In keeping with our demonstration that MPNST cells express erbB4 splice variants containing the Cyt1 domain, Erbb4-null MPNST cells demonstrated altered phosphorylation of Akt and key Akt targets such as, eNOS, ribosomal p70S6 kinase (S6K) and ribosomal p90S6 kinase (RSK1/2/3); the phosphorylation of these molecules was decreased in Cre-treated Erbb4 ablated tumor cells, indicating that erbB4 positively regulates the PI3K/Akt/mTOR signaling cascades in MPNST cells. Here, ERBB4 is linked to malignant peripheral nerve sheath tumor.