Human ULK1, a Novel Serine/Threonine Kinase Related to UNC-51 Kinase ofCaenorhabditis elegans:cDNA Cloning, Expression, and Chromosomal Assignment

Kuroyanagi, Hidehito; Yan, Jin; Seki, Naohiko; Yamanouchi, Yasuko; Suzuki, Yo; Takano, Toshiya; Muramatsu, Masa Aki; Shirasawa, Takuji

doi:10.1006/geno.1998.5340

Cited by 102 publications

(84 citation statements)

References 38 publications

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“…We have previously reported cloning and characterization of the ®rst mammalian UNC-51-like kinase, ULK1 from mouse and human Kuroyanagi et al, 1998). In the present study, we identi®ed and characterized a second murine member of the UNC-51-like kinase family, ULK2.…”

Section: Discussionmentioning

confidence: 80%

“…As a yeast These lines were generated with a combination of rol-6 and pU51-EGFP markers. Others were generated with pU51-EGFP marker serine/threonine kinase APG1 is also homologous to UNC-51 (Matsuura et al, 1997) and ULK1 Kuroyanagi et al, 1998), ULK2 also have an overall identity of 22% to APG1. Therefore, ULKs, UNC-51 and APG1 collectively constitute a novel subfamily of protein kinases.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously cloned a mouse and a human cDNA encoding UNC-51-like kinase (ULK1) and determined its structure Kuroyanagi et al, 1998). ULK1 is structurally related to protein kinases encoded by UNC-51 of C. elegans (Ogura et al, 1994), and with less homology to APG1 of S. cerevisiae (Matsuura et al, 1997).…”

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confidence: 99%

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Mouse ULK2, a novel member of the UNC-51-like protein kinases: unique features of functional domains

Yan¹,

et al. 1999

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The UNC-51 serine/threonine kinase of C. elegans plays an essential role in axonal elongation, and unc-51 mutants exhibit uncoordinated movements. We have previously identi®ed mouse and human cDNAs encoding UNC-51-like kinase (ULK1). Here we report the identi®cation and characterization of the second murine member of this kinase family, ULK2. Mouse ULK2 cDNA encodes a putative polypeptide of 1033 aa which has an overall 52% and 33% amino acid identity to ULK1 and UNC-51, respectively. ULKs and UNC-51 share a typical domain structure of an amino-terminal kinase domain, a central proline/serine rich (PS) domain, and a carboxy-terminal (C) domain. Northern blot analysis showed that ULK2 mRNA is widely expressed in adult tissues. In situ hybridization analysis indicated that ULK2 mRNA is ubiquitously localized in premature as well as mature neurons in developing nervous system. ULK2 gene was mapped to mouse chromosome 11B1.3 and rat chromosome 10q23 by FISH. HA-tagged ULK2 expressed in COS7 cells had an apparent molecular size of *150 kDa and was autophosphorylated in vitro. Truncation mutants suggested that the autophosphorylation occurs in the PS domain. Although expression of ULK2 failed to rescue unc-51 mutant of C. elegans, a series of ULK2/UNC-51 chimeric kinases revealed that function of the kinase and PS domains are conserved among species, while the C domain acts in a speciesspeci®c manner. These results suggest that ULK2 is involved in a previously uncharacterized signaling pathway in mammalian cells.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Mouse ULK2, a novel member of the UNC-51-like protein kinases: unique features of functional domains

Yan¹,

et al. 1999

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“…2). 15 We have mapped the region of ULK1 required for complex formation with Atg13 to the first half of the central PS domain of ULK1, specifically to a region between amino acids 281 and 565 (Suppl. Fig.…”

Section: Discussionmentioning

confidence: 99%

“…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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Inhibition of methylation and changes in gene expression in relation to neural tube defects

Linden

Heil

Petersen

et al. 2008

Birth Defects Research

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Human ULK1, a Novel Serine/Threonine Kinase Related to UNC-51 Kinase ofCaenorhabditis elegans:cDNA Cloning, Expression, and Chromosomal Assignment

Cited by 102 publications

References 38 publications

Mouse ULK2, a novel member of the UNC-51-like protein kinases: unique features of functional domains

Mouse ULK2, a novel member of the UNC-51-like protein kinases: unique features of functional domains

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

Inhibition of methylation and changes in gene expression in relation to neural tube defects

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