J. J., Chen, G., Lemons, J. M. S., Karantza, V., et al. (2011) · Genes & Development · doi:10.1101/gad.2016311 · Cited by 1,323 · see citing works
Peterson, T. R., Laplante, M., Thoreen, C. C., Sancak, Y., Kang, S. A., Kuehl, W. M., Gray, N. S., & Sabatini, D. M. (2009) · Cell · doi:10.1016/j.cell.2009.03.046 · Cited by 1,202 · see citing works
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., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1232044 · Cited by 1,080 · see citing works
Insulin Activation of Rheb, a Mediator of mTOR/S6K/4E-BP Signaling, Is Inhibited by TSC1 and 2
Garami, A., Zwartkruis, F. J. T., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S. C., Hafen, E., Bos, J. L., & Thomas, G. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00220-x · Cited by 1,043 · see citing works
Rapamycin passes the torch: a new generation of mTOR inhibitors
Benjamin, D., Colombi, M., Moroni, C., & Hall, M. N. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3531 · Cited by 981 · see citing works
Gao, T., Furnari, F., & Newton, A. C. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.03.008 · Cited by 906 · see citing works
Itakura, E., & Mizushima, N. (2010) · Autophagy · doi:10.4161/auto.6.6.12709 · Cited by 843 · see citing works
Jiang, P., & Mizushima, N. (2013) · Cell Research · doi:10.1038/cr.2013.161 · Cited by 767 · see citing works
From Promiscuity to Precision: Protein Phosphatases Get a Makeover
Virshup, D. M., & Shenolikar, S. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.02.015 · Cited by 643 · see citing works
Autophagy in Human Health and Disease
Doria, A., Gatto, M., & Punzi, L. (2013) · New England Journal of Medicine · doi:10.1056/nejmc1303158 · Cited by 621 · see citing works
The dynamic nature of autophagy in cancerPreprint
Kimmelman, A. C. (2011) · Genes & Development · doi:10.1101/gad.17558811 · Cited by 587 · see citing works
Shang, L., Chen, S., Du, F., Shen, L., Zhao, L., & Wang, X. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100844108 · Cited by 540 · see citing works
Protein phosphatase 2A regulatory subunits and cancer
Eichhorn, P. J. A., Creyghton, M. P., & Bernards, R. (2009) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2008.05.005 · Cited by 513 · see citing works
Autophagy-Mediated Tumor Promotion
Guo, J. Y., Xia, B., & White, E. (2013) · Cell · doi:10.1016/j.cell.2013.11.019 · Cited by 499 · see citing works
Wong, P., Puente, C., Ganley, I. G., & Jiang, X. (2013) · Autophagy · doi:10.4161/auto.23323 · Cited by 497 · see citing works
Self-citationNutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases.Preprint
Como, C. J. D., & Arndt, K. T. (1996) · Genes & Development · doi:10.1101/gad.10.15.1904 · Cited by 494 · see citing works
Structure of the Protein Phosphatase 2A Holoenzyme
Xu, Y., Xing, Y., Chen, Y., Chao, Y., Lin, Z., Fan, E., Yu, J. W., Strack, S., Jeffrey, P. D., & Shi, Y. (2006) · Cell · doi:10.1016/j.cell.2006.11.033 · Cited by 450 · see citing works
A dual role for autophagy in a murine model of lung cancer
Rao, S., Tortola, L., Perlot, T., Wirnsberger, G., Novatchkova, M., Nitsch, R., Sykacek, P., Frank, L., Schramek, D., Komnenovic, V., et al. (2014) · Nature Communications · doi:10.1038/ncomms4056 · Cited by 444 · see citing works
mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin
Kang, S. A. W., Pacold, M. E., Cervantes, C., Lim, D., Lou, H. J., Ottina, K. A., Gray, N. S., Turk, B. E., Yaffe, M. B., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1236566 · Cited by 432 · see citing works
Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesisPreprint
