ALK-2/ACVR1

Activin A receptor, type I (ACVR1), also known as ALK-2, is a bone morphogenetic protein (BMP) type I receptor. ACVR1 is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation. As a member of the BMP/TGFβ receptor family, the ACVR1 protein contains an extracellular N-terminal ligand-binding domain, a transmembrane (TM) domain, an intracellular glycine-serine-rich (GS) domain, and a protein kinase (PK) domain. The loop positioned in the helix-loop-helix of the GS domain contains the key residues responsible for ACVR1 activation upon phosphorylation. As a type I receptor, ACVR1 forms heterotetrameric receptor complexes with the type II receptors BMPR2, ACVR2A, and ACVR2B. Such complexes consist of two type I and two type II receptors. Upon binding of ligands to the heteromeric complexes, type II receptors transphosphorylate the GS domain of type I receptors. As a result, the kinase domain of type I receptors is activated and subsequently phosphorylates SMAD1/5/8 proteins that transduce the signal. ACVR1 is first described to bind to activin A, a member of the BMP/TGFβ family that usually triggers phosphorylation and activation of SMAD2/3 upon complex formation with type II receptors. Later, ACVR1 is also found to bind several BMPs with distinct affinities, triggering SMAD1/5/8 signalling. Besides canonical SMAD signalling, ACVR1 can activate non-canonical signalling pathways, such as p38 mitogen-activated protein kinases/MAPKs[1].
ACVR1 is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation. Moreover, ACVR1 has been extensively studied for its causal role in fibrodysplasia ossificans progressiva (FOP). ACVR1 is linked to different pathologies, including cardiac malformations and alterations in the reproductive system. More recently, ACVR1 has been experimentally validated as a cancer driver gene in diffuse intrinsic pontine glioma (DIPG)[1].