# Molecular mechanism of Activin receptor inhibition by DLK1

## TL;DR

This study reveals that DLK1 inhibits Activin signaling by binding to ACVR2B, not by affecting Notch signaling as previously thought.

## Contribution

The paper identifies DLK1 as a direct inhibitor of Activin receptor signaling through structural and functional analysis.

## Key findings

- DLK1 binds to ACVR2B and mimics TGF-β ligands to block Activin signaling.
- DLK1 promotes myoblast differentiation by antagonizing Myostatin-ACVR2B signaling.
- DLK1 inhibits SMAD2/3-NICD colocalization, disrupting Notch and TGF-β crosstalk.

## Abstract

Delta-like non-canonical Notch ligand 1 (DLK1) influences myogenesis, adipogenesis, and other aspects of human development through a process that is largely attributed to the downregulation of Notch signaling. Here, we show that DLK1 does not bind to Notch receptors or affect ligand-mediated Notch activation, but instead engages the TGF-β superfamily member Activin receptor type 2B (ACVR2B). The crystal structure of the DLK1-ACVR2B complex reveals that DLK1 mimics the binding mode of canonical TGF-β ligands to compete for access to ACVR2B. In functional assays, DLK1 antagonizes Myostatin-ACVR2B signaling to promote myoblast differentiation, rationalizing a mechanism for the role of DLK1 in muscle development and regeneration. Crosstalk between Notch and TGF-β is mediated by interactions between the transcriptional regulators SMAD2/3 and the Notch intracellular domain (NICD), and DLK1 inhibits SMAD2/3-NICD colocalization. These findings indicate that DLK1 acts directly on ACVR2B to inhibit signaling, whereas the observed effects on Notch may be an indirect result of DLK1 interference with NICD-SMAD complex formation.

Current models suggest that DLK1 is an inhibitory ligand in the Notch pathway. Here, the authors show that DLK1 does not interact with Notch receptors, instead blocking Activin signaling via an interaction with Activin receptor type-2B.