Skip to main content

Signal Transduction Regulation of Autophagy

  • Chapter
  • First Online:
Autophagy and Cancer

Part of the book series: Current Cancer Research ((CUCR,volume 8))

  • 2034 Accesses

Abstract

As a major stress-responsive catabolic pathway, autophagy communicates with a variety of signal transduction pathways ranging from proliferative signaling, metabolic pathways, cell death pathways, and multiple cellular stresses. As such, autophagy needs to be able to integrate diverse signaling events and respond to various complex biological conditions in a highly orchestrated manner. Mechanistically, while the molecular basis underlying the function of the core autophagy machinery has been relatively well established, how does autophagy pathway sense diverse upstream signaling pathways? How does autophagy contribute to the eventual biological outcomes of these signaling pathways? Is there any feedback regulation from autophagy to the upstream signaling pathways? And what governs signal transduction within the core autophagy pathway? This chapter discusses the current understanding of these questions. Particularly, an emphasis is placed on the role of the Atg1/ULK1 complex in sensing the upstream nutrient/energy signaling and relaying the upstream signaling to downstream autophagy machinery.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alers S, Löffler AS, Paasch F, Dieterle AM, Keppeler H, Lauber K et al (2011) Atg13 and FIP200 act independently of Ulk1 and Ulk2 in autophagy induction. Autophagy 7:1423–1433

    PubMed  Google Scholar 

  • Bánréti A, Lukácsovich T, Csikós G, Erdélyi M, Sass M (2012) PP2A regulates autophagy in two alternative ways in Drosophila. Autophagy 8(4):623–636

    PubMed  Google Scholar 

  • Behrends C, Sowa ME, Gygi SP, Harper JW (2010) Network organization of the human autophagy system. Nature 466:68–76

    PubMed  CAS  Google Scholar 

  • Berry DL, Baehrecke EH (2007) Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131:1137–1148

    PubMed  CAS  Google Scholar 

  • Berry DL, Baehrecke EH (2008) Autophagy functions in programmed cell death. Autophagy 4:359–360

    PubMed  Google Scholar 

  • Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A et al (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-­induced cell death. J Cell Biol 171:603–614

    PubMed  Google Scholar 

  • Blankson H, Holen I, Seglen PO (1995) Disruption of the cytokeratin cytoskeleton and inhibition of hepatocytic autophagy by okadaic acid. Exp Cell Res 218:522–530

    PubMed  CAS  Google Scholar 

  • Budovskaya YV, Stephan JS, Deminoff SJ, Herman PK (2005) An evolutionary proteomics approach identifies substrates of the cAMP-dependent protein kinase. Proc Natl Acad Sci USA 102:13933–13938

    PubMed  CAS  Google Scholar 

  • Bursch W (2001) The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ 8:569–581

    PubMed  CAS  Google Scholar 

  • Chan E, Kir S, Tooze S (2007) siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy. J Biol Chem 282:25464–25474

    PubMed  CAS  Google Scholar 

  • Chan E, Longatti A, McKnight N, Tooze S (2009) Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol 29:157–171

    PubMed  CAS  Google Scholar 

  • Chen Y, Klionsky DJ (2011) The regulation of autophagy—unanswered questions. J Cell Sci 124:161–170

    PubMed  CAS  Google Scholar 

  • Cheong H, Yorimitsu T, Reggiori F, Legakis JE, Wang CW, Klionsky DJ (2005) Atg17 regulates the magnitude of the autophagic response. Mol Biol Cell 16:3438–3453

    PubMed  CAS  Google Scholar 

  • Cheong H, Nair U, Geng J, Klionsky DJ (2008) The Atg1 kinase complex is involved in the regulation of protein recruitment to initiate sequestering vesicle formation for nonspecific autophagy in Saccharomyces cerevisiae. Mol Biol Cell 19:668–681

    PubMed  CAS  Google Scholar 

  • Cheong H, Lindsten T, Wu J, Lu C, Thompson CB (2011) Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc Natl Acad Sci USA 108:11121–11126

