DLK1, long classified as a Notch inhibitor, actually does not bind Notch receptors at all. Researchers solved the crystal structure of DLK1 bound to ACVR2B—a TGF-β superfamily receptor—showing DLK1 mimics canonical ligands to competitively block myostatin signaling. This promotes myoblast differentiation and muscle growth. The apparent Notch connection is explained indirectly: DLK1 disrupts crosstalk between SMAD2/3 and the Notch intracellular domain (NICD), which are transcriptional partners. These findings reframe DLK1's role in muscle development and regeneration and open new therapeutic avenues for muscle wasting diseases and cancer.
