Neuregulin‐1β and neuregulin‐1α differentially affect the migration and invasion of malignant peripheral nerve sheath tumor cells

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy associated with neurofibromatosis type 1 (NF1), aggressively invade adjacent nerve and soft tissue. MPNSTs express neuregulin‐1 (NRG‐1) β, which promotes Schwann cell migration during development, and NRG‐1α, whose effects on Schwann cells are unknown. We hypothesized that NRG‐1β and/or NRG‐1α promote MPNST invasion. We found that NRG‐1β promoted MPNST migration in a substrate‐specific manner. The NRG‐1 receptors erbB4 and erbB3 were present in MPNSTs, 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 in a concentration‐dependent manner, acting as a chemotactic factor. Both baseline and NRG‐1β induced migration and invasion were erbB‐dependent and required the action of MEK 1/2, SAPK/JNK, PI3K, Src kinases and ROCK‐I/II. In contrast, NRG‐1α had no effect on the migration of some lines and inhibited the migration of others. While NRG‐1β activated Erk 1/2, SAPK/JNK, Akt and Src family kinases, NRG‐1α did not activate Akt and activated other kinases in a kinetically distinct manner. These findings suggest that NRG‐1β enhances MPNST migration and that NRG‐1β and NRG‐1α differentially modulate this process. Supported by NIH grant NS048353, CA122804 and NIH Blueprint grant NS57098.