Novel biochemical pathways of endoglin in vascular cell physiology

Abstract

The broad role of the transforming growth factor beta (TGFbeta) signaling pathway in vascular development, homeostasis, and repair is well appreciated. Endoglin is emerging as a novel, complex, and poorly understood regulatory component of the TGFbeta receptor complex, whose importance is underscored by its recognition as the site of mutations causing hereditary hemorrhagic telangiectasia (HHT) [McAllister et al., 1994]. Extensive analyses of endoglin function in normal developmental mouse models [Bourdeau et al., 1999; Li et al., 1999; Arthur et al., 2000] and in HHT animal models [Bourdeau et al., 2000; Torsney et al., 2003] exemplify the importance of understanding endoglin's biochemical functions. However, novel mechanisms underlying the regulation of these pathways continue to emerge. These mechanisms include modification of TGFbeta receptor signaling at the ligand and receptor activation level, direct effects of endoglin on cell adhesion and migration, and emerging roles for endoglin in the determination of stem cell fate and tissue patterning. The purpose of this review is to highlight the cellular and molecular studies that underscore the central role of endoglin in vascular development and disease.

Fig. 1

Atomic model and electron microscopy of endoglin. A: The predicted atomic model was generated as described [Llorca et al., 2007]. The amino acid numbers corresponding to the approximate location of disordered regions connecting globular domains are indicated. The molecule is colored according to the three types of domains defined. The orphan domain encompasses amino acid residues Glu26-Ile359 (red), whereas the ZP domain is contained within the fragment Gln360-Gly586. The ZP-N and ZP-C sub-domains are colored in yellow and blue, respectively. B: Fitting of the atomic model into the electron microscopy density map of soluble endoglin. Side (i) and top (ii) views of the electron microscopy density containing the fitted monomer are shown. The fitting of dimeric endoglin based on the atomic prediction of the monomer is also included (iii). C: Cartoon model for the domain organization of endoglin within the dimer. Adapted from Llorca et al. [2007].

Fig. 2

Hypothetical model for endoglin in TGFβ/ALK-1 and TGFβ/ALK-5 pathways. Endoglin extracellular and cytoplasmic domains interact with ALK1 [Blanco et al., 2005] and ALK5 [Guerrero-Esteo et al., 2002], as indicated with brown arrows. Endoglin plays a crucial role on TGFβ signaling by potentiating ALK1/Smad1, ALK5/Smad2 (green arrows), and inhibiting ALK5/Smad3 (red arrow) pathways which lead to the regulation of Id1 [Lebrin et al., 2004; Blanco et al., 2005], eNOS [Santibanez et al., 2007], and PAI-1 genes [Letamendia et al., 1998; Guerrero-Esteo et al., 1999], respectively. The involvement of TβRII and TGFβ has been omitted for simplification. Adapted from [Blanco et al., 2005].

Fig. 3

Hypothetical model for endoglin cytosolic domain-mediated functions. A: Endoglin cytosolic domain is constitutively phosphorylated [Lastres et al., 1994] by serine and threonine kinases, including the TβRII, ALK1, and ALK5 receptors [Guerrero-Esteo et al., 2002; Koleva et al., 2006]. This endoglin phosphorylation potentially regulates multiple protein–protein interactions involving the cytosolic domain. B: Endoglin interacts with the cytosolic proteins zyxin, ZRP-1, Tctex2b, and beta-arrestin [Conley et al., 2004; Sanz-Rodriguez et al., 2004; Koleva et al., 2006; Meng et al., 2006; Lee and Blobe, 2007]. These interactions likely mediate downstream functions, including F-actin dynamics, focal adhesion composition, and protein transport via endocytic vesicles. In turn, these processes regulate cell adhesion, migration, and proliferation.