Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Björn StorkEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101817


Historical Background

ULK1 is a Ser/Thr protein kinase and centrally involved in autophagy. Autophagy is an intracellular degradation process which contributes to the elimination of damaged or long-lived proteins and/or organelles. Autophagy occurs at basal levels in most cell types and ensures cellular homeostasis. However, autophagy can also be actively induced upon stress, including the withdrawal of nutrients or growth factors, treatment with chemotherapeutics, or intracellular infections.

In 1993, Tsukada and Ohsumi reported the isolation and characterization of 15 yeast mutants defective in the accumulation of autophagic bodies in the vacuoles. In a mutant termed apg1 (autophagy), nitrogen starvation did not induce protein degradation, and the apg1 mutant lost viability faster than wild-type cells during nitrogen starvation (Tsukada and Ohsumi 1993). In 1997, Matsuura et al. reported that the APG1gene encodes a protein...

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  1. Alers S, Löffler AS, Paasch F, Dieterle AM, Keppeler H, Lauber K, et al. Atg13 and FIP200 act independently of Ulk1 and Ulk2 in autophagy induction. Autophagy. 2011;7:1423–33. [pii] 18027.CrossRefPubMedCentralGoogle Scholar
  2. Alers S, Löffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2012;32:2–11. doi:10.1128/MCB.06159-11. [pii] MCB.06159-11.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bach M, Larance M, James DE, Ramm G. The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. Biochem J. 2011;440:283–91. doi:10.1042/BJ20101894. [pii] BJ20101894.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974;77:71–94.PubMedPubMedCentralGoogle Scholar
  5. Cao QH, Liu F, Yang ZL, Fu XH, Yang ZH, Liu Q, et al. Prognostic value of autophagy related proteins ULK1, Beclin 1, ATG3, ATG5, ATG7, ATG9, ATG10, ATG12, LC3B and p62/SQSTM1 in gastric cancer. Am J Transl Res. 2016;8:3831–47.PubMedPubMedCentralGoogle Scholar
  6. Chan EY, Kir S, Tooze SA. siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy. J Biol Chem. 2007;282:25464–74. doi:10.1074/jbc.M703663200. [pii] M703663200.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chan EY, Longatti A, McKnight NC, Tooze SA. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol. 2009;29:157–71. doi:10.1128/MCB.01082-08. [pii] MCB.01082-08.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Cheong H, Lindsten T, Wu J, Lu C, Thompson CB. Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc Natl Acad Sci U S A. 2011;108:11121–6. doi:10.1073/pnas.1107969108. [pii] 1107969108.CrossRefGoogle Scholar
  9. Cheong H, Wu J, Gonzales LK, Guttentag SH, Thompson CB, Lindsten T. Analysis of a lung defect in autophagy-deficient mouse strains. Autophagy. 2014;10:45–56. doi:10.4161/auto.26505. [pii] 26505.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, Antonioli M, et al. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol. 2010;191:155–68. doi:10.1083/jcb.201002100. [pii] jcb.201002100.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Dorsey FC, Rose KL, Coenen S, Prater SM, Cavett V, Cleveland JL, et al. Mapping the phosphorylation sites of Ulk1. J Proteome Res. 2009;8:5253–63. doi:10.1021/pr900583m.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Driessen S, Berleth N, Friesen O, Löffler AS, Böhler P, Hieke N, et al. Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy. Autophagy. 2015;11:1458–70. doi:10.1080/15548627.2015.1067359.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Dunlop EA, Hunt DK, Acosta-Jaquez HA, Fingar DC, Tee AR. ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy. 2011;7:737–47. [pii] 15491.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, et al. FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy. 2014;10:1749–60. doi:10.4161/auto.29640. [pii] 29640.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011;331:456–61. doi:10.1126/science.1196371. [pii] science.1196371.