Autoregulation of kinase dephosphorylation by ATP binding in AGC protein kinases

Chan, Tung O.; Pascal, John M.; Armen, Roger S.; Rodeck, Ulrich

doi:10.4161/cc.11.3.19059

Cited by 9 publications

(11 citation statements)

References 32 publications

(35 reference statements)

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“…2). The finding that dephosphorylation of PKC␣ is a minor response to agonist treatment in cells is consistent with evidence that physiological nucleotide occupancy of the active site confers phosphatase resistance to activated PKCs (and other AGC kinases) (42)(43)(44)(45). Spatial considerations also argue for direct targeting of the phosphorylated form.…”

Section: Discussionsupporting

confidence: 65%

“…Dephosphorylation may not be a prerequisite for down-regulation, because phosphorylated PKC␣ is ubiquitinated, and it is the phosphorylated form that is detected in early and late endosomal compartments following internalization (28, 39 -41). Furthermore, physiological levels of nucleotides (or nucleotide analogs) maintain activated PKCs in a phosphatase-resistant conformation (42)(43)(44)(45), indicating that activation may not directly induce PKC dephosphorylation within the cell. Thus, the role of dephosphorylation in desensitization of PKC signaling remains to be resolved.…”

mentioning

confidence: 99%

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Heat Shock Proteins Regulate Activation-induced Proteasomal Degradation of the Mature Phosphorylated Form of Protein Kinase C

Lum

Balaburski

Murphy

et al. 2013

Journal of Biological Chemistry

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Background: Mechanisms of activation-induced PKC down-regulation are poorly understood. A characterized pathway involves priming site dephosphorylation and degradation of the dephosphorylated species. Results: Mature, fully phosphorylated PKC␣ is a major target for activation-induced degradation, via mechanisms controlled by Hsps. Conclusion: Hsps control phosphorylation and degradation of fully primed, activated PKC. Significance: Findings from this study support a new model of PKC desensitization.

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

Heat Shock Proteins Regulate Activation-induced Proteasomal Degradation of the Mature Phosphorylated Form of Protein Kinase C

Lum

Balaburski

Murphy

et al. 2013

Journal of Biological Chemistry

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“…5), we observed insulin-dependent hyper-phosphorylation of Akt Thr-308. Hyper-phosphorylation of inactive Akt has been observed with direct Akt kinase inhibitors (60,61) and oxidation (99). This phenotype is inconsistent with a block upstream in the ISP.…”

Section: Pfkfb3 and Insulin Signallingmentioning

confidence: 86%

“…5H). Although it is thought that Akt phosphorylation at Thr-308 and Ser-473 are representative of Akt activity, it was recently reported that Akt hyperphosphorylation can occur when Akt kinase activity is inhibited, due to a conformational change in Akt that shields the phosphosites from phosphatases (60,61). We therefore assessed Akt activity by measuring phosphorylation of the Akt substrate GSK3 and the downstream substrate S6K.…”

Section: Pfkfb3 Inhibition In 3t3-l1 Adipocytes Decreases Insulinstimmentioning

confidence: 99%

Kinome Screen Identifies PFKFB3 and Glucose Metabolism as Important Regulators of the Insulin/Insulin-like Growth Factor (IGF)-1 Signaling Pathway

Trefely

Khoo

Krycer

et al. 2015

Journal of Biological Chemistry

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Background: Insulin regulates metabolism via the PI3K/Akt pathway. Results: A kinome siRNA screen identified PFKFB3, a glycolysis regulator, as a modulator of insulin action. Manipulation of PFKFB3 activity or glycolysis affected insulin signaling. Conclusion: Intracellular metabolism modulates important signal transduction pathways. Significance: The novel link between glycolysis and growth factor signaling has important implications for the treatment of metabolic diseases.

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“…Recent progress in structural characterization of cyclic AMP-dependent protein kinase (Protein Kinase A, PKA) has expanded our knowledge of kinase signaling (Kuehn 1972;Makman & Klein 1972;Kleppe et al 2011;Chan et al 2012). The PKA holoenzyme is a heterotetramer of two catalytic (C) subunits held in an inactive state by association with a regulatory (R) subunit dimer.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of human chromosome maintenance 1 mediates association with 14-3-3 proteins

Kang¹,

Sein²

2013

Animal Cells and Systems

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Human chromosome maintenance 1 (CRM1) was originally cloned based on homology to a yeast gene. CRM1, which belongs to the family of importin b-related nuclear transport receptors, directly and specifically associates with nuclear export signals (NESs) and mediates nuclear export of proteins containing leucine-rich NESs. We present evidence that CRM1 associates with a 22-kDa 14-3-3 scaffolding protein that is a principal structural and regulatory component of Human embryonic kidney (HEK 293) cells. We found a potential 14-3-3-binding motif ( 1049 KHKRQMSVPG 1058 ) in the CRM1 C-terminal domain that depended on serine 1055 phosphorylation by Protein Kinase A (PKA). We demonstrated that CRM1 is a PKA substrate using an in vitro assay. Using a pull-down approach and co-immunoprecipitation, we found that CRM1 interacted with the 14-3-3 motif in vivo and in vitro. We also detected colocalization of CRM1 and 14-3-3 proteins using confocal microscopy. Nuclear pore localization of CRM1 was disrupted by treatment with a PKA activator or inhibitor or by a S1055D/S1055A mutation in the CRM1 14-3-3-binding motif. Transient transfection assays showed that the apoptosis rate of cells with the S1055D construct was twice that of cells with wild type (WT) or S1055A construct. Our observations indicated that phosphorylation on the serine 1055 residue of CRM1 by PKA promoted 14-3-3 binding and cytoplasmic localization, resulting in enhancement of cell apoptosis.

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Autoregulation of kinase dephosphorylation by ATP binding in AGC protein kinases

Cited by 9 publications

References 32 publications

Heat Shock Proteins Regulate Activation-induced Proteasomal Degradation of the Mature Phosphorylated Form of Protein Kinase C

Heat Shock Proteins Regulate Activation-induced Proteasomal Degradation of the Mature Phosphorylated Form of Protein Kinase C

Kinome Screen Identifies PFKFB3 and Glucose Metabolism as Important Regulators of the Insulin/Insulin-like Growth Factor (IGF)-1 Signaling Pathway

Phosphorylation of human chromosome maintenance 1 mediates association with 14-3-3 proteins

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