TOR signaling in invertebrates

Soulard, Alexandre; Cohen, Aviv; Hall, Michael N.

doi:10.1016/j.ceb.2009.08.007

Cited by 105 publications

(115 citation statements)

References 127 publications

(109 reference statements)

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“…To determine if ipl1-2 suppression is due to a partial loss of TORC1 activity, we tested the ability of a tor1Δ mutation to suppress ipl1-2 thermosensitivity. tor1Δ mutants are viable because Tor1 and the related Tor2 have partially overlapping activities (29). As shown in Fig.…”

Section: Resultsmentioning

confidence: 85%

“…Downstream targets include RNA polymerase subunits and transcription factors regulating nutrient uptake, ribosome biogenesis, and autophagy (reviewed in ref. 29). In addition to Gip4, which does not appear to be the relevant target here, we note two Glc7 regulators (Shp1 and Reg1) among the TORC1 targets identified by screening the rapamycin-sensitive phosphoproteome by mass spectrometry (36,39).…”

Section: Discussionmentioning

confidence: 99%

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Temperature-sensitive ipl1-2/Aurora B mutation is suppressed by mutations in TOR complex 1 via the Glc7/PP1 phosphatase

Tatchell

Makrantoni

Stark

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Ipl1/Aurora B is the catalytic subunit of a complex that is required for chromosome segregation and nuclear division. Before anaphase, Ipl1 localizes to kinetochores, where it is required to establish proper kinetochore-microtubule associations and regulate the spindle assembly checkpoint. The protein phosphatase Glc7/ PP1 opposes Ipl1 for some of these activities. To more thoroughly characterize the Glc7 phosphatase that opposes Ipl1, we have identified mutations that suppress the thermosensitivity of an ipl1-2 mutant. In addition to mutations in genes previously associated with ipl1 suppression, we recovered a null mutant in TCO89, which encodes a subunit of the TOR complex 1 (TORC1), the conserved rapamycin-sensitive kinase activity that regulates cell growth in response to nutritional status. The temperature sensitivity of ipl1-2 can also be suppressed by null mutation of TOR1 or by administration of pharmacological TORC1 inhibitors, indicating that reduced TORC1 activity is responsible for the suppression. Suppression of the ipl1-2 growth defect is accompanied by increased fidelity of chromosome segregation and increased phosphorylation of the Ipl1 substrates histone H3 and Dam1. Nuclear Glc7 levels are reduced in a tco89 mutant, suggesting that TORC1 activity is required for the nuclear accumulation of Glc7. In addition, several mutant GLC7 alleles that suppress the temperature sensitivity of ipl1-2 exhibit negative synthetic genetic interactions with TORC1 mutants. Together, our results suggest that TORC1 positively regulates the Glc7 activity that opposes Ipl1 and provide a mechanism to tie nutritional status with mitotic regulation.

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Section: Resultsmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Temperature-sensitive ipl1-2/Aurora B mutation is suppressed by mutations in TOR complex 1 via the Glc7/PP1 phosphatase

Tatchell

Makrantoni

Stark

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Tor is found in two distinct complexes, TORC1 and TORC2, 31,32 which leads to further complexity in the Tor signaling network. Rag GTPases, MAP4K3 and the insulin signaling pathway converge on TORC1, which then phosphorylates downstream targets such as S6K.…”