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Egan DF, Chun MG, Vamos M, Zou H, Rong J, Miller CJ, et al. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol Cell. 2015;59:285–97. doi:10.1016/j.molcel.2015.05.031. [pii] S1097-2765(15)00398-6.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009;284:12297–305. doi:10.1074/jbc.M900573200. [pii] M900573200.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441:885–9. doi:10.1038/nature04724. [pii] nature04724.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan JL, et al. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 2008;181:497–510. doi:10.1083/jcb.200712064. [pii] jcb.200712064.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Harding TM, Hefner-Gravink A, Thumm M, Klionsky DJ. Genetic and phenotypic overlap between autophagy and the cytoplasm to vacuole protein targeting pathway. J Biol Chem. 1996;271:17621–4.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Hieke N, Löffler AS, Kaizuka T, Berleth N, Böhler P, Driessen S, et al. Expression of a ULK1/2 binding-deficient ATG13 variant can partially restore autophagic activity in ATG13-deficient cells. Autophagy. 2015;11:1471–83. doi:10.1080/15548627.2015.1068488.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009a;20:1981–91. doi:10.1091/mbc.E08-12-1248. [pii] E08-12-1248.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hosokawa N, Sasaki T, Iemura S, Natsume T, Hara T, Mizushima N. Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy. 2009b;5:973–9. [pii] 9296.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Itakura E, Mizushima N. Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy. 2010;6:764–76. [pii] 12709.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Jiang L, Duan BS, Huang JX, Jiao X, Zhu XW, Sheng HH, et al. Association of the expression of unc-51-Like kinase 1 with lymph node metastasis and survival in patients with esophageal squamous cell carcinoma. Int J Clin Exp Med. 2014;7:1349–54.PubMedPubMedCentralGoogle Scholar
  26. Jiao H, Su GQ, Dong W, Zhang L, Xie W, Yao LM, et al. Chaperone-like protein p32 regulates ULK1 stability and autophagy. Cell Death Differ. 2015. doi:10.1038/xyza.2015.34. [pii] xyza201534.Google Scholar
  27. Joo JH, Dorsey FC, Joshi A, Hennessy-Walters KM, Rose KL, McCastlain K, et al. Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy. Mol Cell. 2011;43:572–85. doi:10.1016/j.molcel.2011.06.018. [pii] S1097-2765(11)00464-3.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Joo JH, Wang B, Frankel E, Ge L, Xu L, Iyengar R, et al. The noncanonical role of ULK/ATG1 in ER-to-Golgi trafficking is essential for cellular homeostasis. Mol Cell. 2016;62:491–506. doi:10.1016/j.molcel.2016.04.020. [pii] S1097-2765(16)30096-X.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Joshi A, Iyengar R, Joo JH, Li-Harms XJ, Wright C, Marino R, et al. Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1. Cell Death Differ. 2015. doi:10.1038/cdd.2015.88. [pii] cdd201588.CrossRefGoogle Scholar
  30. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009;20:1992–2003. doi:10.1091/mbc.E08-12-1249. [pii] E08-12-1249.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Karanasios E, Walker SA, Okkenhaug H, Manifava M, Hummel E, Zimmermann H, et al. Autophagy initiation by ULK complex assembly on ER tubulovesicular regions marked by ATG9 vesicles. Nat Commun. 2016;7:12420. doi:10.1038/ncomms12420. [pii] ncomms12420.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13:132–41. doi:10.1038/ncb2152. [pii] ncb2152.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Klionsky DJ, Cregg JM, Dunn WA, Jr., Emr SD, Sakai Y, Sandoval IV, et al. A unified nomenclature for yeast autophagy-related genes. Dev Cell. 2003;5:539–45. [pii] S153458070300296X.PubMedCrossRefGoogle Scholar
  34. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441:880–4. doi:10.1038/nature04723. [pii] nature04723.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Komduur JA, Veenhuis M, Kiel JA. The Hansenula polymorpha PDD7 gene is essential for macropexophagy and microautophagy. FEMS Yeast Res. 2003;3:27–34. [pii] S1567135602001356.PubMedGoogle Scholar
