ALK1 signaling in development and disease: new paradigms

Abstract

Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels. In this review, we present an updated view of the mechanism of ALK1 signaling, put forth a unified hypothesis to explain the cellular missteps that lead to AVMs associated with ALK1 deficiency, and discuss emerging roles for ALK1 signaling in diseases beyond HHT.

Keywords: Activin A receptor like type 1; Angiogenesis; Arteriovenous malformation; Bone morphogenetic protein; Endoglin; Hereditary hemorrhagic telangiectasia.

Fig. 1

ALK1/ENG signaling in endothelial cells. Circulating ligands BMP9 (from liver) or BMP10 (from heart) bind to heterotetramers of two ALK1 receptors and two type II receptors. Ligand binding is facilitated by endoglin (ENG). The type II receptors phosphorylate (red star) ALK1, which phosphorylates SMAD1, SMAD5, or SMAD8. pSMADs bind SMAD4, enter the nucleus, and regulate gene expression. Through an unknown mechanism, ligand-mediated ALK1 activation may also help to maintain PTEN in an active state, thereby opposing PI3K and favoring AKT inactivation. ALK1 may also play a role in transcytosis of LDL from blood to the subendothelial space; this activity does not require ALK1 kinase activity, type II receptor, or endoglin. Blood flow distributes circulating ligands to ALK1 and imparts shear stress on the endothelium, which enhances the association between ALK1 and ENG

Fig. 2

Structural basis for ALK1 signaling. a BMP9 bound in the “open-arm” conformation to its prodomain [126]. The two monomers of BMP9 growth factor (GF) are cyan and dark blue; the two prodomain monomers are light green. b BMP9 bound to the endoglin orphan domain [144]. BMP9 is depicted as in a; the two bound endoglin orphan domains (Eng Orphan) are magenta; the endoglin zona pellucida domain (Eng ZP), which forms a disulfide-linked homodimer, is shown schematically in orange. c BMP9 bound to the endoglin orphan domain and ALK1. BMP9 and endoglin are depicted as in a and b, respectively; the two molecules of the ALK1 extracellular domain (ALK1 ECD) are red; the ALK1 kinase domains (ALK1 KD) are shown schematically in red. d BMP9 signaling complex with ALK1 and ActRIIB [111]. BMP9 and ALK1 are depicted as in a and c, respectively; the two molecules of the ActRIIB extracellular domain (ActRIIB ECD) are dark green; the ActRIIB kinase domains (ActRIIB KD) are shown schematically in dark green. In each panel, interactions shown in boxed region are highlighted in further detail below

Fig. 3

Two-step hypothesis for HHT-associated AVM development. When ALK1/endoglin signaling is active, arterial endothelial cells in distal segments polarize and migrate against the direction of blood flow. In the absence of ALK1/endoglin, these cells migrate in the direction of flow and increase distal vessel caliber adjacent to temporary arteriovenous connections or capillary beds (Step 1). Increased flow rate in downstream vessels then triggers an adaptive response to normalize shear stress, which may be achieved by maintenance and enlargement of a normally transient AV connection or selective enlargement of a capillary segment (Step 2)