Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy associated with neurofibromatosis Type 1 (NF1). These Schwann cell lineage-derived sarcomas aggressively invade adjacent nerve and soft tissue, frequently precluding surgical resection. Little is known regarding the mechanisms underlying this invasive behavior. We have shown that MPNSTs express neuregulin-1 (NRG-1) beta isoforms, which promote Schwann cell migration during development, and NRG-1 alpha isoforms, whose effects on Schwann cells are poorly understood. Hypothesizing that NRG-1 beta and/or NRG-1 alpha promote MPNST invasion, we found that NRG-1 beta promoted MPNST migration in a substrate-specific manner, markedly enhancing migration on laminin but not on collagen type I or fibronectin. The NRG-1 receptors erbB3 and erbB4 were present in MPNST invadopodia (processes mediating invasion), partially colocalized with focal adhesion kinase and the laminin receptor beta(1)-integrin and coimmunoprecipitated with beta(1)-integrin. NRG-1 beta stimulated human and murine MPNST cell migration and invasion in a concentration-dependent manner in three-dimensional migration assays, acting as a chemotactic factor. Both baseline and NRG-1 beta-induced migration were erbB-dependent and required the action of MEK 1/2, SAPK/JNK, PI-3 kinase, Src family kinases and ROCK-I/II. In contrast, NRG-1 alpha had no effect on the migration and invasion of some MPNST lines and inhibited the migration of others. While NRG-1 beta potently and persistently activated Erk 1/2, SAPK/JNK, Akt and Src family kinases, NRG-1 alpha did not activate Akt and activated these other kinases with kinetics distinct from those evident in NRG-1 beta-stimulated cells. These findings suggest that NRG-1 beta enhances MPNST migration and that NRG-1 beta and NRG-1 alpha differentially modulate this process.