A novel Akt/PKB-interacting protein promotes cell adhesion and inhibits familial amyotrophic lateral sclerosis-linked mutant SOD1-induced neuronal death via inhibition of PP2A-mediated dephosphorylation of Akt/PKB

Nawa, Mikiro; Kanekura, Kohsuke; Hashimoto, Yuichi; Aiso, Sadakazu; Matsuoka, Masao

doi:10.1016/j.cellsig.2007.11.004

Cited by 31 publications

(45 citation statements)

References 44 publications

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“…In our previous study, we showed that the overexpression of BTBD10 inhibited the G93A-SOD1-induced death in cultured neuronal cells. 3 Reciprocally, in this study, we found that small interfering RNA (siRNA)-mediated reduction of BTBD10 expression increased cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in NSC34 motor neuron cells (Figure 1a). Reduced expression of BTBD10 also increased the proportion of NSC34 motor neuron cells that belonged to the subG1 population, which represents the fraction of dead cells (Figure 1b).…”

Section: Resultsmentioning

confidence: 91%

“…The C-terminal 330 amino-acid region of BTBD10 is the most highly conserved region (Supplementary Figure S1) and is essential for the interaction with Akt family proteins. 3 To examine the role of BTBD10 in neuronal cell survival in vivo, we isolated two C. elegans lines, named tm3335 or tm3607, bearing artificially mutated btbd-10 genes. tm3335 contains a 297-base pair (bp) deletion plus a 5-bp insertion while tm3607 contains a 207-bp deletion in the middle of exon 4 (Supplementary Figure S2).…”

Section: Resultsmentioning

confidence: 99%

“…11 We further found that overexpression of BTBD10 inhibited FALS-linked mutant SOD1-induced motor neuron death in vitro. 3 Although these findings together suggest that BTBD10 is an upstream regulator of Akt that may be involved in the survival of motor neurons, an in vivo relationship between BTBD10 malfunction and motor neuron death has yet to be established.…”

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confidence: 99%

“…BTBD10 activates Akt by inhibiting PP2A-mediated Akt dephosphorylation and inactivation. 3 BTBD10 also contributes to the insulinstimulated phosphorylation of Akt and pancreatic beta cell proliferation. 11 We further found that overexpression of BTBD10 inhibited FALS-linked mutant SOD1-induced motor neuron death in vitro.…”

mentioning

confidence: 99%

“…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.…”

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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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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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

et al. 2012

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Protein partners of KCTD proteins provide insights about their functional roles in cell differentiation and vertebrate development

et al. 2013

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The KCTD family includes tetramerization (T1) domain containing proteins with diverse biological effects. We identified a novel member of the KCTD family, BTBD10. A comprehensive analysis of protein-protein interactions (PPIs) allowed us to put forth a number of testable hypotheses concerning the biological functions for individual KCTD proteins. In particular, we predict that KCTD20 participates in the AKT-mTOR-p70 S6k signaling cascade, KCTD5 plays a role in cytokinesis in a NEK6 and ch-TOG-dependent manner, KCTD10 regulates the RhoA/RhoB pathway. Developmental regulator KCTD15 represses AP-2α and contributes to energy homeostasis by suppressing early adipogenesis. TNFAIP1-like KCTD proteins may participate in post-replication DNA repair through PCNA ubiquitination. KCTD12 may suppress the proliferation of gastrointestinal cells through interference with GABAb signaling. KCTD9 deserves experimental attention as the only eukaryotic protein with a DNA-like pentapeptide repeat domain. The value of manual curation of PPIs and analysis of existing high-throughput data should not be underestimated.

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Kctd20 promotes the development of non‐small cell lung cancer through activating Fak/AKT pathway and predicts poor overall survival of patients

Zhang

Zhou

Cai

et al. 2017

Molecular Carcinogenesis

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Kctd20 (potassium channel tetramerization protein domain containing 20) is a positive regulator of Akt signaling. However, the role of Kctd20 during the course of tumorigenesis and development is unclear. Using immunohistochemistry, we demonstrated that, in non-small cell lung cancer (NSCLC) patients, Kctd20 protein expression significantly correlates with advanced TNM stage (P < 0.001), positive status for regional lymph node metastasis (P = 0.019), and poor overall survival (P = 0.013). Proliferation and invasion assays showed that Kctd20 dramatically promotes the proliferation and invasion of NSCLC cells (P = 0.007 and P < 0.001, respectively). Subsequent Western Blot and qPCR experiments revealed an upregulation of Cyclin D1 and downregulation of E-cadherin in Kctd20-overexpressing cells. After depleting Kctd20, downregulaton of Cyclin D1, and upegulation of E-cadherin was observed. After overexpressing Kctd20, the levels of phosphorylated Fak (Tyr397) and Akt (Thr308) increased, while after transfection with Kctd20-siRNA these phosporylated proteins were downregulated. Moreover, in Kctd20-overexpressing cells, treatment with an Akt inhibitor reduced expression of p-Akt and Cyclin D1, enhanced E-cadherin expression, and did not impact p-Fak levels. When Kctd20-overexpressing cells were treated with a Fak inhibitor, the same effects were seen, and the level of p-Akt was reduced. Our results suggest that Kctd20 impacts proliferation and invasion of NSCLC through enhancing Fak (Tyr397) and Akt (Thr 308) phosphorylation. Kctd20 may predict prognosis and be targeted therapeutically in NSCLC.

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A novel Akt/PKB-interacting protein promotes cell adhesion and inhibits familial amyotrophic lateral sclerosis-linked mutant SOD1-induced neuronal death via inhibition of PP2A-mediated dephosphorylation of Akt/PKB

Cited by 31 publications

References 44 publications

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

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

Protein partners of KCTD proteins provide insights about their functional roles in cell differentiation and vertebrate development

Kctd20 promotes the development of non‐small cell lung cancer through activating Fak/AKT pathway and predicts poor overall survival of patients

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