    PubMed  CAS  Google Scholar 

  • Choi JD, Ryu M, Ae Park M, Jeong G, Lee JS (2012) FIP200 inhibits β-catenin-mediated transcription by promoting APC-independent β-catenin ubiquitination. Oncogene advance online publication; doi:10.1038/onc.2012.262

    Google Scholar 

  • Deribe YL, Pawson T, Dikic I (2010) Post-translational modifications in signal integration. Nat Struct Mol Biol 17:666–672

    PubMed  CAS  Google Scholar 

  • Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, Antonioli M et al (2010) The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol 191:155–168

    PubMed  Google Scholar 

  • Dorsey F, Rose K, Coenen S, Prater S, Cavett V, Cleveland J et al (2009) Mapping the phosphorylation sites of Ulk1. J Proteome Res 8:5253–5263

    PubMed  CAS  Google Scholar 

  • Dunlop EA, Hunt DK, Acosta-Jaquez HA, Fingar DC, Tee AR (2011) ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy 7:737–747

    PubMed  CAS  Google Scholar 

  • Edinger AL, Thompson CB (2004) Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16:663–669

    PubMed  CAS  Google Scholar 

  • Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W et al (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461

    PubMed  CAS  Google Scholar 

  • Eng CH, Yu K, Lucas J, White E, Abraham RT (2010) Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci Signal 3:ra31

    PubMed  Google Scholar 

  • Florey O, Overholtzer M (2012) Autophagy proteins in macroendocytic engulfment. Trends Cell Biol 22:374–380

    PubMed  CAS  Google Scholar 

  • Florey O, Kim SE, Sandoval CP, Haynes CM, Overholtzer M (2011) Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes. Nat Cell Biol 13:1335–1343

    PubMed  CAS  Google Scholar 

  • Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T (2008) The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19:2092–2100

    PubMed  CAS  Google Scholar 

  • Gammoh N, Lam D, Puente C, Ganley I, Marks PA, Jiang X (2012) Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc Natl Acad Sci USA 109:6561–6565

    PubMed  CAS  Google Scholar 

  • Gan B, Guan JL (2008) FIP200, a key signaling node to coordinately regulate various cellular processes. Cell Signal 20:787–794

    PubMed  CAS  Google Scholar 

  • Gan B, Melkoumian ZK, Wu X, Guan KL, Guan JL (2005) Identification of FIP200 interaction with the TSC1–TSC2 complex and its role in regulation of cell size control. J Cell Biol 170:379–389

    PubMed  CAS  Google Scholar 

  • Gan B, Peng X, Nagy T, Alcaraz A, Gu H, Guan JL (2006) Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways. J Cell Biol 175:121–133

    PubMed  CAS  Google Scholar 

  • Ganley IG, du Lam H, Wang J, Ding X, Chen S, Jiang X (2009) ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284:12297–12305

    PubMed  CAS  Google Scholar 

  • Ganley IG, Wong PM, Gammoh N, Jiang X (2011) Distinct autophagosomal–lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol Cell 42:731–743

    PubMed  CAS  Google Scholar 

  • Gao Z, Gammoh N, Wong PM, Erdjument-Bromage H, Tempst P, Jiang X (2010) Processing of autophagic protein LC3 by the 20S proteasome. Autophagy 6:126–137

    PubMed  CAS  Google Scholar 

  • Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23:2891–2906

    PubMed  CAS  Google Scholar 

  • Gutierrez MG, Munafo DB, Beron W, Colombo MI (2004) Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci 117:2687–2697

    PubMed  CAS  Google Scholar 

  • Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T et al (2007) The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem 282:37298–37302

    PubMed  CAS  Google Scholar 

  • Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889

    PubMed  CAS  Google Scholar 

  • Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan J et al (2008) FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 181:497–510

    PubMed  CAS  Google Scholar 

  • Harding TM, Morano KA, Scott SV, Klionsky DJ (1995) Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J Cell Biol 131:591–602

    PubMed  CAS  Google Scholar 

  • Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y et al (2009a) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20:1981–1991

    PubMed  CAS  Google Scholar 

  • Hosokawa N, Sasaki T, Iemura S, Natsume T, Hara T, Mizushima N (2009b) Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 5:973–979

