ACVR1

ACVR1, also known as activin receptor-like kinase 2 (ALK2), is a type I serine/threonine kinase receptor that participates in the bone morphogenetic protein (BMP) signaling pathway. The ACVR1 gene encodes the receptor in humans and is expressed in multiple tissues where BMP signaling influences development and tissue homeostasis. In the signaling complex, ACVR1 partners with type II BMP receptors (such as ACVR2A, ACVR2B, or BMPR2). Upon ligand binding, type II receptors phosphorylate ACVR1, activating its kinase domain and triggering downstream signaling.

Activation of ACVR1 leads to phosphorylation of SMAD1/5/8, which form a complex with SMAD4 and translocate to the nucleus to regulate transcription of target genes involved in osteogenesis, chondrogenesis, vascular development, and organogenesis. The pathway also interacts with non-SMAD signaling routes, contributing to a broader network of cellular responses.

ACVR1 is expressed broadly and plays a critical role in embryonic development and tissue formation, with particular importance in bone, cartilage, and vascular systems. Dysregulation of ACVR1 signaling can have significant developmental consequences and tissue remodeling effects.

Mutations in ACVR1 cause fibrodysplasia ossificans progressiva (FOP), a rare autosomal dominant disorder characterized by episodic heterotopic ossification—bone formation in soft tissues. The most common mutation is R206H, a gain-of-function change that enhances BMP pathway activity; some mutations may alter ligand responsiveness or signaling dynamics. In FOP, abnormal ACVR1 signaling leads to progressive, disabling ectopic bone formation.

Because of its central role in BMP signaling and skeletal biology, ACVR1 is a focus of research aimed at bone regeneration and therapies to modulate abnormal ossification, while aiming to minimize effects on normal development and tissue maintenance.