Section: Discussionmentioning

confidence: 99%

Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

Pritchett

McCall

2012

Cell Death Differ

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Amino-acid starvation leads to an inhibition of cellular proliferation and the induction of programmed cell death (PCD) in the Drosophila ovary. Disruption of insulin signaling has been shown to inhibit the progression of oogenesis, but it is unclear whether this phenotype mimics starvation. Here, we investigate whether the insulin-mediated phosphoinositide kinase-3 pathway regulates PCD in mid oogenesis. We reasoned that under well-fed conditions, disruption of positive components of the insulin signaling pathway within the germline would mimic starvation and produce degenerating egg chambers. Surprisingly, mutants did not mimic starvation but instead produced many abnormal egg chambers in which the somatic follicle cells disappeared and the germline persisted. These abnormal egg chambers did not show an induction of caspases and lysosomes like that observed in wild-type (WT) degenerating egg chambers. Egg chambers from insulin signaling mutants were resistant to starvation-induced PCD, indicating that a complete block in insulin-signaling prevents the proper response to starvation. However, target of rapamycin (Tor) mutants did show a phenotype that mimicked WT starvation-induced PCD, indicating an insulin independent regulation of PCD via Tor signaling. These results suggest that inhibition of the insulin signaling pathway is not sufficient to regulate starvation-induced PCD in mid oogenesis. Furthermore, starvation-induced PCD is regulated by Tor signaling converging with the canonical insulin signaling pathway. The insulin-mediated class I phosphoinositide kinase-3 (PI3K) pathway is a highly conserved nutrient-sensing pathway in diverse organisms. In mammals, insulin signaling affects oocyte maturation and fertilization. 1,2 Mutations in the insulin signaling pathway in C. elegans can lengthen life span but reduce fertility. 3,4 Improper insulin signaling in Drosophila leads to reduced body size and female sterility. 5 Thus, insulin signaling is essential for reproduction in diverse organisms, but how this pathway regulates fertility is not fully understood.Proper nutrition during Drosophila oogenesis is critical for egg chamber production. 6-8 Depriving flies of yeast as a protein source leads to programmed cell death (PCD) at two stages: early oogenesis in the germarium and mid oogenesis during stages 7-9. 7 Egg chambers undergoing PCD during mid oogenesis are characterized by nuclear condensation and fragmentation of germline-derived nurse cells (NCs), engulfment by somatic follicle cells (FCs), and ultimately FC death. 5 During PCD in mid oogenesis, dying NCs show characteristics of both apoptotic and autophagic PCD. 5 The effector caspase Death caspase-1 (Dcp-1) is essential for germline PCD in mid oogenesis. dcp-1 mutants that have been starved display mid-stage egg chambers that have a persistence of uncondensed NC nuclei but an absence of FCs. 5 This phenotype indicates that the dcp-1 mutant germline is unable to die in response to starvation, although the FCs respond and undergo PCD. dcp-1 mutants ...

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“…We previously characterized the kinases Trypanosoma brucei TOR1 (TbTOR1) and TbTOR2 (5), which are functionally orthologous to TOR kinases described in other invertebrates (4). Surprisingly, Trypanosoma and the related parasite Leishmania are the only eukaryotes whose genomes encode two additional TOR paralogues, TbTOR3 and TbTOR4 (previously TbTOR-like 1 and 2, respectively) (5) in trypanosomes.…”

mentioning

confidence: 99%

Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei

Barquilla

Saldivia

Díaz

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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African trypanosomes are protozoan parasites transmitted by a tsetse fly vector to a mammalian host. The life cycle includes highly proliferative forms and quiescent forms, the latter being adapted to host transmission. The signaling pathways controlling the developmental switch between the two forms remain unknown. Trypanosoma brucei contains two target of rapamycin (TOR) kinases, TbTOR1 and TbTOR2, and two TOR complexes, TbTORC1 and TbTORC2. Surprisingly, two additional TOR kinases are encoded in the T. brucei genome. We report that TbTOR4 associates with an Armadillo domain-containing protein (TbArmtor), a major vault protein, and LST8 to form a unique TOR complex, TbTORC4. Depletion of TbTOR4 caused irreversible differentiation of the parasite into the quiescent form. AMP and hydrolysable analogs of cAMP inhibited TbTOR4 expression and induced the stumpy quiescent form. Our results reveal unexpected complexity in TOR signaling and show that TbTORC4 negatively regulates differentiation of the proliferative form into the quiescent form.parasitology | cell biology | kinetoplastida

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TOR signaling in invertebrates

Cited by 105 publications

References 127 publications

Temperature-sensitive ipl1-2/Aurora B mutation is suppressed by mutations in TOR complex 1 via the Glc7/PP1 phosphatase

Temperature-sensitive ipl1-2/Aurora B mutation is suppressed by mutations in TOR complex 1 via the Glc7/PP1 phosphatase

Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei

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