Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction

Burgering, Boudewijn M.T.; Coffer, Paul J.

doi:10.1038/376599a0

Cited by 1,947 publications

(1,481 citation statements)

References 17 publications

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“…However, recent studies using mutant TrkA receptors indicate that the activation of PI3-kinase depends in the main on phosphorylation of tyrosine Y490, the SHC binding site in human TrkA (Baxter et al, 1995). The PI3-kinase targets S6-kinase (Weng et al, 1995) and Akt/PKB (Burgering and Co er, 1995;Franke et al, 1995) Figure 2b, respectively). As controls for Akt/PKB activation we stimulated cells with EGF (100 ng/ml) or PDGF-AB (50 ng/ml); both of which bound to endogenous receptors in ®broblasts and activated Akt/PKB.…”

Section: Resultsmentioning

confidence: 99%

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

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Survival signalling by ligand-activated tyrosine kinase receptors plays a crucial role in maintaining the balance between cell viability and apoptosis in multicellular organisms. To identify receptor domains and pathways involved in survival signalling, the nerve growth factor receptor TrkA was expressed in Rat-1/MycER TM ®broblasts. We demonstrate that wt-TrkA receptor delays c-Myc-, U.V.-and Cycloheximide-induced apoptosis and activates targets such as the mitogen-activated protein kinase (MAPK) Erk2 and the serine/threonine kinase Akt/PKB, both of which have been implicated in survival signalling. TrkA mutated within its SHC binding site (Y490F) delays c-Myc-induced apoptosis without activating endogenous Akt/PKB. In contrast, the TrkA Y490F mutant receptor does not delay U.V.-induced apoptosis whilst TrkA mutated at its PLC-g binding site (Y785F) is capable of protecting from apoptosis induced by c-Myc or U.V. treatment. The double mutant TrkA YY490/785FF fails to block either of these two apoptotic stimuli. While PI3-kinase inhibitors LY294002 and Wortmannin competely block survival signalling following U.V. treatment, neither drug a ects the ability of TrkA to block c-Myc-induced apoptosis. We show that the Akt/PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U.V.-induced apoptosis, but that apoptosis induced by c-Myc is also blocked by a novel, Akt/PKB-independent, pathway. These observations suggest that TrkA can activate di erent survival signalling pathways, which can interfere with speci®c apoptotic pathways.

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Section: Resultsmentioning

confidence: 99%

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

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“…AKT/PKB is a well characterized downstream target of PI3K with serine/threonine kinase activity which is catalytically inactive in serum starved ®broblasts (Burgering and Co er, 1995;Franke et al, 1995). Its enzymatic activity is rapidly induced by addition of growth factors and was shown to be involved in the protection from apoptosis in a number of cellular systems (Franke et al, 1997;Marte and Downward, 1997).…”

Section: Activation Of Akt Is Su Cient For Gas6 Survival Functionmentioning

confidence: 99%

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

et al. 1999

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“…The Ras-Raf mitogen-activated protein kinase pathway and the phosphatidyl inositol 3 0 kinase and Akt pathway are the major signaling routes for the HER family, including EGFR. [3][4][5][6] These pathways control several important biologic processes, including cellular proliferation, angiogenesis and inhibition of apoptosis. 7 The interest in EGFR is further enhanced by the availability and FDA approval of specific EGFR tyrosine kinase inhibitors (eg, gefitinib).…”

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confidence: 99%

EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations

et al. 2005

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The human epidermal growth factor receptor (HER) family of receptor tyrosine kinase has been extensively studied in breast cancer; however, systematic studies of EGFR gene amplification and protein overexpression in breast carcinoma are lacking. We studied EGFR gene amplification by chromogenic in situ hybridization (CISH) and protein expression by immunohistochemistry in 175 breast carcinomas, using tissue microarrays. Tumors with 45 EGFR gene copies per nucleus were interpreted as positive for gene amplification. Protein overexpression was scored according to standardized criteria originally developed for HER-2. EGFR mRNA levels, as measured by Affymetrix U133 Gene Chip microarray hybridization, were available in 63 of these tumors. HER-2 gene amplification by fluorescence in situ hybridization (FISH) and protein overexpression by immunohistochemistry were also studied. EGFR gene amplification (copy number range: 7-18; median: 12) was detected in 11/175 (6%) tumors, and protein overexpression was found in 13/175 (7%) tumors. Of the 11 tumors, 10 (91%) with gene amplification also showed EGFR protein overexpression (2 þ or 3 þ by immunohistochemistry). The EGFR mRNA level, based on Affymetrix U133 chip hybridization data, was increased relative to other breast cancer samples in three of the five tumors showing gene amplification. Exons 19 and 21 of EGFR, the sites of hotspot mutations in lung adenocarcinomas, were screened in the 11 EGFR-amplified tumors but no mutations were found. Three of these 11 tumors also showed HER-2 overexpression and gene amplification. Approximately 6% of breast carcinomas show EGFR amplification with EGFR protein overexpression and may be candidates for trials of EGFR-targeted antibodies or small inhibitory molecules.

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Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction

Cited by 1,947 publications

References 17 publications

Specific TrkA survival signals interfere with different apoptotic pathways

Specific TrkA survival signals interfere with different apoptotic pathways

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations

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