Collectively, these findings demonstrate that like NRG1β, extracellular ASPN induces HER2 and HER3 activation and downstream signaling pathways, including PI3K/AKT, MAPK/ERK, and calcium signaling, in prostate cancer cells; however, ASPN-induced signaling and transcriptional changes demonstrate intensity, duration, and target repertoire differences compared with NRG1β. Here, AKT1 is linked to prostate cancer.