The EGF-like proteins DLK1 and DLK2 function as inhibitory non-canonical ligands of NOTCH1 receptor that modulate each other's activities

► EGF-like protein DLK2 interacts with DLK1/Pref-1 and the EGF 10-15 region of NOTCH1 receptor. ► DLK2 protein inhibits NOTCH activity. ► DLK proteins compete with JAGGED1 and DLL4 canonical ligands for NOTCH receptor binding. ► The co-expresion of DLK1 and DLK2 results in higher levels of NOTCH activity.