Activin receptor type-1 (ACVR1) (ALK2)

Activin receptor type-1 (ACVR1), commonly known as ALK2, is a type I transmembrane serine/threonine kinase receptor within the transforming growth factor-beta (TGF-β) superfamily [UniProt, PubMed]. It plays a pivotal role in the bone morphogenetic protein (BMP) signaling pathway, forming heterotetrameric complexes with type II receptors to phosphorylate SMAD1/5/8 proteins, which then translocate to the nucleus to regulate genes involved in bone formation and cellular differentiation [PubMed, PMC]. Beyond skeletal development, ACVR1 is involved in heart development and the regulation of systemic iron levels via hepcidin expression [PubMed, PMC]. The receptor is clinically significant due to gain-of-function mutations, most notably the R206H variant, which cause fibrodysplasia ossificans progressiva (FOP), a condition characterized by the transformation of soft tissues into bone [Wikipedia, MedlinePlus]. Additionally, ACVR1 mutations are found in approximately 25% of cases of diffuse intrinsic pontine glioma (DIPG), a highly aggressive pediatric brain tumor [PubMed, MedlinePlus]. Current drug development efforts focus on selective small molecule kinase inhibitors to block pathological ALK2 signaling while sparing physiological BMP functions [PubMed, PMC].

Other names

Activin receptor-like kinase 2ACVR1ACTRIACVR1AACVRLK2SKR1TSRIFOP

Small molecule inhibition of the intracellular kinase domain, preventing phosphorylation of SMAD1/5/8 proteins and subsequent gene transcription.