  36. Konno H, Konno K, Barber GN. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell. 2013;155:688–98. doi:10.1016/j.cell.2013.09.049.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Kundu M, Lindsten T, Yang CY, Wu J, Zhao F, Zhang J, et al. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood. 2008;112:1493–502. doi:10.1182/blood-2008-02-137398. [pii] blood-2008-02-137398.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Kuroyanagi H, Yan J, Seki N, Yamanouchi Y, Suzuki Y, Takano T, et al. Human ULK1, a novel serine/threonine kinase related to UNC-51 kinase of Caenorhabditis elegans: cDNA cloning, expression, and chromosomal assignment. Genomics. 1998;51:76–85. [pii] S088875439895340X.PubMedCrossRefGoogle Scholar
  39. Lai T, Garriga G. The conserved kinase UNC-51 acts with VAB-8 and UNC-14 to regulate axon outgrowth in C. elegans. Development. 2004;131:5991–6000. doi:10.1242/dev.01457. [pii] 131/23/5991.CrossRefPubMedGoogle Scholar
  40. Lazarus MB, Shokat KM. Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1. Bioorg Med Chem. 2015;23:5483–8. doi:10.1016/j.bmc.2015.07.034.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Lazarus MB, Novotny CJ, Shokat KM. Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors. ACS Chem Biol. 2015;10:257–61. doi:10.1021/cb500835z.CrossRefPubMedGoogle Scholar
  42. Lee EJ, Tournier C. The requirement of uncoordinated 51-like kinase 1 (ULK1) and ULK2 in the regulation of autophagy. Autophagy. 2011;7:689–95. [pii] 15450.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Li J, Qi W, Chen G, Feng D, Liu J, Ma B, et al. Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy. Autophagy. 2015. doi:10.1080/15548627.2015.1017180.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Li M, Lindblad JL, Perez E, Bergmann A, Fan Y. Autophagy-independent function of Atg1 for apoptosis-induced compensatory proliferation. BMC Biol. 2016a;14:70. doi:10.1186/s12915–016-0293-y.Google Scholar
  45. Li TY, Sun Y, Liang Y, Liu Q, Shi Y, Zhang CS, et al. ULK1/2 constitute a bifurcate node controlling glucose metabolic fluxes in addition to autophagy. Mol Cell. 2016b;62:359–70. doi:10.1016/j.molcel.2016.04.009. [pii] S1097-2765(16)30059-4.CrossRefPubMedGoogle Scholar
  46. Liang CC, Wang C, Peng X, Gan B, Guan JL. Neural-specific deletion of FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration. J Biol Chem. 2010;285:3499–509. doi:10.1074/jbc.M109.072389. [pii] M109.072389.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Liang Q, Yang P, Tian E, Han J, Zhang H. The C. elegans ATG101 homolog EPG-9 directly interacts with EPG-1/Atg13 and is essential for autophagy. Autophagy. 2012;8:1426–33. doi:10.4161/auto.21163. [pii] 21163.CrossRefPubMedGoogle Scholar
  48. Lim J, Lachenmayer ML, Wu S, Liu W, Kundu M, Wang R, et al. Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS Genet. 2015;11:e1004987. doi:10.1371/journal.pgen.1004987.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Lin SY, Li TY, Liu Q, Zhang C, Li X, Chen Y, et al. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science. 2012;336:477–81. doi:10.1126/science.1217032. [pii] 336/6080/477.CrossRefPubMedGoogle Scholar
  50. Liu CC, Lin YC, Chen YH, Chen CM, Pang LY, Chen HA, et al. Cul3-KLHL20 ubiquitin ligase governs the turnover of ULK1 and VPS34 complexes to control autophagy termination. Mol Cell. 2016;61:84–97. doi:10.1016/j.molcel.2015.11.001. [pii] S1097-2765(15)00861-8.CrossRefPubMedGoogle Scholar
  51. Löffler AS, Alers S, Dieterle AM, Keppeler H, Franz-Wachtel M, Kundu M, et al. Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy. 2011;7:696–706. [pii] 15451.PubMedCrossRefGoogle Scholar
  52. Mack HI, Zheng B, Asara JM, Thomas SM. AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization. Autophagy. 2012;8:1197–214. doi:10.4161/auto.20586.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Matsuura A, Tsukada M, Wada Y, Ohsumi Y. Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene. 1997;192:245–50. [pii] S0378-1119(97)00084-X.PubMedCrossRefGoogle Scholar
