TOR Complex 2 Integrates Cell Movement during Chemotaxis and Signal Relay in <i>Dictyostelium</i>

Lee, Susan; Comer, Frank I.; Sasaki, Atsuo T.; McLeod, Ian X.; Duong, Yung; Okumura, Kōichi; Yates, John R.; Parent, Carole A.; Firtel, Richard A.

doi:10.1091/mbc.e05-04-0342

Cited by 184 publications

(240 citation statements)

References 46 publications

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“…Hall's group (Loewith et al 2002) originally identified more components in TORC2, including Avo1 and Avo2. In addition, Rip3, an Avo1 homolog in Dictyostelium, has recently been found to be an essential component of TORC2 (Lee et al 2005). Bit61 was also reported as another component of TORC2 (Wullschleger et al 2005).…”

Section: Discussionmentioning

confidence: 98%

Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity

Yang

Inoki²,

Ikenoue³

et al. 2006

Genes Dev.

456

416

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Section: Discussionmentioning

confidence: 98%

Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity

Yang

Inoki²,

Ikenoue³

et al. 2006

Genes Dev.

456

416

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“…2B; Inoki et al, 2005b). Recently, TORC2 in Dictyostelium discoideum has been characterized and also shown to regulate cell polarity (Lee et al, 2005).…”

Section: Rapamycin-insensitive Torc2 Regulates Cell Polaritymentioning

confidence: 99%

The TOR signalling network from yeast to man

Virgilio

Loewith

2006

The International Journal of Biochemistry & Cell Biology

209

162

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The target of rapamycin, TOR, is an essential ser/thr protein kinase that functions in two distinct multiprotein complexes, TOR complex 1 and 2. The structure and functions of these complexes have been conserved from yeast to man. TOR complex 1 is inhibited by rapamycin and is thought to couple growth cues to cellular metabolism; TOR complex 2 is not inhibited by rapamycin and appears to regulate spatial aspects of growth such as cell polarity. Work done in a variety of model systems, continues to contribute to our current understanding of this TOR signalling network. Recent studies in flies and mammalian tissue culture cells have elucidated many signalling components upstream of TOR complex 1. These studies also suggest that aberrant mammalian TOR complex 1 signalling contributes to a number of pathologies ranging from metabolic diseases to hyperproliferative disorders and cancers. Consequently the efficacies of rapamycin and related compounds in treating such diseases are being evaluated in clinical trials.

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“…Phosphorylation of the HMs of the two PKBs is mediated by TorC2 (target of rapamycin complex 2). One of the earliest genetic defects in chemotaxis to be described in D. discoideum was in the gene PianissimoA (piaA), later shown to be a subunit of TorC2 (16,17). In PkbA, AL phosphorylation also requires recruitment of the enzyme to the membrane by transient accumulation of PIP 3 .…”

mentioning

confidence: 99%

Phosphoinositide-dependent Protein Kinase (PDK) Activity Regulates Phosphatidylinositol 3,4,5-Trisphosphate-dependent and -independent Protein Kinase B Activation and Chemotaxis

Kamimura

Devreotes

2010

Journal of Biological Chemistry

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Chemotactic cells must sense shallow extracellular gradients and produce localized intracellular responses. We previously showed that the temporal and spatial activation of two protein kinase B (PKB) homologues, PkbA and PkbR1, in Dictyostelium discoideum by phosphorylation of activation loops (ALs) and hydrophobic motifs had important roles in chemotaxis. We found that hydrophobic motif phosphorylation depended on regulation of TorC2 (target of rapamycin complex 2); however, the regulation of AL phosphorylation remains to be determined at a molecular level. Here, we show that two PDK (phosphoinositide-dependent protein kinase) homologues, PdkA and PdkB, function as the key AL kinases. Cells lacking both PdkA and PdkB are defective in PKB activation, chemotaxis, and fruiting body formation upon nutrient deprivation. The pleckstrin homology domain of PdkA is sufficient to localize it to the membrane, but transient activation of PdkA is independent of PIP 3 as well as TorC2 and dispensable for full function. These results confirm the importance of the TorC2-PDK-PKB pathway in chemotaxis and point to a novel mechanism of regulation of PDKs by chemoattractant.Many cells can detect extracellular chemical gradients and move toward or away from higher concentrations in a process referred to as chemotaxis or directed cell migration. In embryogenesis, chemotaxis is used repeatedly to rearrange cells, for instance, during primordial germ cell migration, organ formation, and wiring of the nervous system. In the adult, chemotaxis mediates trafficking of immune cells and participates in wound healing and in maintenance of tissue architecture and allows stem cells to target to and persist in their niches. Chemotaxis also plays an important role in pathological states such as excessive inflammation and cancer metastasis.Current studies indicate that chemotaxis involves a network of interconnected signaling pathways (1). In one important series of events, chemoattractants activate PI3Ks 2 that produce the accumulation of phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) and the protrusion of pseudopodia at the leading edge of the cell (2). It is thought that the effects of PIP 3 are mediated by the local recruitment and activation of AKT/PKB. Unregulated overproduction of PIP 3 , as occurs in cells lacking the lipid phosphatases, PTEN or SHIP1, causes ectopic projections outside of the leading edge and impairs chemotaxis (3, 4). Similarly, direct activation of PI3K, bypassing the receptor, is sufficient to trigger cell extensions (5). Surprisingly, however, cells lacking PIP 3 production can still carry out chemotaxis (6 -8). The apparent paradox was explained in Dictyostelium discoideum by showing that chemoattractants still trigger the phosphorylation of PKB substrates in the absence of PIP 3 (9). This is because the cAMP signaling pathways converge on two PKB homologues, a PIP 3 -dependent enzyme, PkbA, with a PIP 3 -specific pleckstrin homology (PH) domain at its N terminus and a PIP 3 -independent enzyme, PkbR1, which is t...

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TOR Complex 2 Integrates Cell Movement during Chemotaxis and Signal Relay in Dictyostelium

Cited by 184 publications

References 46 publications

Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity

Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity

The TOR signalling network from yeast to man

Phosphoinositide-dependent Protein Kinase (PDK) Activity Regulates Phosphatidylinositol 3,4,5-Trisphosphate-dependent and -independent Protein Kinase B Activation and Chemotaxis

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