Interaction and functional interplay between endoglin and ALK‐1, two components of the endothelial transforming growth factor‐β receptor complex

Abstract

Transforming growth factor-beta (TGF-beta) signaling in endothelial cells is able to modulate angiogenesis and vascular remodeling, although the underlying molecular mechanisms remain poorly understood. Endoglin and ALK-1 are components of the TGF-beta receptor complex, predominantly expressed in endothelial cells, and mutations in either endoglin or ALK-1 genes are responsible for the vascular dysplasia known as hereditary hemorrhagic telangiectasia. Here we find that the extracellular and cytoplasmic domains of the auxiliary TGF-beta receptor endoglin interact with ALK-1 (a type I TGF-beta receptor). In addition, endoglin potentiates TGF-beta/ALK1 signaling, with the extracellular domain of endoglin contributing to this functional cooperation between endoglin and ALK-1. By contrast, endoglin appears to interfere with TGF-beta/ALK-5 signaling. These results suggest that the functional association of endoglin with ALK-1 is critical for the endothelial responses to TGF-beta.

Endoglin inhibits prostate cancer motility via activation of the ALK2-Smad1 pathway

“…ALK2 has the highest sequence homology with ALK1 (ten Dijke et al, 1993). Further, ALK1 and ALK2 bind common ligands, interact with common RII subtypes, and mediate TGFb-associated function (Attisano et al, 1993;Ebner et al, 1993a, b;Miettinen et al, 1994;Ward et al, 2002;Goumans et al, 2003;Lebrin et al, 2004;Blanco et al, 2005;Desgrosellier et al, 2005). Using qRT-PCR, we found that ALK2 was expressed at high levels in PCa cells, and was over fourfold higher than ALK5 in both PC3 and PC3-M cells (Figure 5a).…”

“…However, the TGFb superfamily RI subtypes, ALK1 and ALK5, have kinase activity, and in endothelial cells have been shown to interact with ENG, resulting in augmented Smad signaling (Lebrin et al, 2004;Blanco et al, 2005). Utilizing quantitative reverse transcription (qRT)-PCR, ALK1 was undetectable in PC3 and PC3-M PCa cells (Figure 5a).…”

“…Canonical TGFb signaling minimally involves a heteromeric complex involving type II (RII) and type I (RI) serine/threonine kinase receptors, resulting in RI activation, which in turn phosphorylates/activates Smad transcription factors (Shi and Massague, 2003). ENG is considered an accessory TGFb superfamily receptor, and studies in endothelial cells suggest that it plays a vital role in regulating whether activin receptor-like kinase 1 (ALK1) versus ALK5 RI subtypes are activated in response to TGFb (Lebrin et al, 2004;Blanco et al, 2005;Pece-Barbara et al, 2005).…”

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

“…Endoglin serves as an auxiliary receptor for TGF‐β signaling and is predominantly expressed in proliferating ECs and in tissues undergoing angiogenesis 37. Endoglin promotes ALK1‐mediated Smad1/5 signaling and inhibits ALK5‐mediated Smad2/3 signaling, leading to enhanced EC proliferation and angiogenesis 17, 18, 38, 39. Inhibiting endoglin expression by specific knockdown inhibits TGF‐β/ALK1 signaling and potentiates TGF‐β/ALK5 signaling,40, 41 resulting in reduced proliferation 19.…”

“…Mutation or abnormal expression of endoglin is the etiological reason for hereditary hemorrhagic telangiectasia or preeclampsia, respectively, which are closely related to malformation and dysfunction of blood vessels 14, 15. Inhibiting endoglin by gene knockdown in ECs inhibits TGF‐β/ALK1 signaling, and potentiates TGF‐β/ALK5 signaling,16, 17, 18 resulting in reduced proliferation 17, 19. In contrary, endoglin overexpression suppresses TGF‐β/ALK5 signaling 20, 21.…”