Wei, H., Wei, S., Gan, B., Xu, P., Zou, W., & Guan, J. (2011) · Genes & Development · doi:10.1101/gad.2051011 · Cited by 402 · see citing works
PP2A holoenzyme assembly: In cauda venenum (the sting is in the tail)
Janssens, V., Longin, S., & Goris, J. (2008) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2007.12.004 · Cited by 390 · see citing works
Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
Xing, Y., Xu, Y., Chen, Y., Jeffrey, P. D., Chao, Y., Lin, Z., Li, Z., Strack, S., Stock, J. B., & Shi, Y. (2006) · Cell · doi:10.1016/j.cell.2006.09.025 · Cited by 334 · see citing works
Swingle, M. R., Ni, L., & Honkanen, R. E. (2007) · Humana Press eBooks · doi:10.1385/1-59745-267-x:23 · Cited by 291 · see citing works
Structure of a Protein Phosphatase 2A Holoenzyme: Insights into B55-Mediated Tau Dephosphorylation
Xu, Y., Chen, Y., Zhang, P., Jeffrey, P. D., & Shi, Y. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.08.006 · Cited by 285 · see citing works
α4 Is an Essential Regulator of PP2A Phosphatase Activity
Kong, M., Ditsworth, D., Lindsten, T., & Thompson, C. B. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.025 · Cited by 162 · see citing works
The B55α Subunit of PP2A Drives a p53-Dependent Metabolic Adaptation to Glutamine Deprivation
Reid, M. A., Wang, W.-I., Rosales, K. R., Welliver, M. X., Pan, M., & Kong, M. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.02.008 · Cited by 154 · see citing works
The PP2A-Associated Protein α4 Is an Essential Inhibitor of Apoptosis
Kong, M., Fox, C. J., Mu, J., Solt, L., Xu, A., Cinalli, R. M., Birnbaum, M. J., Lindsten, T., & Thompson, C. B. (2004) · Science · doi:10.1126/science.1100537 · Cited by 149 · see citing works
Autoregulation of Protein Phosphatase Type 2A Expression
Baharians, Z., & Schönthal, A. H. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.30.19019 · Cited by 146 · see citing works
Structural basis of protein phosphatase 2A stable latency
Jiang, L., Stanevich, V., Satyshur, K. A., Kong, M., Watkins, G. R., Wadzinski, B. E., Sengupta, R., & Xing, Y. (2013) · Nature Communications · doi:10.1038/ncomms2663 · Cited by 68 · see citing works
Mumby, M. C. (2007) · ACS Chemical Biology · doi:10.1021/cb700021z · Cited by 67 · see citing works
Autophagy: a targetable linchpin of cancer cell metabolism
Leone, R. D., & Amaravadi, R. K. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.01.008 · Cited by 66 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Autophagy: Regulator of cell death
Liu, S., Yao, S., Yang, H., Liu, S., & Wang, Y. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06154-8 · Cited by 1,193 · see citing works
Recent insights into the function of autophagy in cancerPreprint
Amaravadi, R. K., Kimmelman, A. C., & White, E. (2016) · Genes & Development · doi:10.1101/gad.287524.116 · Cited by 810 · see citing works
The mammalian ULK1 complex and autophagy initiation
Zachari, M., & Ganley, I. G. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170021 · Cited by 789 · see citing works
Mechanisms of Autophagy Initiation
Hurley, J. H., & Young, L. N. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044820 · Cited by 655 · see citing works
mTORC1 as the main gateway to autophagy
Rabanal-Ruiz, Y., Otten, E. G., & Korolchuk, V. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170027 · Cited by 505 · see citing works
Autophagy: machinery and regulation
Yin, Z., Pascual, C., & Klionsky, D. J. (2016) · Microbial Cell · doi:10.15698/mic2016.12.546 · Cited by 567 · see citing works
Autophagy in cancer metastasis
Mowers, E. E., Sharifi, M. N., & Macleod, K. F. (2016) · Oncogene · doi:10.1038/onc.2016.333 · Cited by 476 · see citing works
mTOR substrate phosphorylation in growth control.
