Tti1 and Tel2 Are Critical Factors in Mammalian Target of Rapamycin Complex Assembly

Kaizuka, Takeshi; Hara, Taichi; Oshiro, Noriko; Kikkawa, Ushio; Yonezawa, Kazuyoshi; Takehana, Kenji; Iemura, Shun Ichiro; Natsume, Tohru; Mizushima, Noboru

doi:10.1074/jbc.m110.121699

Cited by 226 publications

(215 citation statements)

References 41 publications

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“…Genome instability also occurs in clk-2 mutant germlines, but strong alleles lead to a late G2-like cell cycle arrest. Subsequent studies on mammalian and yeast CLK-2 orthologs, referred to as TEL2 in yeasts, established that CLK-2/TEL2 is required for the full activation of all PIKKs-type protein kinases, a class of protein kinases that includes ATM/ atm-1 and ATL-1, thus explaining checkpoint-signalling phenotypes (Hayashi et al 2007 ;Kanoh and Yanagida 2007 ;Hurov et al 2010 ;Takai et al 2010 ;Kaizuka et al 2010 ) . The current model suggests that CLK-2/TEL2 might have a chaperonlike function required for the full activation of those kinases (Horejsi et al 2010 ) .…”

Section: Upstream Dna Damage Checkpoint Signalling In the C Elegansmentioning

confidence: 99%

Germ Cell Apoptosis and DNA Damage Responses

Bailly

Gartner

2012

Advances in Experimental Medicine and Biology

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In the past 12 years, since the fi rst description of C. elegans germ cell apoptosis, this area of research rapidly expanded. It became evident that multiple genetic pathways lead to the apoptotic demise of germ cells. We are only beginning to understand how these pathways that all require the CED-9/Bcl-2, Apaf-1/CED-4 and CED-3 caspase core apoptosis components are regulated. Physiological apoptosis, which likely accounts for the elimination of more than 50% of all germ cells, even in unperturbed conditions, is likely to be required to maintain tissue homeostasis. The best-studied pathways lead to DNA damage-induced germ cell apoptosis in response to a variety of genotoxic stimuli. This apoptosis appears to be regulated similar to DNA damage-induced apoptosis in the mouse germ line and converges on p53 family transcription factors. DNA damage response pathways not only lead to apoptosis induction, but also directly affect DNA repair, and a transient cell cycle arrest of mitotic germ cells. Finally, distinct pathways activate germ cell apoptosis in response to defects in meiotic recombination and meiotic chromosome pairing.

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Section: Upstream Dna Damage Checkpoint Signalling In the C Elegansmentioning

confidence: 99%

Germ Cell Apoptosis and DNA Damage Responses

Bailly

Gartner

2012

Advances in Experimental Medicine and Biology

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“…mTOR forms two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, by binding with multiple companion proteins ( Figure 1). mLST8, DEPTOR, and the Tti1/ Tel2 complex exist in both mTORC1 and mTORC2 (2)(3)(4)(5). On the other hand, RAPTOR and PRAS40 are specific to mTORC1 (6-11) whereas RICTOR, mSin1, and PROCTOR1/2 are specific to mTORC2 (10,(12)(13)(14)(15)(16).…”

