The Caenorhabditis elegans AMP-activated Protein Kinase AAK-2 Is Phosphorylated by LKB1 and Is Required for Resistance to Oxidative Stress and for Normal Motility and Foraging Behavior

Lee, Hyojin; Cho, Jeong Soo; Lambacher, Nils J.; Lee, Jieun; Lee, Se-Jin; Lee, Tae Hoon; Gartner, Anton; Koo, Hyeon Sook

doi:10.1074/jbc.m709115200

Cited by 94 publications

(98 citation statements)

References 35 publications

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“…Interestingly, the activity of AAK-2 is also required for protection against oxidative stress [48]. Similar results were obtained in Drosophila Melanogaster model, where the inhibition of drosophila AMPK shortened lifespan and increased susceptibility to oxidative stress and starvation [49] In accordance, gain-of-function LKB1 mutant extended lifespan in flies [50].…”

Section: Ampksupporting

confidence: 71%

Sestrins Link Tumor Suppressors with the AMPK-TOR Signaling Network

Budanov¹

2012

Protein Phosphorylation in Human Health

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Section: Ampksupporting

confidence: 71%

Sestrins Link Tumor Suppressors with the AMPK-TOR Signaling Network

Budanov¹

2012

Protein Phosphorylation in Human Health

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“…After 1 min of adaptation, the number of sinusoidal curves made during locomotion for 1 min was scored as the number of body bending. 38 Antibodies. Polyclonal antibodies to BTBD10 were generated, as previously described.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

et al. 2012

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BTBD10, an Akt interactor, activates Akt by decreasing the protein phosphatase 2A-mediated dephosphorylation and inactivation of Akt. Overexpression of BTBD10 suppresses motor neuron death that is induced by a familial amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 (SOD1) mutant, G93A-SOD1 in vitro. In this study, we further investigated the BTBD10-mediated suppression of motor neuron death. We found that the small interfering RNA-mediated inhibition of BTBD10 expression led to the death of cultured motor neurons. In Caenorhabditis elegans (C. elegans), disruption of the btbd-10 gene caused not only loss of neurons, including both motor and touch-receptor neurons, but also a locomotion defect. In addition, we found that the expression of BTBD10 was generally decreased in the motor neurons from patients of sporadic ALS and transgenic mice overexpressing G93A-SOD1 (G93A-SOD1-transgenic mice). Collectively, these results suggest that the reduced expression of BTBD10 leads to motor neuron death both in vitro and in vivo. A gain-of-toxic-function of an intracellular molecule or a loss of normal function of an essential intracellular molecule, including an intracellular prosurvival signal, contributes to cell death. The Akt family of proteins (Akt1, 2 and 3 in mammalian cells) provides a major intracellular prosurvival signal by phosphorylating many target proteins. 1 The major upstream activator of Akt is the phosphatidylinositol 3-kinase (PI3K)-mediated signal that activates Akt by phosphorylation. Akt's activity is also regulated by protein phosphatase-mediated dephosphorylation. 2 In our previous study, we showed that BTBD10 activates Akt by inhibiting protein phosphatase 2A (PP2A)-mediated Akt dephosphorylation. 3 Recent advances in genetics and neuroscience have suggested that both gains of toxic and/or losses of normal function of intracellular molecules contribute to the pathogenesis of neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a representative motor neuron-specific neurodegenerative disease. 4 Approximately 10% of ALS cases are genetically inherited. 4,5 Dominant mutations in the superoxide dismutase 1 (SOD1) gene (the first identified familial ALS (FALS)-linked gene) account for approximately 20% of FALS cases. The gain-of-toxic-function of SOD1, caused by a FALS-linked mutation, is thought to be closely linked to the ALS pathogenesis. The second identified FALS-linked gene, a FALS-linked mutation of which results in an autosomal-recessive phenotype, encodes a protein named alsin. 6,7 Loss of alsin function, caused by a FALSlinked mutation, leads to the abnormal endolysosomal trafficking and contributes to motor neuron death. 8 We have independently shown that wild-type alsin suppresses mutant SOD1-induced neuronal cell death by activating a prosurvival pathway involving Rac1, PI3K and Akt3, and that FALS-linked mutations in the gene abolish the alsin function. 9,10 To further characterize the Akt-mediated prosurvival pathways that are linked to the ALS pathogenesi...

