Significance A proper balance of Bmp and Tgf-ß/Nodal signaling is critical to ensure normal development and to prevent disease. Our studies identify a signaling cascade that functions to coordinately enhance Bmp signaling and reduce Nodal output by activating the ubiquitin ligase Nedd4l. Mutations in NEDD4L that lead to gain or loss of activity underlie congenital disorders and disease in humans. Understanding how Nedd4l activity is regulated in different contexts may provide insight into how mutations in NEDD4L result in human pathology.