    PubMed  CAS  Google Scholar 

  • Hutagalung AH, Novick PJ (2011) Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev 91:119–149

    PubMed  CAS  Google Scholar 

  • Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N et al (2000) A ubiquitin-like system mediates protein lipidation. Nature 408:488–492

    PubMed  CAS  Google Scholar 

  • Ikebuchi K, Chano T, Ochi Y, Tameno H, Shimada T, Hisa Y et al (2009) RB1CC1 activates the promoter and expression of RB1 in human cancer. Int J Cancer 125:861–867

    PubMed  CAS  Google Scholar 

  • Itakura E, Mizushima N (2010) Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6:764–776

    PubMed  CAS  Google Scholar 

  • Itakura E, Kishi-Itakura C, Koyama-Honda I, Mizushima N (2012) Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy. J Cell Sci 125:1488–1499

    PubMed  CAS  Google Scholar 

  • Joo JH, Dorsey FC, Joshi A, Hennessy-Walters KM, Rose KL, McCastlain K et al (2011) Hsp90-­Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy. Mol Cell 43:572–585

    PubMed  CAS  Google Scholar 

  • Jung C, Jun C, Ro S, Kim Y, Otto N, Cao J et al (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20:1992–2003

    PubMed  CAS  Google Scholar 

  • Jung CH, Seo M, Otto NM, Kim DH (2011) ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 7:1212–1221

    PubMed  CAS  Google Scholar 

  • Kabeya Y, Kamada Y, Baba M, Takikawa H, Sasaki M, Ohsumi Y (2005) Atg17 functions in cooperation with Atg1 and Atg13 in yeast autophagy. Mol Biol Cell 16:2544–2553

    PubMed  CAS  Google Scholar 

  • Kabeya Y, Noda NN, Fujioka Y, Suzuki K, Inagaki F, Ohsumi Y (2009) Characterization of the Atg17–Atg29–Atg31 complex specifically required for starvation-induced autophagy in Saccharomyces cerevisiae. Biochem Biophys Res Commun 389:612–615

    PubMed  CAS  Google Scholar 

  • Kageyama S, Omori H, Saitoh T, Sone T, Guan JL, Akira S et al (2011) The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella. Mol Biol Cell 22:2290–2300

    PubMed  CAS  Google Scholar 

  • Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y (2000) Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150:1507–1513

    PubMed  CAS  Google Scholar 

  • Kamada Y, Yoshino K, Kondo C, Kawamata T, Oshiro N, Yonezawa K et al (2010) Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol Cell Biol 30:1049–1058

    PubMed  CAS  Google Scholar 

  • Kawamata T, Kamada Y, Kabeya Y, Sekito T, Ohsumi Y (2008) Organization of the pre-­autophagosomal structure responsible for autophagosome formation. Mol Biol Cell 19:2039–2050

    PubMed  CAS  Google Scholar 

  • Kijanska M, Dohnal I, Reiter W, Kaspar S, Stoffel I, Ammerer G et al (2010) Activation of Atg1 kinase in autophagy by regulated phosphorylation. Autophagy 6:1168–1178

    PubMed  CAS  Google Scholar 

  • Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141

    PubMed  CAS  Google Scholar 

  • Kimmelman AC (2011) The dynamic nature of autophagy in cancer. Genes Dev 25:1999–2010

    PubMed  CAS  Google Scholar 

  • Klionsky DJ (2005) The molecular machinery of autophagy: unanswered questions. J Cell Sci 118:7–18

    PubMed  CAS  Google Scholar 

  • Koinuma D, Shinozaki M, Nagano Y, Ikushima H, Horiguchi K, Goto K et al (2011) RB1CC1 protein positively regulates transforming growth factor-beta signaling through the modulation of Arkadia E3 ubiquitin ligase activity. J Biol Chem 286:32502–32512

    PubMed  CAS  Google Scholar 

  • Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I et al (2005) Impairment of starvation-­induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169:425–434

    PubMed  CAS  Google Scholar 

  • Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884

    PubMed  CAS  Google Scholar 

  • Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T et al (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131:1149–1163

    PubMed  CAS  Google Scholar 

  • Korolchuk VI, Menzies FM, Rubinsztein DC (2009a) A novel link between autophagy and the ubiquitin-proteasome system. Autophagy 5:862–863