Battaglioni, S., Benjamin, D., Wälchli, M., Maier, T., & Hall, M. (2022) · Cell · doi:10.1016/j.cell.2022.04.013 · Cited by 388 · see citing works
Autophagy: An Essential Degradation Program for Cellular Homeostasis and Life
Chun, Y., & Kim, J. (2018) · Cells · doi:10.3390/cells7120278 · Cited by 385 · see citing works
Guo, J. Y., Teng, X., Laddha, S. V., Ma, S., Nostrand, S. C. V., Yang, Y., Khor, S., Chan, C. S., Rabinowitz, J. D., & White, E. (2016) · Genes & Development · doi:10.1101/gad.283416.116 · Cited by 373 · see citing works
Autophagy and Autophagy-Related Diseases: A Review
Ichimiya, T., Yamakawa, T., Hirano, T., Yokoyama, Y., Hayashi, Y., Hirayama, D., Wagatsuma, K., Itoi, T., & Nakase, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238974 · Cited by 338 · see citing works
The Emerging Roles of mTORC1 in Macromanaging Autophagy
Dossou, A. S., & Basu, A. (2019) · Cancers · doi:10.3390/cancers11101422 · Cited by 291 · see citing works
Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy
Qian, X., Li, X., Cai, Q., Zhang, C., Yu, Q., Jiang, Y., Lee, J.-H., Hawke, D. H., Wang, Y., Xia, Y., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.027 · Cited by 281 · see citing works
A molecular perspective of mammalian autophagosome biogenesis
Mercer, T. J., Gubaš, A., & Tooze, S. A. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.810366 · Cited by 265 · see citing works
p62/ SQSTM 1: ‘Jack of all trades’ in health and cancer
Sánchez‐Martín, P., Saito, T., & Komatsu, M. (2018) · FEBS Journal · doi:10.1111/febs.14712 · Cited by 242 · see citing works
Antidepressants act by inducing autophagy controlled by sphingomyelin–ceramide
Gulbins, A., Schumacher, F., Becker, K. A., Wilker, B., Soddemann, M., Boldrin, F., Müller, C. P., Edwards, M. J., Goodman, M. D., Caldwell, C. C., et al. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0090-9 · Cited by 230 · see citing works
The multifaceted role of autophagy in cancer
Russell, R. C., & Guan, K. (2022) · The EMBO Journal · doi:10.15252/embj.2021110031 · Cited by 229 · see citing works
Nutrient-regulated Phosphorylation of ATG13 Inhibits Starvation-induced Autophagy
Puente, C., Hendrickson, R. C., & Jiang, X. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.689646 · Cited by 223 · see citing works
Self-citationAutophagic dysregulation in doxorubicin cardiomyopathy
Bartlett, J. J., Trivedi, P. C., & Pulinilkunnil, T. (2017) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2017.01.007 · Cited by 218 · see citing works
The Role of Autophagy in Cancer
Santana-Codina, N., Mancias, J. D., & Kimmelman, A. C. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-041816-122338 · Cited by 207 · see citing works
CCT2 is an aggrephagy receptor for clearance of solid protein aggregates
Ma, X., Lu, C., Chen, Y., Li, S., Ma, N., Tao, X., Li, Y., Wang, J., Zhou, M., Yan, Y., et al. (2022) · Cell · doi:10.1016/j.cell.2022.03.005 · Cited by 206 · see citing works
Self-citationThe multifaceted role of autophagy in cancer and the microenvironment
Folkerts, H., Hilgendorf, S., Vellenga, E., Bremer, E., & Wiersma, V. R. (2018) · Medicinal Research Reviews · doi:10.1002/med.21531 · Cited by 201 · see citing works
Autophagy as a therapeutic target in pancreatic cancer
