ALK1

Transforming Growth Factor beta (TGFβ) superfamily ligands exert their biological activities via binding to heteromeric receptor complexes of two types (I and II) ofserine/threonine kinases. Type II receptors are constitutively active kinases that phosphorylate-type I receptors upon ligand binding. In turn, activated type I kinases phosphorylate downstream signaling molecules including the various smads. Transmembrane proteoglycans, including the type III receptor (betaglycan) and endoglin, can bind and present some of the TGFβ superfamily ligands to type I and II receptor complexes and enhance their cellular responses. Seven type I receptors (also termed activin receptor-like kinase (ALK)) and five type II receptors have been isolated from mammals. ALK2, 3, 4, 5, and 6 are also known as Activin R1A, BMPR1A, Activin R1B, TGFβ R1, and BMPR1B, respectively, reflecting their ligand preferences. Evidence suggests that TGFβ1, TGFβ3 and an unknown ligand present in serum can activate chimeric ALK1. ALK1 shares with other type I receptors a cysteine-rich domain with conserved cysteine spacing in the extracellular region, and a glycineand serine-rich domain (the GS domain) preceding the kinase domain. ALK1 is expressed highly in endothelial cells and other highly vascularized tissues. The expression patterns of ALK1 parallels that of endoglin. Mutations in ALK1 as well as in endoglin are associated with hereditary hemorrhagic telangiectasia (HHT), suggesting a critical role for ALK 1 in the control of blood vessel development or repair. Human and mouse ALK1 share approximately 71% amino acid sequence identity in their extracellular regions.