FIGURE 1.

Hereditary hemorrhagic telangiectasia is a genetically heterogeneous disorder caused by mutations in several genes in the TGF-β/BMP signaling pathway. BMP9 binds to specific type I (R-I; namely ALK1) and type II (R-II) cell surface receptors that exhibit serine/threonine kinase activity, as well as to the auxiliary receptor endoglin. Upon ligand binding, the R-II transphosphorylates ALK1 (R-I), which then propagates the signal by phosphorylating receptor-regulated Smads (R-Smads) Smad1/5/8. Once phosphorylated, R-Smads form heteromeric complexes with Smad4 and translocate into the nucleus where they regulate transcriptional activity of target genes, including Id1. Endoglin, ALK1, BMP9, and Smad4 proteins are encoded by ENG, ACVRL1, GDF2, and SMAD4, whose pathogenic mutations give rise to HHT and JP/HHT, respectively. This figure was adapted from (Fernández-L et al., 2006).