    PubMed  Google Scholar 

  • Korolchuk VI, Mansilla A, Menzies FM, Rubinsztein DC (2009b) Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell 33:517–527

    PubMed  CAS  Google Scholar 

  • Korolchuk VI, Menzies FM, Rubinsztein DC (2010) Mechanisms of cross-talk between the ubiquitin-­proteasome and autophagy-lysosome systems. FEBS Lett 584:1393–1398

    PubMed  CAS  Google Scholar 

  • Kraft C, Peter M, Hofmann K (2010) Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol 12:836–841

    PubMed  CAS  Google Scholar 

  • Kraft C, Kijanska M, Kalie E, Siergiejuk E, Lee SS, Semplicio G et al (2012) Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy. EMBO J 31(18):3691–3703

    PubMed  CAS  Google Scholar 

  • Kroemer G, Mariño G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40:280–293

    PubMed  CAS  Google Scholar 

  • Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T et al (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036

    PubMed  CAS  Google Scholar 

  • Kundu M, Lindsten T, Yang C, Wu J, Zhao F, Zhang J et al (2008) Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 112:1493–1502

    PubMed  CAS  Google Scholar 

  • Kuroyanagi H, Yan J, Seki N, Yamanouchi Y, Suzuki Y, Takano T et al (1998) Human ULK1, a novel serine/threonine kinase related to UNC-51 kinase of Caenorhabditis elegans: cDNA cloning, expression, and chromosomal assignment. Genomics 51:76–85

    PubMed  CAS  Google Scholar 

  • Lee EJ, Tournier C (2011) The requirement of uncoordinated 51-like kinase 1 (ULK1) and ULK2 in the regulation of autophagy. Autophagy 7:689–695

    PubMed  CAS  Google Scholar 

  • Lee JW, Park S, Takahashi Y, Wang HG (2010) The association of AMPK with ULK1 regulates autophagy. PLoS One 5:e15394

    PubMed  Google Scholar 

  • Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115:2679–2688

    PubMed  CAS  Google Scholar 

  • Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G et al (1998) Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 72:8586–8596

    PubMed  CAS  Google Scholar 

  • Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H et al (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–676

    PubMed  CAS  Google Scholar 

  • Liang CC, Wang C, Peng X, Gan B, Guan JL (2010) Neural-specific deletion of FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration. J Biol Chem 285:3499–3509

    PubMed  CAS  Google Scholar 

  • Lin SY, Li TY, Liu Q, Zhang C, Li X, Chen Y et al (2012) GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 336:477–481

    PubMed  CAS  Google Scholar 

  • Löffler AS, Alers S, Dieterle AM, Keppeler H, Franz-Wachtel M, Kundu M et al (2011) Ulk1-­mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy 7:696–706

    PubMed  Google Scholar 

  • Luo S, Garcia-Arencibia M, Zhao R, Puri C, Toh PP, Sadiq O et al (2012) Bim inhibits autophagy by recruiting beclin 1 to microtubules. Mol Cell 47:359–370

    PubMed  CAS  Google Scholar 

  • Mack HID, Zheng B, Asara J, Thomas SM (2012) AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization. Autophagy 8(8):1197–1214

    PubMed  CAS  Google Scholar 

  • Martinez J, Almendinger J, Oberst A, Ness R, Dillon CP, Fitzgerald P et al (2011) Microtubule-­associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc Natl Acad Sci USA 108:17396–17401

    PubMed  CAS  Google Scholar 

  • Matsunaga K, Morita E, Saitoh T, Akira S, Ktistakis NT, Izumi T et al (2010) Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J Cell Biol 190:511–521

    PubMed  CAS  Google Scholar 

  • Matsuura A, Tsukada M, Wada Y, Ohsumi Y (1997) Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene 192:245–250

    PubMed  CAS  Google Scholar 

  • McEwan DG, Dikic I (2011) The three musketeers of autophagy: phosphorylation, ubiquitylation and acetylation. Trends Cell Biol 21:195–201