Section: Overview Of Mtor Signaling Pathwaymentioning

confidence: 99%

mTOR: a pharmacologic target for autophagy regulation

Kim¹,

Guan²

2015

J. Clin. Invest.

1,621

1,141

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Overview of mTOR signaling pathwayNutrients, growth factors, and cellular energy levels are key determinants of cell growth and proliferation. mTOR, a serine/threonine kinase, is a master regulator of cellular metabolism and promotes cell growth in response to environmental cues. Deregulation of mTOR signaling has been implicated in many human diseases, including diabetes, neurodegenerative diseases, and cancer (1). mTOR forms two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, by binding with multiple companion proteins (Figure 1). mLST8, DEPTOR, and the Tti1/ Tel2 complex exist in both mTORC1 and mTORC2 (2-5). On the other hand, RAPTOR and PRAS40 are specific to mTORC1 (6-11) whereas RICTOR, mSin1, and PROCTOR1/2 are specific to mTORC2 (10,(12)(13)(14)(15)(16). The two kinase complexes have specific substrate preferences and therefore elicit distinct downstream signaling events to modulate cellular function.One of the well-established roles of mTORC1 is to promote anabolic cellular metabolism to supply the necessary building blocks for cell growth and proliferation. mTORC1 integrates various stimuli and signaling networks to stimulate synthesis of protein, lipid, and nucleotides and block catabolic processes such as autophagy at the post-translational and transcriptional levels (reviewed in refs. 17, 18). The tuberous sclerosis (TSC) tumor suppressor complex (TSC1/TSC2) is arguably the most important upstream negative regulator of mTORC1. Genetic mutations in hamartin or tuberin (encoding TSC1 and TSC2, respectively) cause tumor development in various tissues such as angiofibromas, angiomyolipomas, lymphangioleiomyomatosis, and renal cell carcinoma. Loss-of-function mutations in either TSC1 or TSC2 lead to constitutive mTORC1 activation, which contributes to uncontrolled growth and underlies the TSC disease (19). These findings provide the scientific basis of using mTORC1 inhibitors for the treatment of TSC and related diseases such as cancer.A well-established upstream regulator of mTORC1 is the growth factor/PI3K/AKT signaling pathway. Growth factors such as insulin and IGF activate their cognate receptors (receptor tyrosine kinases [RTKs]) and subsequently activate the PI3K/ AKT signaling axis. Activated AKT directly phosphorylates and thereby inhibits TSC1/2, a GTPase-activating protein (GAP) for the Ras homolog enriched in brain (Rheb) GTPase (19-23). The AKT-dependent phosphorylation results in dissociation of TSC1/2 from lysosome, where Rheb is localized, promoting Rheb activation (24). Since GTP-bound Rheb is a potent mTORC1 activator, inhibition of TSC1/2 by AKT-dependent phosphorylation results in mTORC1 activation (25,26). Additionally, AKT directly phosphorylates and inhibits PRAS40, an mTORC1 component that negatively regulates the complex's kinase activity, leading to mTORC1 activation (8-11). Furthermore, the activated RTK also stimulates the Ras/Erk/p90 ribosomal S6 kinase 1 (RSK1) signaling axis, which directly phosphorylates TSC2 to inactivate its GAP activity (27,28). In co...

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“…A requirement for the human Tel2/Tti1/Tti2 complex in the formation of TORC1 and TORC2 was inferred by Kaizuka et al (2010).…”

Section: Tel2 Is Required For the Assembly Of Torc1 And Torc2mentioning

confidence: 99%

Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes

Takai

Xie²,

Lange³

et al. 2010

Genes Dev.

176

267

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We reported previously that the stability of all mammalian phosphatidylinositol 3-kinase-related protein kinases (PIKKs) depends on their interaction with Tel2, the ortholog of yeast Tel2 and Caenorhabditis elegans Clk-2. Here we provide evidence that Tel2 acts with Hsp90 in the maturation of PIKK complexes. Quantitative immunoblotting showed that the abundance of Tel2 is low compared with the PIKKs, and Tel2 preferentially bound newly synthesized ATM, ATR, mTOR, and DNA-PKcs. Tel2 complexes contained, in addition to Tti1-Tti2, the Hsp90 chaperone, and inhibition of Hsp90 interfered with the interaction of Tel2 with the PIKKs. Analysis of in vivo labeled nascent protein complexes showed that Tel2 and Hsp90 mediate the formation of the mTOR TORC1 and TORC2 complexes and the association of ATR with ATRIP. The structure of yeast Tel2, reported here, shows that Tel2 consists of HEAT-like helical repeats that assemble into two separate a-solenoids. Through mutagenesis, we identify a surface patch of conserved residues involved in binding to the Tti1-Tti2 complex in vitro. In vivo, mutation of this conserved patch affects cell growth, levels of PIKKs, and ATM/ATR-mediated checkpoint signaling, highlighting the importance of Tti1-Tti2 binding to the function of Tel2. Taken together, our data suggest that the Tel2-Tti1-Tti2 complex is a PIKK-specific cochaperone for Hsp90.[Keywords: Tel2; Hsp90; ATR; mTOR; PIKK; structure] Supplemental material is available at http://www.genesdev.org.

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Tti1 and Tel2 Are Critical Factors in Mammalian Target of Rapamycin Complex Assembly

Cited by 226 publications

References 41 publications

Germ Cell Apoptosis and DNA Damage Responses

Germ Cell Apoptosis and DNA Damage Responses

mTOR: a pharmacologic target for autophagy regulation

Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes

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