Protein Kinase B Kinases That Mediate Phosphatidylinositol 3,4,5-Trisphosphate-Dependent Activation of Protein Kinase B

Stephens, Len R.; Anderson, Karen E.; Stokoe, David; Erdjument‐Bromage, Hediye; Painter, Gavin F.; Holmes, Andrew B.; Gaffney, Piers R. J.; Reese, Colin B.; McCormick, Frank; Tempst, Paul; Coadwell, John; Hawkins, Phillip T.

doi:10.1126/science.279.5351.710

Cited by 990 publications

(803 citation statements)

References 20 publications

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“…PDPK1 was first identified based on its ability to phosphorylate Thr308 of AKT. [30][31][32] However, conservation of aminoacid sequences similar to those surrounding Thr308 of AKT in the AGC family of Ser/Thr protein kinases suggested that PDPK1 may phosphorylate other AGC protein kinase family members, including PKC isoforms. In agreement with this, recent reports have demonstrated that PDPK1 can phosphorylate PKC isoforms.…”

Section: Resultsmentioning

confidence: 99%

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

et al. 2014

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Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47 phox , a subunit of NOX1 to plasma membrane. Of note, PKCd, when it was activated by PDPK1, directly bound to the SH3-N domain of p47 phox and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47 phox C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47 phox -NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCd, p47 phox and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCd, p47 phox or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/ PDPK1/PKCd/p47 phox /NOX1 for ROS generation and consequent malignant cellular transformation.

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Section: Resultsmentioning

confidence: 99%

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

et al. 2014

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“…PIP3 serves as substrate for the protein and lipid phosphatase activity-bearing tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome ten), which specifically removes the phosphate group in the D3 position of the inositol ring and thereby attenuates IIS pathway activity (Vanhaesebroeck and Alessi, 2000). Upon PIP3 production, Akt/ protein kinase B (PKB) translocates to the membrane mediated by binding of PIP3 to its PH domain and is fully activated by mTORC2 phosphorylating Ser473 in the C-terminal located hydrophobic motif (Hresko and Mueckler, 2005; and by 3 0 -phosphoinositide-dependent kinase-1 (PDK1) phosphorylating Thr308 in the activation/T-loop (Alessi et al, 1997;Stokoe et al, 1997;Stephens et al, 1998). Numerous downstream effectors of Akt/PKB have been described, among many others forkhead transcription factors, GSK3b, Bad and the cell cycle inhibitor p27 KIP1 (Brazil et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Stress and mTORture signaling

2006

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“…Direct binding of the PH domain of Akt to PtdIns(3,4,5)P 3 permits phosphorylation of Akt by a phosphoinositide-dependent kinase (PDK1) at Thr308 [17].…”

Section: Introductionmentioning

confidence: 99%

p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

Grethe¹,

Coltella²,

Pörn-Ares³

2006

Biochemical and Biophysical Research Communications

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Doxorubicin is the anthracycline with the widest spectrum of antitumor activity, and it has been shown that the antitumor activity is mediated in vivo by selective triggering of apoptosis in proliferating endothelial cells. We studied cultured human endothelial cells and observed that doxorubicin-induced apoptosis was mediated by p38 mitogen-activated protein kinase (MAPK). Doxorubicin-provoked apoptosis was significantly inhibited by expression of dominant negative p38 MAPK or pharmacological inhibition with SB203580.Furthermore, blocking phosphatidylinositol-3-kinase/Akt signaling significantly increased doxorubicin-induced caspase-3 activity and cell death, indicating that Akt is a survival factor in this system. Notably, we also found that doxorubicin-provoked apoptosis included p38 MAPK-mediated inhibition of Akt and Bad phosphorylation. Furthermore, doxorubicinstimulated phosphorylation of Bad in cells expressing dominant negative p38 MAPK was impeded by the inhibition of PI3-K. In addition to the impact on Bad phosphorylation, doxorubicin-treatment caused p38 MAPK-dependent downregulation of Bcl-xL protein.

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Protein Kinase B Kinases That Mediate Phosphatidylinositol 3,4,5-Trisphosphate-Dependent Activation of Protein Kinase B

Cited by 990 publications

References 20 publications

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

Stress and mTORture signaling

p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

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