    PubMed  CAS  Google Scholar 

  • McIntire SL, Garriga G, White J, Jacobson D, Horvitz HR (1992) Genes necessary for directed axonal elongation or fasciculation in C. elegans. Neuron 8:307–322

    PubMed  CAS  Google Scholar 

  • McKnight NC, Jefferies HB, Alemu EA, Saunders RE, Howell M, Johansen T et al (2012) Genome-wide siRNA screen reveals amino acid starvation-induced autophagy requires SCOC and WAC. EMBO J 31:1931–1946

    PubMed  CAS  Google Scholar 

  • Meijer WH, van der Klei IJ, Veenhuis M, Kiel JA (2007) 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 3:106–116

    PubMed  CAS  Google Scholar 

  • Meiselbach H, Sticht H, Enz R (2006) Structural analysis of the protein phosphatase 1 docking motif: molecular description of binding specificities identifies interacting proteins. Chem Biol 13:49–59

    PubMed  CAS  Google Scholar 

  • Meléndez A, Neufeld TP (2008) The cell biology of autophagy in metazoans: a developing story. Development 135:2347–2360

    PubMed  Google Scholar 

  • Mercer C, Kaliappan A, Dennis P (2009) A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy 5:649–662

    PubMed  CAS  Google Scholar 

  • Mizushima N (2010) The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22:132–139

    PubMed  CAS  Google Scholar 

  • Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147:728–741

    PubMed  CAS  Google Scholar 

  • Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD et al (1998) A protein conjugation system essential for autophagy. Nature 395:395–398

    PubMed  CAS  Google Scholar 

  • Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132

    PubMed  CAS  Google Scholar 

  • Mochizuki H, Toda H, Ando M, Kurusu M, Tomoda T, Furukubo-Tokunaga K (2011) Unc-51/ATG1 controls axonal and dendritic development via kinesin-mediated vesicle transport in the Drosophila brain. PLoS One 6:e19632

    PubMed  CAS  Google Scholar 

  • Mok J, Kim PM, Lam HY, Piccirillo S, Zhou X, Jeschke GR et al (2010) Deciphering protein kinase specificity through large-scale analysis of yeast phosphorylation site motifs. Sci Signal 3:ra12

    PubMed  Google Scholar 

  • Mostowy S, Cossart P (2011) Autophagy and the cytoskeleton: new links revealed by intracellular pathogens. Autophagy 7:780–782

    PubMed  Google Scholar 

  • Nakatogawa H, Ichimura Y, Ohsumi Y (2007) Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130:165–178

    PubMed  CAS  Google Scholar 

  • Nakatogawa H, Ohbayashi S, Sakoh-Nakatogawa M, Kakuta S, Suzuki SW, Kirisako H et al (2012) The autophagy-related protein kinase Atg1 interacts with the ubiquitin-like protein Atg8 via the Atg8 family interacting motif to facilitate autophagosome formation. J Biol Chem 287(34):28503–28507

    PubMed  CAS  Google Scholar 

  • Ochi Y, Chano T, Ikebuchi K, Inoue H, Isono T, Arai A et al (2011) RB1CC1 activates the p16 promoter through the interaction with hSNF5. Oncol Rep 26:805–812

    PubMed  CAS  Google Scholar 

  • Ogura K, Wicky C, Magnenat L, Tobler H, Mori I, Müller F et al (1994) Caenorhabditis elegans unc-51 gene required for axonal elongation encodes a novel serine/threonine kinase. Genes Dev 8:2389–2400

    PubMed  CAS  Google Scholar 

  • Okazaki N, Yan J, Yuasa S, Ueno T, Kominami E, Masuho Y et al (2000) 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 85:1–12

    PubMed  CAS  Google Scholar 

  • Orsi A, Razi M, Dooley H, Robinson D, Weston A, Collinson L et al (2012) Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, is required for autophagy. Mol Biol Cell 23(10):1860–1873

    PubMed  CAS  Google Scholar 

  • Overholtzer M, Mailleux AA, Mouneimne G, Normand G, Schnitt SJ, King RW et al (2007) A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131:966–979

    PubMed  CAS  Google Scholar 

  • Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H et al (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282:24131–24145

