ATM-mediated PTEN phosphorylation promotes PTEN nuclear translocation and autophagy in response to DNA-damaging agents in cancer cells

Chen, Jing Hong; Zhang, Peng; Chen, Wen Dan; Li, Dan Dan; Wu, Xiao; Deng, Rong; Jiao, Lin; Li, Xuan; Ji, Jiao; Feng, Gong Kan; Zeng, Yi Xin; Jiang, Jian; Zhu, Xiao Feng

doi:10.1080/15548627.2015.1009767

Cited by 135 publications

(113 citation statements)

References 46 publications

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“…[30][31][32] Accumulating evidence has unveiled the complex crosstalk between DDR pathways and autophagy. Activation of ATM [33][34][35][36] by various insults induces autophagy, and TP53 [37][38][39] and MTOR 35,36,[39][40][41] are 2 representative downstream signaling nodes connecting the DDR pathways to autophagy. The descriptions of autophagy regulation by ATR are rather scarce, but there is strong evidence showing that ATR is a potential upstream regulator of autophagy.…”

Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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Abbreviations: 3-MA, 3-methyladenine; AMBRA1, autophagy/Beclin 1 regulator 1; ATG, autophagy related; ATM, ATM serine/threonine kinase; ATR, ATR serine/threonine kinase; BH3, Bcl-2 homology 3; CCD, coiled-coil domain; CDK, cyclin-dependent kinase; CISD2, CDGSH iron sulfur domain 2; class I/II PI3K, class I/II phosphoinositide 3-kinase; class III PtdIns3K, class III phosphatidylinositol 3-kinase; DAPK1, death-associated protein kinase 1; DDR, DNA damage response; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; FYCO1, FYVE and coiledcoil domain containing 1; GAP, GTPase-activating protein; HMGB1, high mobility group box 1; HSPA1A, heat shock 70kDa protein 1A; IR, ionizing radiation; MAPK8, mitogen-activated protein kinase 8; MEFs, mouse embryonic fibroblasts; MTMR, myotubularin-related protein; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, mechanistic target of rapamycin complex 1; MVBs, spherical multivesicular bodies; NRBF2, nuclear receptor binding factor 2; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide dependent protein kinase 1; PE, phosphatidylethanolamine; PIKFYVE, phosphoinositide kinase, FYVE finger containing; PINK1, PTEN-induced putative kinase 1; PtdIns3K-C1, class III phosphatidylinositol 3-kinase complex I; PtdIns3K-C2, class III phosphatidylinositol 3-kinase complex II; PKB, protein kinase B; PRKA, protein kinase, AMP-activated; PRKD1, protein kinase D1; PRKDC, protein kinase, DNA-activated, catalytic polypeptide; PtdIns5P, phosphatidylinositol 5-phosphate; PtdIns4P, phosphatidylinositol 4-phosphate; PtdIns(4,5)P 2 , phosphatidylinositol 4,5-bisphosphate; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns(3,5)P 2 , phosphatidylinositol 3,5-bisphosphate; PtdIns(3,4,5)P 3 , phosphatidylinositol 3,4,5-trisphosphate; RHEB, Ras homolog enriched in brain; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TECPR1, tectonin b-propeller repeat containing 1; TFEB, transcription factor EB; TRIM28, tripartite motif containing 28; TSC, tuberous sclerosis; UV, ultraviolet; UVRAG, UV radiation resistance associated; WDFY3, WD repeat and FYVE domain containing 3; WIPI, WD repeat domain, phosphoinositide interacting; ZFYVE1, zinc finger, FYVE domain containing 1.Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiati...

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Section: Three Classes Of Ptdins3k and Pi3k Enzymesmentioning

confidence: 99%

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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“…PTEN induces autophagy together with the JUN-SESN2-AMPK pathway in response to DNA damage. 57 There are also numerous stress-responsive transcription factors that regulate autophagy, including TP53, STAT3 and NFKB. 58 Multiple TP53 target genes are responsible for regulating autophagy including MTOR.…”

Section: How Does the Nucleus Sense Autophagic Signaling?mentioning

confidence: 99%

“…56 A connection among the ATM/ATR pathway, DNA repair and autophagy has been established. 55,57 ATM phosphorylates PTEN and regulates its translocation into the nucleus. PTEN induces autophagy together with the JUN-SESN2-AMPK pathway in response to DNA damage.…”

Section: How Does the Nucleus Sense Autophagic Signaling?mentioning

confidence: 99%

Nuclear autophagy: An evolutionarily conserved mechanism of nuclear degradation in the cytoplasm

et al. 2016

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Macroautophagy/autophagy is a catabolic process that is essential for cellular homeostasis. Studies on autophagic degradation of cytoplasmic components have generated interest in nuclear autophagy. Although its mechanisms and roles have remained elusive, tremendous progress has been made toward understanding nuclear autophagy. Nuclear autophagy is evolutionarily conserved in eukaryotes that may target various nuclear components through a series of processes, including nuclear sensing, nuclear export, autophagic substrate encapsulation and autophagic degradation in the cytoplasm. However, the molecular processes and regulatory mechanisms involved in nuclear autophagy remain largely unknown. Numerous studies have highlighted the importance of nuclear autophagy in physiological and pathological processes such as cancer. This review focuses on current advances in nuclear autophagy and provides a summary of its research history and landmark discoveries to offer new perspectives.

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“…Furthermore, ATM mutant fibroblasts display reduced AKT/mTOR activity upon growth factor stimulation37 and a recent report indicates that ATM supports oncogenic HER2 signalling in breast cancer cells38. A direct link between ATM and AKT/mTOR has also been suggested by the ability of ATM to phosphorylate 4EBP1 and PTEN3940. In response to reactive oxygen species (ROS), reactive nitrogen species or temozolomide (an alkylating agent), ATM inhibits mTORC1 via LKB1, AMPK and ULK1, resulting in increased autophagy4142434445.…”

Section: Discussionmentioning

confidence: 99%

MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

et al. 2016

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Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours.

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ATM-mediated PTEN phosphorylation promotes PTEN nuclear translocation and autophagy in response to DNA-damaging agents in cancer cells

Cited by 135 publications

References 46 publications

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Nuclear autophagy: An evolutionarily conserved mechanism of nuclear degradation in the cytoplasm

MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

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