Platelet-derived growth factor-BB activates calcium/calmodulin-dependent and -independent mechanisms that mediate Akt phosphorylation in the neurofibromin-deficient human Schwann cell line ST88-14
| Autor: | Jason R. Farrer, Robert G. Farrer, George H. DeVries |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Neurofibromatosis 1
Calmodulin Becaplermin Schwann cell chemistry.chemical_element Calcium Biochemistry Calcium in biology Cell Line medicine Humans Receptors Platelet-Derived Growth Factor Enzyme Inhibitors Phosphorylation Molecular Biology Protein kinase B Egtazic Acid PI3K/AKT/mTOR pathway Chelating Agents Sulfonamides Neurofibromin 1 biology Cell Biology Proto-Oncogene Proteins c-sis Cell biology medicine.anatomical_structure chemistry biology.protein Cancer research Angiogenesis Inducing Agents Schwann Cells Proto-Oncogene Proteins c-akt Platelet-derived growth factor receptor Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 288(16) |
| ISSN: | 1083-351X |
| Popis: | Neurofibromatosis type 1-derived Schwann cells isolated from malignant peripheral nerve sheath tumors (MPNSTs) overexpress PDGF receptor-β and generate an aberrant intracellular calcium increase in response to PDGF-BB. Using the human MPNST Schwann cell line ST88-14, we demonstrate that, in addition to a transient phosphorylation of Akt, PDGF-BB stimulation produces an atypical sustained phosphorylation of Akt that is dependent on calcium and calmodulin (CaM). The sustained Akt phosphorylation did not occur in PDGF-BB-stimulated normal human Schwann cells or ST88-14 cells stimulated with stem cell factor, whose receptor is also overexpressed in ST88-14 cells. The sustained Akt phosphorylation induced by PDGF-BB was inhibited by pretreatment of the cells with either the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester (BAPTA-AM) or the CaM antagonist W7, whereas the transient portion was not inhibited. Akt also co-immunoprecipitated with CaM in a PDGF-BB-dependent manner, suggesting that direct interaction between Akt and CaM is involved in the sustained phosphorylation of Akt. Furthermore, we provide evidence that anti-apoptotic effects of PDGF-BB on serum-deprived ST88-14 cells can be inhibited by W7, implicating the PDGF-BB-induced activation of calcium/CaM in promoting cell survival, presumably through sustained Akt activation. We conclude that the activation of the calcium/CaM/Akt pathway resulting from stimulation of overexpressed PDGF receptor-β may contribute to the survival and tumorigenicity of MPNST cells. |
| Databáze: | OpenAIRE |
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