Piffoux, M., Eriau, E., & Cassier, P. A. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-01039-5 · Cited by 182 · see citing works
Autophagy, Metabolism, and CancerPreprint
Guo, J. Y., & White, E. (2016) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2016.81.030981 · Cited by 182 · see citing works
The role of lysosomes in cancer development and progression
Tang, T., Yang, Z., Wang, D., Yang, X., Wang, J., Li, L., Wen, Q., Gao, L., Bian, X., & Yu, S. (2020) · Cell & Bioscience · doi:10.1186/s13578-020-00489-x · Cited by 169 · see citing works
Self-citationMartina, J. A., & Puertollano, R. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.003471 · Cited by 167 · see citing works
Regulation and function of autophagy in pancreatic cancer
Li, J., Chen, X., Kang, R., Zeh, H. J., Klionsky, D. J., & Tang, D. (2020) · Autophagy · doi:10.1080/15548627.2020.1847462 · Cited by 160 · see citing works
Mitochondria-Associated Membranes Response to Nutrient Availability and Role in Metabolic Diseases
Theurey, P., & Rieusset, J. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.09.002 · Cited by 159 · see citing works
The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance
Biancur, D. E., & Kimmelman, A. C. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.04.011 · Cited by 151 · see citing works
A reversible phospho-switch mediated by ULK1 regulates the activity of autophagy protease ATG4B
Pengo, N., Agrotis, A., Prak, K., Jones, J. M., & Ketteler, R. (2017) · Nature Communications · doi:10.1038/s41467-017-00303-2 · Cited by 145 · see citing works
Cancer-associated Fibroblasts Promote Irradiated Cancer Cell Recovery Through Autophagy
Wang, Y., Gan, G., Wang, B., Wu, J., Cao, Y., Zhu, D., Xu, Y., Wang, X., Han, H., Li, X., et al. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.02.019 · Cited by 144 · see citing works
Ruvolo, P. P. (2016) · BBA Clinical · doi:10.1016/j.bbacli.2016.08.002 · Cited by 143 · see citing works
Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation
Nazio, F., Carinci, M., Valacca, C., Bielli, P., Strappazzon, F., Antonioli, M., Ciccosanti, F., Rodolfo, C., Campello, S., Fimia, G. M., et al. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201605089 · Cited by 137 · see citing works
Advances in Autophagy Regulatory Mechanisms
Gallagher, L. E., Williamson, L. E., & Chan, E. Y. W. (2016) · Cells · doi:10.3390/cells5020024 · Cited by 135 · see citing works
Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases
Tubbs, E., & Rieusset, J. (2016) · Journal of Molecular Endocrinology · doi:10.1530/jme-16-0189 · Cited by 126 · see citing works
Alborixin clears amyloid-β by inducing autophagy through PTEN-mediated inhibition of the AKT pathway
Wani, A., Gupta, M., Ahmad, M. N., Shah, A. M., Ahsan, A. U., Qazi, P. H., Malik, F. A., Singh, G., Sharma, P. R., Kaddoumi, A., et al. (2019) · Autophagy · doi:10.1080/15548627.2019.1596476 · Cited by 129 · see citing works
A DNA-based voltmeter for organelles
Saminathan, A., Devany, J. M., Veetil, A. T., Suresh, B., Pillai, K. S., Schwake, M., & Krishnan, Y. (2020) · Nature Nanotechnology · doi:10.1038/s41565-020-00784-1 · Cited by 128 · see citing works
Non-genomic mechanisms of protein phosphatase 2A (PP2A) regulation in cancer
Kauko, O., & Westermarck, J. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2018.01.005 · Cited by 111 · see citing works
