AbstractMalignant 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) β isoforms, which promote Schwann cell migration during development, and NRG‐1α isoforms, whose effects on Schwann cells are poorly understood. Hypothesizing that NRG‐1β and/or NRG‐1α promote MPNST invasion, we found that NRG‐1β 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 β1‐integrin and coimmunoprecipitated with β1‐integrin. NRG‐1β 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‐1β‐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‐1α had no effect on the migration and invasion of some MPNST lines and inhibited the migration of others. While NRG‐1β potently and persistently activated Erk 1/2, SAPK/JNK, Akt and Src family kinases, NRG‐1α did not activate Akt and activated these other kinases with kinetics distinct from those evident in NRG‐1β‐stimulated cells. These findings suggest that NRG‐1β enhances MPNST migration and that NRG‐1β and NRG‐1α differentially modulate this process. © 2009 Wiley‐Liss, Inc.