  54. McAlpine F, Williamson LE, Tooze SA, Chan EY. Regulation of nutrient-sensitive autophagy by uncoordinated 51-like kinases 1 and 2. Autophagy. 2013;9:361–73. doi:10.4161/auto.23066. [pii] 23066.CrossRefPubMedPubMedCentralGoogle Scholar
  55. McIntire SL, Garriga G, White J, Jacobson D, Horvitz HR. Genes necessary for directed axonal elongation or fasciculation in C. elegans. Neuron. 1992;8:307–22. [pii] 0896-6273(92)90297-Q.PubMedCrossRefGoogle Scholar
  56. Meijer WH, van der Klei IJ, Veenhuis M, Kiel JA. ATG genes involved in non-selective autophagy are conserved from yeast to man, but the selective Cvt and pexophagy pathways also require organism-specific genes. Autophagy. 2007;3:106–16. [pii] 3595.PubMedCrossRefGoogle Scholar
  57. Mercer CA, Kaliappan A, Dennis PB. A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy. 2009;5:649–62. [pii] 8249.PubMedCrossRefGoogle Scholar
  58. Mochizuki H, Toda H, Ando M, Kurusu M, Tomoda T, Furukubo-Tokunaga K. Unc-51/ATG1 controls axonal and dendritic development via kinesin-mediated vesicle transport in the Drosophila brain. PLoS One. 2011;6:e19632. doi:10.1371/journal.pone.0019632. [pii] PONE-D-10-05532.CrossRefPubMedPubMedCentralGoogle Scholar
  59. Mukaiyama H, Oku M, Baba M, Samizo T, Hammond AT, Glick BS, et al. Paz2 and 13 other PAZ gene products regulate vacuolar engulfment of peroxisomes during micropexophagy. Genes Cells. 2002;7:75–90. [pii] 499.PubMedCrossRefGoogle Scholar
  60. Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, Bordi M, et al. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol. 2013;15:406–16. doi:10.1038/ncb2708. [pii] ncb2708.CrossRefPubMedGoogle Scholar
  61. Ogura K, Goshima Y. The autophagy-related kinase UNC-51 and its binding partner UNC-14 regulate the subcellular localization of the netrin receptor UNC-5 in Caenorhabditis elegans. Development. 2006;133:3441–50. doi:10.1242/dev.02503. [pii] dev.02503.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Ogura K, Wicky C, Magnenat L, Tobler H, Mori I, Muller F, et al. Caenorhabditis elegans unc-51 gene required for axonal elongation encodes a novel serine/threonine kinase. Genes Dev. 1994;8:2389–400.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Ogura K, Shirakawa M, Barnes TM, Hekimi S, Ohshima Y. The UNC-14 protein required for axonal elongation and guidance in Caenorhabditis elegans interacts with the serine/threonine kinase UNC-51. Genes Dev. 1997;11:1801–11.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Okazaki N, Yan J, Yuasa S, Ueno T, Kominami E, Masuho Y, et al. Interaction of the Unc-51-like kinase and microtubule-associated protein light chain 3 related proteins in the brain: possible role of vesicular transport in axonal elongation. Brain Res Mol Brain Res. 2000;85:1–12. [pii] S0169328X00002187.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Papinski D, Schuschnig M, Reiter W, Wilhelm L, Barnes CA, Maiolica A, et al. Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase. Mol Cell. 2014;53:471–83. doi:10.1016/j.molcel.2013.12.011.CrossRefPubMedPubMedCentralGoogle Scholar
  66. Park JM, Jung CH, Seo M, Otto NM, Grunwald D, Kim KH, et al. The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy. 2016;12:547–64. doi:10.1080/15548627.2016.1140293.CrossRefPubMedPubMedCentralGoogle Scholar
  67. Petherick KJ, Conway OJ, Mpamhanga C, Osborne SA, Kamal A, Saxty B, et al. Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. J Biol Chem. 2015;290:11376–83. doi:10.1074/jbc.C114.627778. [pii] C114.627778.CrossRefPubMedPubMedCentralGoogle Scholar
  68. Ptacek J, Devgan G, Michaud G, Zhu H, Zhu X, Fasolo J, et al. Global analysis of protein phosphorylation in yeast. Nature. 2005;438:679–84. doi:10.1038/nature04187. [pii] nature04187.CrossRefPubMedPubMedCentralGoogle Scholar
