Identification of Mouse ULK1, a Novel Protein Kinase Structurally Related toC. elegansUNC-51

Yan, Jin; Kuroyanagi, Hidehito; Kuroiwa, Asato; Matsuda, Y.; Tokumitsu, Hiroshi; Tomoda, Toshifumi; Shirasawa, Takuji; Muramatsu, Masa Aki

doi:10.1006/bbrc.1998.8546

Cited by 130 publications

(117 citation statements)

References 18 publications

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“…2 Atg1 homologues have been reported in several species, including mammals, where there are two Atg1 homologues, UNC (uncoordinated movement)-51-like kinase 1 (ULK1) and ULK2. 76,77 Tooze and coworkers 78 have shown that siRNA-mediated knockdown of ULK1, but not ULK2, inhibited rapamycin-induced autophagy, further suggesting a role downstream of mTOR. This is consistent with our earlier finding in which rapamycin failed to rescue neurodegeneration in Drosophila with heterozygous loss of Atg1.…”

Section: Downstream Targets Of Mtor and Mtor-independent Regulatorsmentioning

confidence: 99%

Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies

et al. 2008

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The formation of intra-neuronal mutant protein aggregates is a characteristic of several human neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease (PD) and polyglutamine disorders, including Huntington's disease (HD). Autophagy is a major clearance pathway for the removal of mutant huntingtin associated with HD, and many other disease-causing, cytoplasmic, aggregate-prone proteins. Autophagy is negatively regulated by the mammalian target of rapamycin (mTOR) and can be induced in all mammalian cell types by the mTOR inhibitor rapamycin. It can also be induced by a recently described cyclical mTOR-independent pathway, which has multiple drug targets, involving links between Ca 2 þ -calpain-G sa and cAMPEpac-PLC-e-IP 3 signalling. Both pathways enhance the clearance of mutant huntingtin fragments and attenuate polyglutamine toxicity in cell and animal models. The protective effects of rapamycin in vivo are autophagy-dependent. In Drosophila models of various diseases, the benefits of rapamycin are lost when the expression of different autophagy genes is reduced, implicating that its effects are not mediated by autophagy-independent processes (like mild translation suppression). Also, the mTORindependent autophagy enhancers have no effects on mutant protein clearance in autophagy-deficient cells. In this review, we describe various drugs and pathways inducing autophagy, which may be potential therapeutic approaches for HD and related conditions.

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Section: Downstream Targets Of Mtor and Mtor-independent Regulatorsmentioning

confidence: 99%

Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies

et al. 2008

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“…Genetic approaches have demonstrated the relevance of autophagy in mitochondrial clearance in the RBC maturation model. For example, deletion of Ulk1, the mammalian homolog of yeast ATG1, encoding a serine/threonine kinase involved in autophagy induction, [117][118][119] results in a defect in mitochondrial clearance during erythroid maturation. 61 ULK1 is also involved in PINK1-PARK2-induced mitophagy.…”

Section: Erythroid Maturation Modelmentioning

confidence: 99%

Mitophagy in hematopoietic stem cells

Joshi

Kundu

2013

Autophagy

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“…9,14 The autophagy process and many of the autophagy-specific proteins are conserved in higher eukaryotes. Unc-51 like kinase 1 (ULK1) and unc-51 like kinase 2 (ULK2) have sequence homology to Atg1, [15][16][17] but only recently was ULK1 confirmed to have a functional role in autophagy. Three different studies have used siRNA to deplete cells of ULK1, demonstrating that ULK1 is important for the starvation-induced trafficking of mAtg9, for lipid modification of GFP-LC3, and for the macroautophagymediated degradation of a cytosolic protein.…”

Section: Introductionmentioning

confidence: 99%

A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy

Mercer

Kaliappan²,

Dennis³

2009

Autophagy

380

321

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Macroautophagy is an intracellular, vesicle-mediated mechanism for the sequestration and ultimate lysosomal degradation of cytoplasmic proteins, organelles and macromolecules. The macroautophagy process and many of the autophagy-specific (Atg) proteins are remarkably well conserved in higher eukaryotes. In yeast, the Atg1 kinase complex includes Atg1, Atg13, Atg17, and at least four other interacting proteins, some of which are phosphorylated in a TOR-dependent manner, placing the Atg1 signaling complex downstream of a major nutrient-sensing pathway. Atg1 orthologs, including mammalian unc-51-like kinase 1 (ULK1), have been identified in higher eukaryotes and have been functionally linked to autophagy. This suggests that other components of the Atg1 complex exist in higher eukaryotes. Recently, a putative human Atg13 ortholog, FLJ20698, was identified by gapped-BLAST analysis. We show here that FLJ20698 (Atg13) is a ULK1-interacting phosphoprotein that is essential for macroautophagy. Furthermore, we identify a novel, human Atg13-interacting protein, FLJ11773, which we have termed Atg101. Atg101 is essential for autophagy and interacts with ULK1 in an Atg13-dependent manner. Additionally, we present evidence that intracellular localization of the ULK1 complex is regulated by nutrient conditions. Finally, we demonstrate that Atg101 stabilizes the expression of Atg13 in the cell, suggesting that Atg101 contributes to Atg13 function by protecting Atg13 from proteasomal degradation. Therefore, the identification of the novel protein, Atg101, and the validation of Atg13 and Atg101 as ULK1-interacting proteins, suggests an Atg1 complex is involved in the induction of macroautophagy in mammalian cells.

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Identification of Mouse ULK1, a Novel Protein Kinase Structurally Related toC. elegansUNC-51

Cited by 130 publications

References 18 publications

Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies

Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies

Mitophagy in hematopoietic stem cells

A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy

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