Concomitant activation of the PI3K-Akt and the Ras-ERK signaling pathways is essential for transformation by the V-SEA tyrosine kinase oncogene

Agazie, Yehenew M.; Ischenko, Irene; Hayman, Michael J.

doi:10.1038/sj.onc.1205115

Cited by 34 publications

(39 citation statements)

References 56 publications

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“…On top of this, we observed that the effect of the LY compound was more drastic than the PD compound, which may indicate the relative contribution of each pathway. In our previous report (Agazie et al, 2002), we demonstrated that transformation by the V-SEA tyrosine kinase oncogene requires the in-tandem functioning of both these pathways. Thus, our findings with K/ E-FR3 provide evidence that oncogenic RTKs may utilize a common mechanism in transforming cells.…”

Section: Discussionmentioning

confidence: 82%

“…After 14 days of incubation, plates were examined for formation of foci under a microscope. To isolate clones of K/E-FR3-expressing cells, several foci were picked, grown separately and then seeded into soft agar as described previously (Agazie et al, 2002). After incubation for 6 days, separate colonies were picked and expanded.…”

Section: Production Of Recombinant Retrovirus Expressing Wt-or C459s-mentioning

confidence: 99%

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The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3

et al. 2003

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Receptor tyrosine kinases (RTKs) such as the fibroblast growth factor receptor (FGFR) and the epidermal growth factor receptor are overexpressed in a variety of cancers. In addition to overexpression, the FGFRs are found mutated in some cancers. The Src homology 2 domaincontaining phosphotyrosine phosphatase (SHP2) is a critical mediator of RTK signaling, but its role in oncogenic RTK-induced cell transformation and cancer development is largely unknown. In the current report, we demonstrate that constitutively activated FGFR3 (K/E-FR3) transforms NIH-3T3 cells, and that SHP2 is a critical mediator of this transformation. Infection of K/E-FR3-transformed 3T3 cells with a retrovirus carrying a dominant-negative mutant of SHP2 (C/S-SHP2) retarded cell growth, reversed the transformation phenotype and inhibited focus-forming ability. Furthermore, treatment of K/E-FR3-transformed NIH-3T3 cells with PD98059 or LY294002, specific inhibitors of MEK and PI3K, respectively, inhibited focus formation. Biochemical analysis showed that K/E-FR3 activates the Ras-ERK and the PI3K signaling pathways, and that the C/S SHP2 mutant suppressed this effect via competitive displacement of interaction of the endogenous SHP2 with FRS2. However, the C/S SHP2 protein did not show any effect on receptor autophosphorylation, FRS2 tyrosine phosphorylation or interaction of Grb2 with K/E-FR3 or FRS2. Together, the results show that K/E-FR3 is transforming and that the Ras-ERK and the PI3K-Akt signaling pathways, which are positively regulated by SHP2, are important for K/E-FR3-induced transformation.

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Section: Discussionmentioning

confidence: 82%

Section: Production Of Recombinant Retrovirus Expressing Wt-or C459s-mentioning

confidence: 99%

The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3

et al. 2003

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“…Phosphatidylinositol-3-kinase (PI3K) has also been shown to interact directly with the Ron receptor (7,29) resulting in the downstream activation of AKT and increased cell proliferation (30,31). In Fig.…”

Section: Resultsmentioning

confidence: 99%

Ron Receptor Signaling Augments Mammary Tumor Formation and Metastasis in a Murine Model of Breast Cancer

Peace¹,

Toney-Earley²,

Collins

et al. 2005

Cancer Research

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The tyrosine kinase receptor Ron has been implicated in several types of cancer, including overexpression in human breast cancer. This is the first report describing the effect of Ron signaling on tumorigenesis and metastasis in a mouse model of breast cancer. Mice with a targeted deletion of the Ron tyrosine kinase signaling domain (TKÀ/À) were crossed to mice expressing the polyoma virus middle T antigen (pMT) under the control of the mouse mammary tumor virus promoter. Both pMT-expressing wild-type control (pMT+/À TK+/+) and pMT+/À TKÀ/À mice developed mammary tumors and lung metastases. However, a significant decrease in mammary tumor initiation and growth was found in the pMT+/À TKÀ/À mice compared with controls. An examination of mammary tumors showed that there was a significant decrease in microvessel density, significantly decreased cellular proliferation, and a significant increase in terminal deoxynucleotidyl transferase-mediated nick end labelingpositive staining in mammary tumor cells from the pMT+/À TKÀ/À mice compared with the pMT+/À TK+/+ mice. Biochemical analyses on mammary tumor lysates showed that whereas both the pMT-expressing TK+/+ and TKÀ/À tumors have increased Ron expression compared with normal mammary glands, the pMT-expressing TKÀ/À tumors have deficits in mitogen-activated protein kinase and AKT activation. These results indicate that Ron signaling synergizes with pMT signaling to induce mammary tumor formation, growth, and metastasis. This effect may be mediated in part through the regulation of angiogenesis and through proliferative and cell survival pathways regulated by mitogen-activated protein kinase and AKT. (Cancer Res 2005; 65(4): 1285-93)

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“…The ability of cells to form colonies in soft agar was performed as previously described. 38 Briefly, 6 cm cell culture plates were overlaid with 0.3% agar in the growth medium and allowed to solidify. Cells were suspended in 3 ml of growth medium and mixed with melted agar to a final concentration of 0.3% and immediately poured onto the agar overlay.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells

Agazie

2008

Cell Death Differ

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The Src homology phosphotyrosyl phosphatase 2 (SHP2) is an essential transducer of mitogenic and cell survival signaling in the epidermal growth factor receptor (EGFR) signaling pathway. However, the role of SHP2 in aberrant EGFR and human EGFR2 (HER2) signaling and cancer, particularly in breast cancer, has not been investigated. Here, we report that SHP2 is required for mitogenic and cell survival signaling and for sustaining the transformation phenotypes of breast cancer cell lines that overexpress EGFR and HER2. Inhibition of SHP2 suppressed EGF-induced activation of the Ras-ERK and the phosphatidylinositol 3 kinase-Akt signaling pathways, abolished anchorage-independent growth, induced epithelial cell morphology and led to reversion to a normal breast epithelial phenotype. Furthermore, inhibition of SHP2 led to upregulation of E-cadherin (epithelial marker) and downregulation of fibronectin and vimentin (mesenchymal markers). These results indicate that SHP2 promotes breast cancer cell phenotypes by positively modulating mitogenic and cell survival signaling, by suppressing E-cadherin expression which is known to play a tumor suppressor role and by sustaining the mesenchymal state as evidenced by the positive impact on fibronectin and vimentin expression. Therefore, SHP2 promotes epithelial to mesenchymal transition, whereas its inhibition leads to mesenchymal to epithelial transition. On the basis of these premises, we propose that interference with SHP2 function might help treat breast cancer.

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Concomitant activation of the PI3K-Akt and the Ras-ERK signaling pathways is essential for transformation by the V-SEA tyrosine kinase oncogene

Cited by 34 publications

References 56 publications

The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3

The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3

Ron Receptor Signaling Augments Mammary Tumor Formation and Metastasis in a Murine Model of Breast Cancer

Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells

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