Engineering NGF receptors to bind Grb2 directly uncovers differences in signaling ability between Grb2- and ShcA-binding sites

► The Tyr-Tyr-Asn motif supports activation of the Ras-Erk pathway. ► Grb2- and ShcA-binding sites display somewhat different abilities to activate the Ras-Erk pathway. ► Grb2- and ShcA-binding sites have similar abilities to activate the PI 3-kinase-Akt pathway. ► NGF receptor-dependent activation of the PI 3-kinase-Akt pathway depends on the Tyr 490. ► Grb2- and ShcA-binding sites display dramatically different abilities to turn on DNA synthesis.