    PubMed  CAS  Google Scholar 

  • Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N et al (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939

    PubMed  CAS  Google Scholar 

  • Polson HE, de Lartigue J, Rigden DJ, Reedijk M, Urbé S, Clague MJ et al (2010) Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 6:506–522

    Google Scholar 

  • Ptacek J, Devgan G, Michaud G, Zhu H, Zhu X, Fasolo J et al (2005) Global analysis of protein phosphorylation in yeast. Nature 438:679–684

    PubMed  CAS  Google Scholar 

  • Reggiori F, Tucker KA, Stromhaug PE, Klionsky DJ (2004) The Atg1–Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Dev Cell 6:79–90

    PubMed  CAS  Google Scholar 

  • Samari HR, Møller MT, Holden L, Asmyhr T, Seglen PO (2005) Stimulation of hepatocytic AMP-­activated protein kinase by okadaic acid and other autophagy-suppressive toxins. Biochem J 386:237–244

    PubMed  CAS  Google Scholar 

  • Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S et al (2007) Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450:1253–1257

    PubMed  CAS  Google Scholar 

  • Sanjuan MA, Milasta S, Green DR (2009) Toll-like receptor signaling in the lysosomal pathways. Immunol Rev 227:203–220

    PubMed  CAS  Google Scholar 

  • Sarkar S, Floto R, Berger Z, Imarisio S, Cordenier A, Pasco M et al (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170:1101–1111

    PubMed  CAS  Google Scholar 

  • Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC (2009) Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ 16:46–56

    PubMed  CAS  Google Scholar 

  • Sekito T, Kawamata T, Ichikawa R, Suzuki K, Ohsumi Y (2009) Atg17 recruits Atg9 to organize the pre-autophagosomal structure. Genes Cells 14:525–538

    PubMed  CAS  Google Scholar 

  • Shang L, Chen S, Du F, Li S, Zhao L, Wang X (2011) Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci USA 108:4788–4793

    PubMed  CAS  Google Scholar 

  • Shao Y, Gao Z, Marks PA, Jiang X (2004) Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA 101:18030–18035

    PubMed  CAS  Google Scholar 

  • Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB et al (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6:1221–1228

    PubMed  CAS  Google Scholar 

  • Shintani T, Yamazaki F, Katoh T, Umekawa M, Matahira Y, Hori S et al (2010) Glucosamine induces autophagy via an mTOR-independent pathway. Biochem Biophys Res Commun 391:1775–1779

    PubMed  CAS  Google Scholar 

  • Sou YS, Waguri S, Iwata J, Ueno T, Fujimura T, Hara T et al (2008) The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol Biol Cell 19:4762–4775

    PubMed  CAS  Google Scholar 

  • Stephan JS, Yeh YY, Ramachandran V, Deminoff SJ, Herman PK (2009) The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy. Proc Natl Acad Sci USA 106:17049–17054

    PubMed  CAS  Google Scholar 

  • Suttangkakul A, Li F, Chung T, Vierstra RD (2011) The ATG1/ATG13 protein kinase complex is both a regulator and a target of autophagic recycling in Arabidopsis. Plant Cell 23:3761–3779

    PubMed  CAS  Google Scholar 

  • Tang HW, Wang YB, Wang SL, Wu MH, Lin SY, Chen GC (2011) Atg1-mediated myosin II activation regulates autophagosome formation during starvation-induced autophagy. EMBO J 30:636–651

    PubMed  CAS  Google Scholar 

  • Thumm M, Egner R, Koch B, Schlumpberger M, Straub M, Veenhuis M et al (1994) Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett 349:275–280

    PubMed  CAS  Google Scholar 

  • Toda H, Mochizuki H, Flores R, Josowitz R, Krasieva TB, Lamorte VJ et al (2008) UNC-51/ATG1 kinase regulates axonal transport by mediating motor-cargo assembly. Genes Dev 22:3292–3307

    PubMed  CAS  Google Scholar 

  • Todde V, Veenhuis M, van der Klei IJ (2009) Autophagy: principles and significance in health and disease. Biochim Biophys Acta 1792:3–13

