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

Abstract

Background: Malignant peripheral nerve sheath tumor (MPNST) cells overexpress PDGF receptor-␤, which increases intracellular calcium when activated. Results: Calcium/calmodulin (CaM) is involved in sustained phosphorylation of Akt and promotion of cell survival in an MPNST cell line. Conclusion: MPNST cells evade normal cell death through CaM-dependent sustained activation of Akt. Significance: Activation of CaM by abnormally expressed growth factor receptors may contribute to NF1 tumor formation.

Dynamic Visualization of mTORC1 Activity in Living Cells

“…Upstream of mTORC1, Akt activity appeared to be largely dependent on calcium as well. We show that intracellular calcium chelation attenuated the phosphorylation of Akt S473, but had no effect on the phosphorylation of Akt T308, which is consistent with previous findings (Farrer et al, 2010; Razmara et al, 2013). It has been shown that the S473 phosphorylation is less critical for regulating Akt activity towards TSC2 (Jacinto et al, 2006), which may explain the reduced effect of chelation of intracellular calcium onmTORC1 activity (40% reduction) compared with the effect on Akt activity (70% reduction).…”

Eukaryotic elongation factor 2 kinase controls proliferation and migration of vascular smooth muscle cells

“…inhibits proliferation (Coen et al 2013) and migration (Tada et al 2008) of SMCs also support the present results. Several reports showed that PDGF-BB increased intracellular Ca 2+ concentration through induction of diacylglycerol and inositol 1,4,5-trisphosphate via acti-vation of phospholipase C, which leads to the activation of CaM-dependent signals including Akt and ERK (Rhee 2001, Egan et al 2005, Farrer et al 2013. It is thus suggested that PDGF-BB-induced CaM activation via intracellular Ca 2+ increase may mediate the eEF2Kregulated signals in this study.…”

“…, Farrer et al . ). It is thus suggested that PDGF‐BB‐induced CaM activation via intracellular Ca 2+ increase may mediate the eEF2K‐regulated signals in this study.…”

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

“…PI3K–AKT signalling downstream of Rras2 has a role in the initiation of neurofibromas 92 ; activation of the PI3K pathway through loss of Pten in mice promotes the transformation of Nf1 -driven neurofibromas to MPNSTs 93 . Sustained activation of AKT in MPNST cells requires calcium and calmodulin 94 . On the basis of these results, it will be important to consider cell type-specific neurofibromin–RAS effector pathways when attempting to identify therapeutic targets.…”