Regulation and Roles of Autophagy at Synapses
Nikoletopoulou, V., & Tavernarakis, N. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.03.006 · Cited by 115 · see citing works
Nwadike, C., Williamson, L. E., Gallagher, L. E., Guan, J., & Chan, E. Y. W. (2018) · Molecular and Cellular Biology · doi:10.1128/mcb.00023-18 · Cited by 113 · see citing works
Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation
Kimball, S. R., Gordon, B. S., Moyer, J. E., Dennis, M. D., & Jefferson, L. S. (2016) · Cellular Signalling · doi:10.1016/j.cellsig.2016.03.008 · Cited by 97 · see citing works
Meeusen, B., & Janssens, V. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.10.002 · Cited by 96 · see citing works
Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress‐induced autophagy
Torii, S., Yoshida, T., Arakawa, S., Honda, S., Nakanishi, A., & Shimizu, S. (2016) · EMBO Reports · doi:10.15252/embr.201642565 · Cited by 94 · see citing works
PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer
(2019) · Advances in Cancer Research · doi:10.1016/bs.acr.2019.03.009 · Cited by 93 · see citing works
Autophagosome biogenesis and human health
Kawabata, T., & Yoshimori, T. (2020) · Cell Discovery · doi:10.1038/s41421-020-0166-y · Cited by 96 · see citing works
Regulation of Autophagy Enzymes by Nutrient Signaling
King, K. E., Losier, T. T., & Russell, R. C. (2021) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2021.01.006 · Cited by 90 · see citing works
ULK1 O-GlcNAcylation Is Crucial for Activating VPS34 via ATG14L during Autophagy Initiation
Pyo, K. E., Kim, C. R., Lee, M., Kim, J., Kim, K. I., & Baek, S. H. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.042 · Cited by 87 · see citing works
Thuwajit, C., Ferraresi, A., Titone, R., Thuwajit, P., & Isidoro, C. (2017) · Medicinal Research Reviews · doi:10.1002/med.21473 · Cited by 84 · see citing works
Phosphoregulation of the autophagy machinery by kinases and phosphatases
Licheva, M., Raman, B., Kraft, C., & Reggiori, F. (2021) · Autophagy · doi:10.1080/15548627.2021.1909407 · Cited by 83 · see citing works
Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas
Khan, T., Relitti, N., Brindisi, M., Magnano, S., Zisterer, D. M., Gemma, S., Butini, S., & Campiani, G. (2019) · Medicinal Research Reviews · doi:10.1002/med.21646 · Cited by 78 · see citing works
Fine-tuning of AMPK–ULK1–mTORC1 regulatory triangle is crucial for autophagy oscillation
Holczer, M., Hajdú, B., Lőrincz, T., Szarka, A., Bánhegyi, G., & Kapuy, O. (2020) · Scientific Reports · doi:10.1038/s41598-020-75030-8 · Cited by 77 · see citing works
Shariq, M., Quadir, N., Sharma, N., Singh, J., Sheikh, J. A., Khubaib, M., Hasnain, S. E., & Ehtesham, N. Z. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.636644 · Cited by 77 · see citing works
CDK1, the Other ‘Master Regulator’ of Autophagy
Odle, R., Florey, O., Ktistakis, N. T., & Cook, S. J. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.11.001 · Cited by 74 · see citing works
Dong, L., He, J., Luo, L., & Wang, K. (2023) · Pharmaceuticals · doi:10.3390/ph16010092 · Cited by 73 · see citing works
Fasting-induced hormonal regulation of lysosomal function
Chen, L., Wang, K., Long, A., Jia, L., Zhang, Y., Deng, H., Li, Y., Han, J., & Wang, Y. (2017) · Cell Research · doi:10.1038/cr.2017.45 · Cited by 71 · see citing works
