TGF-? receptor function in the endothelium

Abstract

Genetic studies in mice and humans have revealed the pivotal role of transforming growth factor-beta (TGF-beta) signaling during angiogenesis. Mice deficient for various TGF-beta signaling components present an embryonic lethality due to vascular defects. In patients, mutations in the TGF-beta type I receptor ALK1 or in the accessory TGF-beta receptor endoglin are linked to an autosomal dominant disorder of vascular dysplasia termed Hereditary Haemorrhagic Telangiectasia (HHT). It has puzzled researchers for years to explain the effects of TGF-beta being a stimulator and an inhibitor of angiogenesis in vitro and in vivo. Recently, a model has been proposed in which TGF-beta by binding to the TGF-beta type II receptor can activate two distinct type I receptors in endothelial cells (ECs), i.e., the EC-restricted ALK1 and the broadly expressed ALK-5, which have opposite effects on ECs behavior. ALK1 via Smad1/5 transcription factors stimulates EC proliferation and migration, whereas ALK5 via Smad2/3 inhibits EC proliferation and migration. Here, the new findings are presented concerning the molecular mechanisms that take place in ECs to precisely regulate and even switch between TGF-beta-induced biological responses. In particular, the role of the accessory TGF-beta receptor endoglin in the regulation of EC behavior is addressed and new insights are discussed concerning the possible mechanisms that are implicated in the development of HHT.

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression

“…TGFβ binds to its specific receptors including TGFβR3. TGFβR3 is one of the proteins that have a more indirect role in TGFβ signal transduction 33. The down‐regulation of TGFβR3 on EC potentiates the inhibitory effect of TGFβ on EC migration and growth 50.…”

The role of bone morphogenetic proteins in myeloma cell survival

“…[30][31][32][33][34] ALK6 (BMPR1B) is variably expressed. [31,35] The SMADs -1, -4 and -5 are also expressed, but not SMAD8.…”

Active TGF-β signaling and decreased expression of PTEN separates angiosarcoma of bone from its soft tissue counterpart

“…44 It binds and activates ALK5, one of its specific type I receptors, and thereby inducing phosphorylation of Smad2/ Smad3, resulting in the expression of the PAI-1. 45 To date, it is accepted that the TGF-b signaling pathway has an important role during embryogenesis, cell Figure 4 The difference in protein expression (sumscores) of all studied antibodies between angiosarcoma of bone (ASB) and soft tissue (ASST) illustrated by dot plots and their corresponding P-value. Table 3 The different pathways based on a combination of different immunohistochemical markers that are used for global testing between angiosarcoma of bone and angiosarcoma of soft tissue…”

“…45,46 Deregulation of this pathway causes resistance to the TGF-b-mediated growth arrest and gives rise to malignancies. [47][48][49] However, the molecular mechanisms provoking this deregulation, that is, genetic and epigenetic aberrations, and the underlying oncogenic activities of TGF-b still remain unclear.…”