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“…LGIV: pig-1 alleles used include gm280 and gm301 (Cordes et al 2006), ced-3(n717), and ced-3(n2436) (Shaham et al 1999) LGV: par-4(it57ts) (Watts et al 2000) and par-1(zu310ts) (Kemphues et al 1988) LGX: sad-1(ky289) (Crump et al 2001), aak-2(gt33) (Lee et al 2008), and gmIs87[Pmab-5::pig-1(T169D)::gfp; Pmyo-2::mcherry]…”

Section: Nematode Strains and Geneticsmentioning

confidence: 99%

Caenorhabditis elegans PIG-1/MELK Acts in a Conserved PAR-4/LKB1 Polarity Pathway to Promote Asymmetric Neuroblast Divisions

et al. 2013

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Asymmetric cell divisions produce daughter cells with distinct sizes and fates, a process important for generating cell diversity during development. Many Caenorhabditis elegans neuroblasts, including the posterior daughter of the Q cell (Q.p), divide to produce a larger neuron or neuronal precursor and a smaller cell that dies. These size and fate asymmetries require the gene pig-1, which encodes a protein orthologous to vertebrate MELK and belongs to the AMPK-related family of kinases. Members of this family can be phosphorylated and activated by the tumor suppressor kinase LKB1, a conserved polarity regulator of epithelial cells and neurons. In this study, we present evidence that the C. elegans orthologs of LKB1 (PAR-4) and its partners STRAD (STRD-1) and MO25 (MOP-25.2) regulate the asymmetry of the Q.p neuroblast division. We show that PAR-4 and STRD-1 act in the Q lineage and function genetically in the same pathway as PIG-1. A conserved threonine residue (T169) in the PIG-1 activation loop is essential for PIG-1 activity, consistent with the model that PAR-4 (or another PAR-4-regulated kinase) phosphorylates and activates PIG-1. We also demonstrate that PIG-1 localizes to centrosomes during cell divisions of the Q lineage, but this localization does not depend on T169 or PAR-4. We propose that a PAR-4-STRD-1 complex stimulates PIG-1 kinase activity to promote asymmetric neuroblast divisions and the generation of daughter cells with distinct fates. Changes in cell fate may underlie many of the abnormal behaviors exhibited by cells after loss of PAR-4 or LKB1.A SYMMETRIC cell divisions produce daughter cells with distinct fates, a process important for generating cell diversity in organisms as different as bacteria, plants, and animals. In Caenorhabditis elegans, asymmetric divisions of neuroblasts often produce cells fated to die. The posterior daughter of the Q cell (Q.p) neuroblasts, for example, divide to produce a neuronal precursor and a cell that dies, but how this fate asymmetry is generated in these divisions is poorly understood. PIG-1 regulates asymmetric neuroblast divisions that generate apoptotic cells by controlling spindle positioning, myosin distribution, and daughter cell fate (Cordes et al. 2006;Ou et al. 2010). PIG-1 is the sole C. elegans ortholog of MELK (maternal embryonic leucine zipper kinase), a serine/ threonine kinase that has been implicated in many developmental processes including stem cell renewal, apoptosis, cell cycle progression, and spliceosome assembly (Davezac et al. 2002;Vulsteke et al. 2004;Nakano et al. 2005;Lin et al. 2007;Jung et al. 2008). MELK and PIG-1 represent a subgroup of a large family of serine/threonine kinases that include molecules like PAR-1 and SAD-1, which regulate cell polarity, and AMPKs, which regulate metabolic processes (Bright et al. 2009). These family members are often regulated directly by the LKB1 kinase (Lizcano et al. 2004).Loss of the tumor suppressor LKB1 causes Peutz-Jeghers syndrome, a disease in humans that is characterized...

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The Caenorhabditis elegans AMP-activated Protein Kinase AAK-2 Is Phosphorylated by LKB1 and Is Required for Resistance to Oxidative Stress and for Normal Motility and Foraging Behavior

Cited by 94 publications

References 35 publications

Sestrins Link Tumor Suppressors with the AMPK-TOR Signaling Network

Sestrins Link Tumor Suppressors with the AMPK-TOR Signaling Network

Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

Caenorhabditis elegans PIG-1/MELK Acts in a Conserved PAR-4/LKB1 Polarity Pathway to Promote Asymmetric Neuroblast Divisions

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