  69. Rajesh S, Bago R, Odintsova E, Muratov G, Baldwin G, Sridhar P, et al. Binding to syntenin-1 protein defines a new mode of ubiquitin-based interactions regulated by phosphorylation. J Biol Chem. 2011;286:39606–14. doi:10.1074/jbc.M111.262402. [pii] M111.262402.CrossRefPubMedPubMedCentralGoogle Scholar
  70. Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol. 2013;15:741–50. doi:10.1038/ncb2757.CrossRefPubMedPubMedCentralGoogle Scholar
  71. Sakamoto R, Byrd DT, Brown HM, Hisamoto N, Matsumoto K, Jin Y. The Caenorhabditis elegans UNC-14 RUN domain protein binds to the kinesin-1 and UNC-16 complex and regulates synaptic vesicle localization. Mol Biol Cell. 2005;16:483–96. doi:10.1091/mbc.E04-07-0553. [pii] E04-07-0553.CrossRefPubMedPubMedCentralGoogle Scholar
  72. Saleiro D, Mehrotra S, Kroczynska B, Beauchamp EM, Lisowski P, Majchrzak-Kita B, et al. Central role of ULK1 in type I interferon signaling. Cell Rep. 2015;11:605–17. doi:10.1016/j.celrep.2015.03.056. [pii] S2211-1247(15)00347-2.CrossRefPubMedPubMedCentralGoogle Scholar
  73. Scott RC, Juhasz G, Neufeld TP. Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death. Curr Biol. 2007;17:1–11. doi:10.1016/j.cub.2006.10.053.CrossRefPubMedPubMedCentralGoogle Scholar
  74. Shang L, Chen S, Du F, Li S, Zhao L, Wang X. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci U S A. 2011;108:4788–93. doi:10.1073/pnas.1100844108. [pii] 1100844108.CrossRefGoogle Scholar
  75. Straub M, Bredschneider M, Thumm M. AUT3, a serine/threonine kinase gene, is essential for autophagocytosis in Saccharomyces cerevisiae. J Bacteriol. 1997;179:3875–83.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Stromhaug PE, Bevan A, Dunn WA, Jr. GSA11 encodes a unique 208-kDa protein required for pexophagy and autophagy in Pichia pastoris. J Biol Chem. 2001;276:42422–35. doi:10.1074/jbc.M104087200. [pii] M104087200.CrossRefPubMedPubMedCentralGoogle Scholar
  77. Tang HW, Wang YB, Wang SL, Wu MH, Lin SY, Chen GC. Atg1-mediated myosin II activation regulates autophagosome formation during starvation-induced autophagy. EMBO J. 2011;30:636–51. doi:10.1038/emboj.2010.338. [pii] emboj2010338.CrossRefPubMedPubMedCentralGoogle Scholar
  78. Tang J, Deng R, Luo RZ, Shen GP, Cai MY, Du ZM, et al. Low expression of ULK1 is associated with operable breast cancer progression and is an adverse prognostic marker of survival for patients. Breast Cancer Res Treat. 2012;134:549–60. doi:10.1007/s10549-012-2080-y.CrossRefPubMedPubMedCentralGoogle Scholar
  79. Thumm M, Egner R, Koch B, Schlumpberger M, Straub M, Veenhuis M, et al. Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett. 1994;349:275–80. [pii] 0014-5793(94)00672-5.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Tian E, Wang F, Han J, Zhang H. epg-1 functions in autophagy-regulated processes and may encode a highly divergent Atg13 homolog in C. elegans. Autophagy. 2009;5:608–15. [pii] 8624.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Tian W, Li W, Chen Y, Yan Z, Huang X, Zhuang H, et al. Phosphorylation of ULK1 by AMPK regulates translocation of ULK1 to mitochondria and mitophagy. FEBS Lett. 2015;589:1847–54. doi:10.1016/j.febslet.2015.05.020.CrossRefPubMedPubMedCentralGoogle Scholar
  82. Toda H, Mochizuki H, Flores R, 3rd, Josowitz R, Krasieva TB, Lamorte VJ, et al. UNC-51/ATG1 kinase regulates axonal transport by mediating motor-cargo assembly. Genes Dev. 2008;22:3292–307. doi:10.1101/gad.1734608. [pii] 22/23/3292.CrossRefGoogle Scholar
  83. Tomoda T, Bhatt RS, Kuroyanagi H, Shirasawa T, Hatten ME. A mouse serine/threonine kinase homologous to C. elegans UNC51 functions in parallel fiber formation of cerebellar granule neurons. Neuron. 1999;24:833–46. [pii] S0896-6273(00)81031-4.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Tomoda T, Kim JH, Zhan C, Hatten ME. Role of Unc51.1 and its binding partners in CNS axon outgrowth. Genes Dev. 2004;18:541–58. doi:10.1101/gad.1151204. [pii] 1151204.CrossRefGoogle Scholar
