Activin receptor-like kinase 2 and Smad6 regulate epithelial–mesenchymal transformation during cardiac valve formation

Abstract

Epithelial-mesenchymal transformation (EMT) occurs during both development and tumorigenesis. Transforming growth factor beta (TGFbeta) ligands signal EMT in the atrioventricular (AV) cushion of the developing heart, a critical step in valve formation. TGFbeta signals through a complex of type I and type II receptors. Several type I receptors exist although activin receptor-like kinase (ALK) 5 mediates the majority of TGFbeta signaling. Here, we demonstrate that ALK2 is sufficient to induce EMT in the heart. Both ALK2 and ALK5 are expressed throughout the heart with ALK2 expressed abundantly in endocardial cells of the outflow tract (OFT), ventricle, and AV cushion. Misexpression of constitutively active (ca) ALK2 in non-transforming ventricular endocardial cells induced EMT, while caALK5 did not, thus demonstrating that ALK2 activity alone is sufficient to stimulate EMT. Smad6, an inhibitor of Smad signaling downstream of ALK2, but not ALK5, inhibited EMT in AV cushion endocardial cells. These data suggest that ALK2 activation may stimulate EMT in the AV cushion and that Smad6 may act downstream of ALK2 to negatively regulate EMT.

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).…”

Identification of Progenitor Cells That Contribute to Heterotopic Skeletogenesis

“…In addition, BMPs have the ability to redirect the differentiation of connective tissue progenitor cells [33][34][35] to orchestrate an endothelial-to-mesenchymal transition in these cells, often through inflammatory cell intermediates [36][37][38][39][40] . Interestingly, misexpression of constitutively active ACVR1/ALK2, a BMP type-I receptor and the gene mutated in fibrodysplasia ossificans progressiva, is sufficient to stimulate an endothelialto-mesenchymal transformation in endothelial cells of the heart 41 . Notably, BMP4, as well as hypoxia and inflammatory cytokines-conditions and factors that are present in the earliest preosseous lesions of heterotopic ossification-upregulate Tie2 in endothelial cells, which contributes to the angiogenic response 39,42 .…”

Transforming growth factor‐β stimulates epithelial–mesenchymal transformation in the proepicardium

“…TBRII can also interact with another type I receptor, ALK2 (Ebner et al, 1993). ALK2 has been implicated in mediating TGF␤-stimulated EMT in AV cushion endocardial cells (Lai et al, 2000;Desgrosellier et al, 2005) and cultured NMuMG breast cancer epithelial cells (Miettinen et al, 1994). These data suggest that TGF␤ may signal by the activation of ALK5 or ALK2.…”

“…Activity of Smad6 protein produced by viral infection was determined by its ability to decrease Smad1-dependent alkaline phosphatase activity in C3H10T1/2 cells (McDonnell et al, 2001). Data regarding activity of viral constructs have been reported (Desgrosellier et al, 2005).…”