Interleukin-3-Induced Phosphorylation of BAD Through the Protein Kinase Akt

Peso, Luis del; González-Garcı́a, Maribel; Page, Carmen; Herrera, Román; Núñez, Gabriel

doi:10.1126/science.278.5338.687

Cited by 1,996 publications

(425 citation statements)

References 22 publications

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“…Here we show that a similar pathway seems to be activated by Gas6 in serum starved NIH3T3 cells. Accordingly Gas6-induced Bad phosphorylation should create a binding site for the ubiquitously expressed family of proteins 14-3-3, thus delivering Bcl-2 and Bcl-X L antiapoptotic activities (Del Peso et al, 1997;Zha et al, 1996). However since Bad is expressed in a limited range of tissues and cell lines (Downward, 1998b) it is unlikely that this is the only mechanism by which a survival factor, such as Gas6, can prevent cell death.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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“…which in turn phosphorylates the BCL-2-related protein BAD. [42][43][44][45] If phosphorylated by AKT BAD can bind to 14-3-3 proteins and its proapoptotic potential is blocked 46 (Figure 2). Thus, the CRKL/PI3-K interaction may be quite important in cell viability signaling.…”

Section: Figurementioning

confidence: 99%

Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells

Sattler

Salgia

1998

Leukemia

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CRKL is a 39 kDa adapter protein, originally cloned in proximity to the BCR gene on chromosome 22, which has a key regulatory role in hematopoietic cells. CRKL has one SH2 and two SH3 domains, with 60% homology to CRK II. CRKL is a prominent substrate of the BCR/ABL oncoprotein in chronic myelogenous leukemia and binds to both BCR/ABL and c-ABL. CRKL has been shown to be tryosine phosphorylated in response to normal hematopoietic growth factor receptor signaling with ligands such as thrombopoietin, erythropoietin or steel factor. Additionally, CRKL is involved in signaling initiated by crosslinking of ␤ integrins, and B cell or T cell receptors. Structurally, the amino-terminal SH3 domain of CRKL has been shown to bind proteins such as C3G, SOS, PI3-K, c-ABL or BCR/ABL. The SH2 domain of CRKL can bind to tyrosine phosphorylated proteins such as CBL, HEF1, CAS or paxillin. This review summarizes the current knowledge on the function of this unique adapter protein in normal hematopoietic and leukemic cell signaling.

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“…Its activation has been implicated in a number of human cancers by promoting proliferation and inhibiting apoptosis caused by various death stimuli (Del Peso et al, 1997;Franke et al, 1997;Kulik et al, 1997). AKT is activated in response to survival signals from growth factors or cytokines via mechanisms involving PI3-K and PDK-1 (Alessi et al, 1997;Franke et al, 1997;Kulik et al, 1997;Bellacosa et al, 1998).…”

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confidence: 99%

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

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Activation of kinases signalling pathways contributes to various malignant phenotypes in human cancers, including breast tumour. To examine the possible activation of these signalling molecules, we examined the phosphorylation status in 12 protein kinases and transcription factors in normal primary human mammary epithelial cells, telomerase-immortalised human breast epithelial cell line, and two breast cancer lines, MDA-MB-468 and MCF-7, using Kinexus phosphorylated protein screening assays. The phosphorylation of FAK, mTOR, p70S6K, and PDK-1 were elevated in both breast cancer cell lines, whereas the phosphorylation of AKT, EGFR, ErbB2/ Her2, PDGFR, Shc, and Stat3 were elevated in only one breast cancer line compared to normal primary mammary epithelial cells and telomerase-immortalised breast epithelial cells. The same findings were confirmed by Western blotting and by kinase assays. We further substantiated the phosphorylation status of these molecules in tissue microarray slides containing 89 invasive breast cancer tissues as well as six normal mammary tissues with immunohistochemistry staining using phospho-specific antibodies. Consistent findings were obtained as greater than 70% of invasive breast carcinomas expressed moderate to high levels of phosphorylated PDK-1, AKT, p70S6K, and EGFR. In sharp contrast, phosphorylation of the same proteins was nearly undetectable or was at low levels in normal mammary tissues under the same assay. Elevated phosphorylation of PDK-1, AKT, mTOR, p70S6K, S6, EGFR, and Stat3 were highly associated with invasive breast tumours (Po0.05). Taken together, our results suggest that activation of these kinase pathways by phosphorylation may in part account for molecular pathogenesis of human breast carcinoma. Particularly, moderate to high level of PDK-1 phosphorylation was found in 86% of high-grade metastasised breast tumours. This is the first report demonstrating phosphorylation of PDK-1 is frequently elevated in breast cancer with concomitantly increased phosphorylation of downstream kinases, including AKT, mTOR, p70S6K, S6, and Stat3. This finding thus suggested PDK-1 may promote oncogenesis in part through the activation of AKT and p70S6K and rationalised that PDK-1 as well as downstream components of PDK-1 signalling pathway may be promising therapeutic targets to treat breast cancer. Breast cancer remains to be a major cause of death in women worldwide, despite improvements in cancer prevention, early detection, treatment, and understanding the molecular pathogenesis. It hence demands an urgent need to unveil the exact mechanism of oncogenesis and tumour progression, which may prelude the development of new strategies for treatment. Breast carcinoma emerges through multistep processes progressing from hyperplasia to premalignant change, in situ carcinoma, invasion, and distal metastasis, in concomitant with gain of oncogenic activities and loss of tumour suppressor gene functions.Protein kinases have been implicated in playing crucial roles in regulating cell growth, met...

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Interleukin-3-Induced Phosphorylation of BAD Through the Protein Kinase Akt

Cited by 1,996 publications

References 22 publications

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

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

Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

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