Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling

Ikenoue, Tsuneo; Inoki, Ken; Yang, Qian; Zhou, Xiaoming; Guan, Kun Liang

doi:10.1038/emboj.2008.146

Cited by 176 publications

(281 citation statements)

References 14 publications

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“…More recent evidence has demonstrated that the mammalian Target of Rapamycin (mTOR) pathway regulates TM phosphorylation of some, but not all, PKCs [59][60][61]. mTOR is a serine/threonine kinase that associates with other proteins to form multi-protein complexes.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…One of these complexes, mTORC1, is sensitive to the drug rapamycin while the other complex, mTORC2, is insensitive to acute rapamycin treatment [62]. mTORC2 has been implicated in TM phosphorylation of cPKCs ( , I , II , ) and PKC in murine embryonic fibroblasts (MEFs) [59,60]. In MEFs that lack critical components of the mTORC2 complex, the levels of expression of cPKCs and PKC are vastly reduced and TM phosphorylation is also absent on the residual pool of PKC (A-loop and HM phosphorylation are also absent).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…12 levels of expression of PKC , , , and are unaffected in cells that lack mTORC2-specific components [59,60]. This implies that other signalling pathways or autophosphorylation may regulate these isoforms at this site.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…While cPKCs were initially reported to autophosphorylate at both the TM and HM [57], the mTORC2 complex has also been implicated in HM phosphorylation of PKC in MEFs [71,72,59], while mTORC2 also influences PKC phosphorylation at this site in T lymphocytes [61]. Interestingly, while the levels of expression of PKC are unaffected following deletion of mTORC2 components in MEFs [59,60], phosphorylation of PKC (and PKC * ) at the HM motif is sensitive to rapamycin treatment in human embryonic kidney cells, which therefore implicates the mTORC1 complex in phosphorylation of these isoforms [73,66].…”

mentioning

confidence: 99%

“…Interestingly, while the levels of expression of PKC are unaffected following deletion of mTORC2 components in MEFs [59,60], phosphorylation of PKC (and PKC * ) at the HM motif is sensitive to rapamycin treatment in human embryonic kidney cells, which therefore implicates the mTORC1 complex in phosphorylation of these isoforms [73,66]. It is clear therefore that mTORC1, mTORC2 and possibly other pathways impact on the HM of different…”

mentioning

confidence: 99%

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Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites

Freeley

Kelleher

Long

2011

Cellular Signalling

103

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Section: Accepted M Manuscriptmentioning

confidence: 99%

Section: Accepted M Manuscriptmentioning

confidence: 99%

Section: Accepted M Manuscriptmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites

Freeley

Kelleher

Long

2011

Cellular Signalling

103

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The tumor promoter‐activated protein kinase Cs are a system for regulating filopodia

et al. 2017

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Different protein kinase C (PKC) isoforms have distinct roles in regulating cell functions. The conventional (α, β, γ) and novel (δ, ɛ, η, θ) classes are targets of phorbol ester tumor promoters, which are surrogates of endogenous second messenger, diacylglycerol. The promoter‐stimulated disappearance of filopodia was investigated by use of blocking peptides (BPs) that inhibit PKC maturation and/or docking. Filopodia were partially rescued by a peptide representing PKC ɛ hydrophobic sequence, but also by a myristoylated PKC α/β pseudosubstrate sequence, and an inhibitor of T‐cell protein tyrosine phosphatase (TC‐PTP). The ability to turn over filopodia was widely distributed among PKC isoforms. PKC α and η hydrophobic sequences enhanced filopodia in cells in the absence of tumor promoter treatment. With transcriptional knockdown of PKC α, the content of PKC ɛ predominated over other isoforms. PKC ɛ could decrease filopodia significantly in promoter‐treated cells, and this was attributed to ruffling. The presence of PKC α counteracted the PKC ɛ‐mediated enhancement of ruffling. The results showed that there were two mechanisms of filopodia downregulation. One operated in the steady‐state and relied on PKC α and η. The other was stimulated by tumor promoters and relied on PKC ɛ. Cycles of protrusion and retraction are characteristic of filopodia and are essential for the cell to orient itself during chemotaxis and haptotaxis. By suppressing filopodia, PKC ɛ can create a long‐term “memory” of an environmental signal that may act in nature as a mnemonic device to mark the direction of a repulsive signal.

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Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date

Bastien

McNeill

Fine

2014

Cancer

125

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During the last decade, extensive multiplatform genome-wide analysis has yielded a wealth of knowledge regarding the genetic and molecular makeup of glioblastoma multiforme (GBM). These profiling studies support the emerging view that GBM comprises a group of highly heterogeneous tumor types, each with its own distinct molecular and genetic signatures. This heterogeneity complicates the process of defining reliable intertumor/intratumor biological states, which will ultimately be needed for classifying tumors and for designing effective customized therapies that target resultant disease pathways. The increased understanding of the molecular pathogenesis of GBM has brought the hope and expectation that such knowledge will lead to better and more rational therapies directed toward specific molecular targets. To date, however, these expectations have largely been unrealized. This review discusses some of the principal genetic and epigenetic aberrations found in GBM that appear promising for targeted therapies now and in the near future, and it offers suggestions for future directions concerning the rather disappointing results of clinical trials to date. Cancer 2014;121:502-16.

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Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling

Cited by 176 publications

References 14 publications

Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites

Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites

The tumor promoter‐activated protein kinase Cs are a system for regulating filopodia

Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date

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