ALK1

ALK1, short for activin receptor-like kinase 1, is a type I serine/threonine kinase receptor in the TGF-β/BMP signaling family. The ACVRL1 gene encodes ALK1 and is expressed predominantly in vascular endothelial cells, where it helps regulate angiogenesis and vascular remodeling. ALK1 responds to bone morphogenetic proteins BMP9 and BMP10, forming a receptor complex with type II receptors and the co-receptor endoglin (ENG) to propagate signaling.

In endothelial cells, ligand binding leads to phosphorylation of SMAD1/5/8 by ALK1. These receptor-regulated SMADs pair with SMAD4 and translocate to the nucleus to regulate target gene expression involved in vascular maturation and quiescence. Endoglin modulates ALK1 signaling, influencing responsiveness to shear stress and angiogenic cues, and cross-talk exists with other TGF-β/BMP pathways that govern vessel formation.

Mutations in ACVRL1 cause hereditary hemorrhagic telangiectasia type 2 (HHT2), an autosomal dominant vascular disorder characterized by epistaxis, mucocutaneous telangiectasias, and arteriovenous malformations (AVMs) in lungs, liver, brain, and other organs. The HHT2 phenotype reflects impaired ALK1 signaling and defective vascular stabilization. Mutation types include missense, nonsense, frameshift, and splice-site changes, with variable expressivity and penetrance.

Biological and clinical research continues to explore ALK1’s role in vascular development, its interaction with ENG and BMP9/10, and potential therapeutic strategies that target the ALK1 signaling axis for HHT and related vascular disorders.