  85. Torii S, Yoshida T, Arakawa S, Honda S, Nakanishi A, Shimizu S. Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress-induced autophagy. EMBO Rep. 2016;17:1552–64. doi:10.15252/embr.201642565. [pii] embr.201642565.CrossRefPubMedPubMedCentralGoogle Scholar
  86. Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 1993;333:169–74. [pii] 0014-5793(93)80398-E.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Wang C, Liang CC, Bian ZC, Zhu Y, Guan JL. FIP200 is required for maintenance and differentiation of postnatal neural stem cells. Nat Neurosci. 2013;16:532–42. doi:10.1038/nn.3365. [pii] nn.3365.CrossRefPubMedPubMedCentralGoogle Scholar
  88. Webster CP, Smith EF, Bauer CS, Moller A, Hautbergue GM, Ferraiuolo L, et al. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 2016;35:1656–76. doi:10.15252/embj.201694401. [pii] embj.201694401.CrossRefPubMedPubMedCentralGoogle Scholar
  89. Wesselborg S, Stork B. Autophagy signal transduction by ATG proteins: from hierarchies to networks. Cell Mol Life Sci 2015. doi:10.1007/s00018-015-2034-8.CrossRefPubMedPubMedCentralGoogle Scholar
  90. Wolf FW, Hung MS, Wightman B, Way J, Garriga G. vab-8 is a key regulator of posteriorly directed migrations in C. elegans and encodes a novel protein with kinesin motor similarity. Neuron. 1998;20:655–66. [pii] S0896-6273(00)81006-5.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Wong PM, Puente C, Ganley IG, Jiang X. The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy. 2013;9:124–37. doi:10.4161/auto.23323. [pii] 23323.CrossRefPubMedPubMedCentralGoogle Scholar
  92. Wong PM, Feng Y, Wang J, Shi R, Jiang X. Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A. Nat Commun. 2015;6:8048. doi:10.1038/ncomms9048. [pii] ncomms9048.Google Scholar
  93. Wu W, Tian W, Hu Z, Chen G, Huang L, Li W, et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep. 2014;15:566–75. doi:10.1002/embr.201438501.CrossRefPubMedPubMedCentralGoogle Scholar
  94. Xu H, Yu H, Zhang X, Shen X, Zhang K, Sheng H, et al. UNC51-like kinase 1 as a potential prognostic biomarker for hepatocellular carcinoma. Int J Clin Exp Pathol. 2013;6:711–7.PubMedPubMedCentralGoogle Scholar
  95. Yan J, Kuroyanagi H, Kuroiwa A, Matsuda Y, Tokumitsu H, Tomoda T, et al. Identification of mouse ULK1, a novel protein kinase structurally related to C. elegans UNC-51. Biochem Biophys Res Commun. 1998;246:222–7. [pii] S0006291X98985461.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Yan J, Kuroyanagi H, Tomemori T, Okazaki N, Asato K, Matsuda Y, et al. Mouse ULK2, a novel member of the UNC-51-like protein kinases: unique features of functional domains. Oncogene. 1999;18:5850–9. doi:10.1038/sj.onc.1202988.CrossRefPubMedPubMedCentralGoogle Scholar
  97. Yun M, Bai HY, Zhang JX, Rong J, Weng HW, Zheng ZS, et al. ULK1: a promising biomarker in predicting poor prognosis and therapeutic response in human nasopharyngeal carcinoma. PLoS One. 2015;10:e0117375. doi:10.1371/journal.pone.0117375. [pii] PONE-D-13-28951.CrossRefPubMedPubMedCentralGoogle Scholar
  98. Zhang HY, Ma YD, Zhang Y, Cui J, Wang ZM. Elevated levels of autophagy-related marker ULK1 and mitochondrion-associated autophagy inhibitor LRPPRC are associated with biochemical progression and overall survival after androgen deprivation therapy in patients with metastatic prostate cancer. J Clin Pathol. 2016. doi:10.1136/jclinpath-2016-203926. [pii] jclinpath-2016-203926.CrossRefPubMedPubMedCentralGoogle Scholar
  99. Zhou X, Babu JR, da Silva S, Shu Q, Graef IA, Oliver T, et al. Unc-51-like kinase 1/2-mediated endocytic processes regulate filopodia extension and branching of sensory axons. Proc Natl Acad Sci U S A. 2007;104:5842–7. doi:10.1073/pnas.0701402104. [pii] 0701402104.CrossRefGoogle Scholar
  100. Zou Y, Chen Z, He X, Wu X, Chen Y, Wang J, et al. High expression levels of unc-51-like kinase 1 as a predictor of poor prognosis in colorectal cancer. Oncol Lett. 2015;10:1583–8. doi:10.3892/ol.2015.3417. [pii] OL-0-0-3417.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Molecular Medicine IMedical Faculty, Heinrich Heine UniversityDüsseldorfGermany