PP2C phosphatases promote autophagy by dephosphorylation of the Atg1 complex
Memişoğlu, G., Eapen, V. V., Yang, Y., Klionsky, D. J., & Haber, J. E. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1817078116 · Cited by 70 · see citing works
Targeting KRAS: from metabolic regulation to cancer treatment
Shi, Y., Zheng, H., Wang, T., Zhou, S., Zhao, S., Li, M., & Cao, B. (2025) · Molecular Cancer · doi:10.1186/s12943-024-02216-3 · Cited by 75 · see citing works
Shin, J. H., Park, C. W., Yoon, G., Hong, S. M., & Choi, K. Y. (2018) · Oncogenesis · doi:10.1038/s41389-018-0064-4 · Cited by 70 · see citing works
Targeting mTOR in Acute Lymphoblastic Leukemia
Simioni, C., Martelli, A. M., Zauli, G., Melloni, E., & Neri, L. M. (2019) · Cells · doi:10.3390/cells8020190 · Cited by 68 · see citing works
Castro‐Gonzalez, S., Shi, Y., Colomer-Lluch, M., Song, Y., Mowery, K., Almodóvar, S., Bansal, A., Kirchhoff, F., Sparrer, K. M. J., Liang, C., et al. (2020) · Autophagy · doi:10.1080/15548627.2020.1725401 · Cited by 66 · see citing works
Torii, S., Yamaguchi, H., Nakanishi, A., Arakawa, S., Honda, S., Moriwaki, K., Nakano, H., & Shimizu, S. (2020) · Nature Communications · doi:10.1038/s41467-020-15577-2 · Cited by 65 · see citing works
Autophagic elimination of ribosomes during spermiogenesis provides energy for flagellar motility
Lei, Y., Zhang, X., Xu, Q., Liu, S., Li, C., Jiang, H., Lin, H., Kong, E., Liu, J., Qi, S., et al. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.07.015 · Cited by 64 · see citing works
Furukawa, K., Fukuda, T., Yamashita, S.-I., Saigusa, T., Kurihara, Y., Yoshida, Y., Kirisako, H., Nakatogawa, H., & Kanki, T. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.064 · Cited by 63 · see citing works
Autophagy and cancer cell metabolism
Anderson, C. M., & Macleod, K. F. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.06.002 · Cited by 63 · see citing works
PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling
Thürmer, M., Gollowitzer, A., Pein, H., Neukirch, K., Gelmez, E., Waltl, L., Wielsch, N., Winkler, R., Loeser, K., Grander, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30374-9 · Cited by 62 · see citing works
Autophagy in cancer: a complex relationship
Wilde, L. R., Tanson, K., Curry, J., & Martinez‐Outschoorn, U. (2018) · Biochemical Journal · doi:10.1042/bcj20170847 · Cited by 61 · see citing works
Activation of Aurora A kinase increases YAP stability via blockage of autophagy
Wang, P., Gong, Y., Guo, T., Li, M., Fang, L., Yin, S., Muhammad, K. I., Liu, Y., Xu, J., Xu, L., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1664-4 · Cited by 61 · see citing works
Malhotra, J. D., Jabbour, S. K., Orlick, M., Riedlinger, G., Guo, Y., White, E., & Aisner, J. (2019) · Cancer Treatment and Research Communications · doi:10.1016/j.ctarc.2019.100158 · Cited by 61 · see citing works
Target of Rapamycin in Control of Autophagy: Puppet Master and Signal Integrator
Mugume, Y., Kazibwe, Z., & Bassham, D. C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218259 · Cited by 61 · see citing works
Djeffal, S., Mamache, B., Elgroud, R., Hireche, S., & Bouaziz, O. (2018) · Veterinary World · doi:10.14202/vetworld.2018.1102-1108 · Cited by 60 · see citing works
The Dawn of Mitophagy: What Do We Know by Now?
