Activin A receptor type 1 (ACVR1) (ALK2)

Activin A receptor type 1 (ACVR1), commonly referred to as ALK2, is a type I transmembrane serine/threonine kinase receptor belonging to the transforming growth factor-beta (TGF-beta) superfamily (UniProt Q04771). It plays a fundamental role in the bone morphogenetic protein (BMP) signaling pathway, which is essential for skeletal development, heart formation, and iron homeostasis (PubMed: 16633310). Under normal conditions, ALK2 mediates signals from BMP ligands to activate SMAD1/5/8 transcription factors. However, specific gain-of-function mutations, such as the R206H substitution, cause the receptor to become constitutively active and respond inappropriately to Activin A, leading to Fibrodysplasia Ossificans Progressiva (FOP) (Nature Genetics, 2006). This rare genetic condition is characterized by the progressive transformation of soft tissues into heterotopic bone, severely limiting mobility. Additionally, ACVR1 mutations are found in approximately 25% of cases of diffuse intrinsic pontine glioma (DIPG), a highly aggressive pediatric brain tumor (Nature Genetics, 2014). Consequently, ALK2 has emerged as a high-priority therapeutic target, with several small-molecule kinase inhibitors currently in clinical development to mitigate aberrant signaling in these life-threatening diseases (Journal of Bone and Mineral Research, 2020).

Other names

ALK-2ACTRIACVR1ASKR1TSRISerine/threonine-protein kinase receptor R1

Small molecule inhibition of the ALK2 kinase domain to prevent BMP-induced SMAD phosphorylation and subsequent gene expression, or competitive inhibition of the ATP-binding site within the intracellular kinase domain (PubMed: 25119035).