Neurofibromatosis type 1 (NF1) is a genetic disease caused by the loss of neurofibromin, which can lead to formation of highly invasive malignant peripheral nerve sheath tumors (MPNST). We characterized platelet-derived growth factor-beta (PDGF-beta) receptor expression levels and signal transduction pathways in NF1 MPNST cell lines and compared them with the expression of PDGF-beta receptors in normal human Schwann cells (nhSC). As examined by Western blotting, PDGF-beta receptor expression levels were similar in nhSC and NF1 MPNST cell lines. MAPK and Akt also were phosphorylated in both cell types to a similar degree in response to PDGF B chains (PDGF-BB). However, increased intracellular calcium (Ca2+) levels in response to PDGF-BB were observed only in the NF1 MPNST cell lines; nhSC did not show any increase in intracellular calcium when stimulated with PDGF-BB. The calcium response in NF1 MPNST cell lines was blocked with thapsigargin, suggesting that the PDGF-BB-stimulated increases in intracellular calcium originated in the internal compartment of the cell rather than reflecting influx of calcium from the extracellular compartment. Calmodulin kinase II (CAMKII) is phosphorylated in response to PDGF-BB in the NF1 MPNST cell lines, whereas no phosphorylation of CAMKII was observed in nhSCs. The decreased growth of NF1 MPNST cell lines after treatment with a CAMKII inhibitor is consistent with the view that aberrant activation of the calcium-signaling pathway by PDGF-BB contributes to the formation of MPNST in NF1 patients.