Belousov, D. M., Вячеславовна, М. Е., Somasundaram, S. G., Kirkland, C. E., & Aliev, G. M. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200522202319 · Cited by 59 · see citing works
Proteinuria causes dysfunctional autophagy in the proximal tubule
Nolin, A. C., Mulhern, R. M., Panchenko, M. V., Pisarek-Horowitz, A., Wang, Z., Shirihai, O., Borkan, S. C., & Havasi, A. (2016) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00125.2016 · Cited by 58 · see citing works
Roy, N., & Paira, P. (2024) · ACS Omega · doi:10.1021/acsomega.3c08890 · Cited by 60 · see citing works
Signaling Pathways Underlying Anthracycline Cardiotoxicity
Sala, V., Sala, A. D., Hirsch, E., & Ghigo, A. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8019 · Cited by 57 · see citing works
Insulin and Autophagy in Neurodegeneration
de Mello, N. P., Orellana, A. M., Mazucanti, C. H., Lima, G. D. M., Scavone, C., & Kawamoto, E. M. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00491 · Cited by 56 · see citing works
Regulation of protein phosphatase 2A (PP2A) tumor suppressor function by PME-1
Kaur, A., & Westermarck, J. K. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160161 · Cited by 53 · see citing works
Dietary Energy Modulation and Autophagy: Exploiting Metabolic Vulnerabilities to Starve Cancer
Cozzo, A. J., Coleman, M. F., Pearce, J. B., Pfeil, A. J., Etigunta, S. K., & Hursting, S. D. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.590192 · Cited by 55 · see citing works
Beyond starvation: An update on the autophagic machinery and its functions
Kawabata, T., & Yoshimori, T. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.12.005 · Cited by 52 · see citing works
Relevance of Autophagy and Mitophagy Dynamics and Markers in Neurodegenerative Diseases
Giorgi, C., Bouhamida, E., Danese, A., Previati, M., Pinton, P., & Patergnani, S. (2021) · Biomedicines · doi:10.3390/biomedicines9020149 · Cited by 50 · see citing works
Biological Roles of Alternative Autophagy.
Shimizu, S. (2018) · PubMed Central · doi:10.14348/molcells.2018.2215 · Cited by 51 · see citing works
Protein complexes and neighborhoods driving autophagy
Sankar, D. S., & Dengjel, J. (2020) · Autophagy · doi:10.1080/15548627.2020.1847461 · Cited by 51 · see citing works
Beclin1 and HMGB1 ameliorate the α-synuclein-mediated autophagy inhibition in PC12 cells
Wang, K., Huang, J., Xie, W., Huang, L., Zhong, C., & Chen, Z. (2016) · Diagnostic Pathology · doi:10.1186/s13000-016-0459-5 · Cited by 50 · see citing works
ESTERLINE, R. L., Oscarsson, J., & Burns, J. M. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.03.018 · Cited by 50 · see citing works
Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A
Svarcbahs, R., Jäntti, M. H., Kilpeläinen, T. P., Julku, U. H., Urvas, L., Kivioja, S., Norrbacka, S., & Myöhänen, T. T. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104558 · Cited by 50 · see citing works
Ali, M. Z., Devkota, S., Roh, J.-I., Lee, J., & Lee, H. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.08.094 · Cited by 49 · see citing works
ULK1 phosphorylation of striatin activates protein phosphatase 2A and autophagy
Hu, Z., Sankar, D. S., Vu, B., Leytens, A., Vionnet, C., Wu, W., Stumpe, M., Martínez-Martínez, E., Stork, B., & Dengjel, J. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109762 · Cited by 47 · see citing works
Balancing life and death: BCL‐2 family members at diverse ER–mitochondrial contact sites
Means, R. E., & Katz, S. G. (2021) · FEBS Journal · doi:10.1111/febs.16241 · Cited by 50 · see citing works
Targeting the Metabolic Rewiring in Pancreatic Cancer and Its Tumor Microenvironment
Yamamoto, K., Iwadate, D., Kato, H., Nakai, Y., Tateishi, K., & Fujishiro, M. (2022) · Cancers · doi:10.3390/cancers14184351 · Cited by 48 · see citing works
Ortega, M. A., Fraile‐Μartinez, O., León-Oliva, D. D., Boaru, D. L., López-González, L., Montero, C. G., Álvarez-Mon, M. Á., Guijarro, L. G., Torres‐Carranza, D., Sáez, M. A., et al. (2024) · International Journal of Biological Sciences · doi:10.7150/ijbs.95122 · Cited by 48 · see citing works
Stanciu, G. D., Rusu, R. N., Bild, V., Filipiuc, L. E., Tamba, B.-I., & Ababei, D. C. (2021) · Biomedicines · doi:10.3390/biomedicines9050576 · Cited by 47 · see citing works
Physiological functions of ULK1/2
Pareek, G., & Kundu, M. (2024) · Journal of Molecular Biology · doi:10.1016/j.jmb.2024.168472 · Cited by 49 · see citing works
PP2A-B55: substrates and regulators in the control of cellular functions
Amin, P., Awal, S., Vigneron, S., Roque, S., Méchali, F., Labbé, J. C., Lorca, T., & Castro, A. (2021) · Oncogene · doi:10.1038/s41388-021-02068-x · Cited by 45 · see citing works
The true colors of autophagy in doxorubicin‑induced cardiotoxicity (Review)
Xiao, B., Hong, L., Cai, X., Mei, S., Ping, Z., & Shao, L. (2019) · Oncology Letters · doi:10.3892/ol.2019.10576 · Cited by 45 · see citing works
Autophagy and cancer: Basic mechanisms and inhibitor development
Hama, Y., Ogasawara, Y., & Noda, N. N. (2023) · Cancer Science · doi:10.1111/cas.15803 · Cited by 44 · see citing works
Sphingolipids as Regulators of Autophagy and Endocytic Trafficking
Young, M. M., & Wang, H. (2018) · Advances in cancer research · doi:10.1016/bs.acr.2018.04.008 · Cited by 44 · see citing works
Echavarría-Consuegra, L., Smit, J. M., & Reggiori, F. (2019) · Open Biology · doi:10.1098/rsob.190009 · Cited by 44 · see citing works
Sagrillo‐Fagundes, L., Bienvenue‐Pariseault, J., & Vaillancourt, C. (2019) · PLoS ONE · doi:10.1371/journal.pone.0202458 · Cited by 46 · see citing works
The serine/threonine protein phosphatase 2A controls autoimmunity
Sharabi, A., Kasper, I. R., & Tsokos, G. C. (2017) · Clinical Immunology · doi:10.1016/j.clim.2017.07.012 · Cited by 42 · see citing works
Functional Amino Acids and Autophagy: Diverse Signal Transduction and Application
Liu, C., Ji, L., Hu, J., Zhao, Y., Johnston, L. J., Zhang, X., & Ma, X. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111427 · Cited by 41 · see citing works
- Authors
- Wong, P.-M., Feng, Y., Wang, J., Shi, R., & Jiang, X.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Jiang, Xuejun
- Venue
- Nature Communications
- Published
- 2015-08-27
- Volume
- 6
- Issue
- 1
- Pages
- 8048-8048
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4552084
- OpenAlex
- W1126563578
- Cited by
- 239
- References
- 49
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 26 · 2023: 14 · 2022: 24 · 2021: 25 · 2020: 29 · 2019: 18 · 2018: 29 · 2017: 21 · 2016: 23 · 2015: 3
- FWCI
- 19.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Commonwealth Foundation
- Memorial Sloan-Kettering Cancer Center
- Beckman Research Institute, City of Hope
- Cycle for Survival
- National Institutes of Health
- National Cancer Institute (R01CA166413, P30CA008748)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- autophagy regulation, mTORC1, protein phosphatase 2A, amino acid starvation, pancreatic ductal adenocarcinoma, anchorage-independent growth, mTOR inhibition
- MeSH terms
- Autophagy-Related Protein-1 Homolog, Mechanistic Target of Rapamycin Complex 1, Amino Acids, Animals, Autophagy, Humans, Microscopy, Fluorescence, Pancreatic Neoplasms, Phosphorylation, Starvation, Protein Serine-Threonine Kinases, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Multiprotein Complexes, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Mice, Protein Phosphatase 2, Gene Knockdown Techniques, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