    PubMed  CAS  Google Scholar 

  • Tomoda T, Bhatt RS, Kuroyanagi H, Shirasawa T, Hatten ME (1999) A mouse serine/threonine kinase homologous to C. elegans UNC51 functions in parallel fiber formation of cerebellar granule neurons. Neuron 24:833–846

    PubMed  CAS  Google Scholar 

  • Tomoda T, Kim JH, Zhan C, Hatten ME (2004) Role of Unc51.1 and its binding partners in CNS axon outgrowth. Genes Dev 18:541–558

    PubMed  CAS  Google Scholar 

  • Tsukada M, Ohsumi Y (1993) Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett 333:169–174

    PubMed  CAS  Google Scholar 

  • Wellen KE, Thompson CB (2012) A two-way street: reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol 13:270–276

    PubMed  CAS  Google Scholar 

  • Wong AS, Cheung ZH, Ip NY (2011) Molecular machinery of macroautophagy and its deregulation in diseases. Biochim Biophys Acta 1812:1490–1497

    PubMed  CAS  Google Scholar 

  • Xie R, Nguyen S, McKeehan K, Wang F, McKeehan WL, Liu L (2011) Microtubule-associated protein 1S (MAP1S) bridges autophagic components with microtubules and mitochondria to affect autophagosomal biogenesis and degradation. J Biol Chem 286:10367–10377

    PubMed  CAS  Google Scholar 

  • Yan J, Kuroyanagi H, Kuroiwa A, Matsuda Y, Tokumitsu H, Tomoda T et al (1998) Identification of mouse ULK1, a novel protein kinase structurally related to C. elegans UNC-51. Biochem Biophys Res Commun 246:222–227

    PubMed  CAS  Google Scholar 

  • Yan J, Kuroyanagi H, Tomemori T, Okazaki N, Asato K, Matsuda Y et al (1999) Mouse ULK2, a novel member of the UNC-51-like protein kinases: unique features of functional domains. Oncogene 18:5850–5859

    PubMed  CAS  Google Scholar 

  • Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814–822

    PubMed  CAS  Google Scholar 

  • Yeh YY, Wrasman K, Herman PK (2010) Autophosphorylation within the Atg1 activation loop is required for both kinase activity and the induction of autophagy in Saccharomyces cerevisiae. Genetics 185:871–882

    PubMed  CAS  Google Scholar 

  • Yeh YY, Shah KH, Herman PK (2011) An Atg13 protein-mediated self-association of the Atg1 protein kinase is important for the induction of autophagy. J Biol Chem 286:28931–28939

    PubMed  CAS  Google Scholar 

  • Yi C, Ma M, Ran L, Zheng J, Tong J, Zhu J et al (2012) Function and molecular mechanism of acetylation in autophagy regulation. Science 336:474–477

    PubMed  CAS  Google Scholar 

  • Yorimitsu T, He C, Wang K, Klionsky DJ (2009) Tap42-associated protein phosphatase type 2A negatively regulates induction of autophagy. Autophagy 5:616–624

    PubMed  CAS  Google Scholar 

  • Young A, Chan E, Hu X, Köchl R, Crawshaw S, High S et al (2006) Starvation and ULK1-­dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci 119:3888–3900

    PubMed  CAS  Google Scholar 

  • Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF et al (2009) Autophagy mediates the mitotic senescence transition. Genes Dev 23:798–803

    PubMed  CAS  Google Scholar 

  • Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S et al (2004) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304:1500–1502

    PubMed  CAS  Google Scholar 

  • Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J et al (2010) Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465:942–946

    PubMed  CAS  Google Scholar 

  • Zhou X, Babu JR, da Silva S, Shu Q, Graef IA, Oliver T et al (2007) Unc-51-like kinase 1/2-­mediated endocytic processes regulate filopodia extension and branching of sensory axons. Proc Natl Acad Sci USA 104:5842–5847

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xuejun Jiang .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Wong, PM., Jiang, X. (2013). Signal Transduction Regulation of Autophagy. In: Wang, HG. (eds) Autophagy and Cancer. Current Cancer Research, vol 8. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6561-4_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-6561-4_4

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-6560-7

  • Online ISBN: 978-1-4614-6561-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics