Endoglin Is an Accessory Protein That Interacts with the Signaling Receptor Complex of Multiple Members of the Transforming Growth Factor- Superfamily

University of Toronto, Toronto, Ontario, Canada
Journal of Biological Chemistry (Impact Factor: 4.57). 02/1999; 274(2):584-94. DOI: 10.1074/jbc.274.2.584
Source: PubMed


Endoglin (CD105) is a transmembrane glycoprotein that binds transforming growth factor (TGF)-β1 and -β3, and coprecipitates
with the Ser/Thr kinase signaling receptor complex by affinity labeling of endothelial and leukemic cells. The present study
shows that in addition to TGF-β1 and -β3, endoglin interacts with activin-A, bone morphogenetic protein (BMP)-7, and BMP-2
but requires coexpression of the respective ligand binding kinase receptor for this association. Endoglin cannot bind ligands
on its own and does not alter binding to the kinase receptors. It binds TGF-β1 and -β3 by associating with the TGF-β type
II receptor and interacts with activin-A and BMP-7 via activin type II receptors, ActRII and ActRIIB, regardless of which
type I receptor partner is coexpressed. However, endoglin binds BMP-2 by interacting with the ligand binding type I receptors,
ALK3 and ALK6. The formation of heteromeric signaling complexes was not altered by the presence of endoglin, although it was
coprecipitated with these complexes. Endoglin did not interact with BMP-7 through complexes containing the BMP type II receptor,
demonstrating specificity of its action. Our data suggest that endoglin is an accessory protein of multiple kinase receptor
complexes of the TGF-β superfamily.

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Available from: Michelle Letarte, Nov 23, 2015
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    • "Endoglin is a 95-kDa glycoprotein that binds TGF-β1 and -β3 in conjunction with TβRII (Barbara et al., 1999) and can also bind directly BMP-9 or -10 (David et al., 2007, 2009). Endoglin has been reported to increase TGF-β1 binding to TβRII (Letamendia et al., 1998; Barbara et al., 1999), with controversial effects on TGF-β signaling (Lastres et al., 1996; Letamendia et al., 1998; Barbara et al., 1999; Guerrero-Esteo et al., 2002). Endoglin-mediated regulation of ALK1 signaling to Smad1/5/8 is contentious; loss-of-function studies with either small interfering RNA (siRNA)–mediated knockdown or in endoglin-null endothelial cells suggest either positive or negative regulation (Lebrin et al., 2004; Pece-Barbara et al., 2005). "
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    ABSTRACT: Complex formation among transforming growth factor-β (TGF-β) receptors and its modulation by coreceptors represent an important level of regulation for TGF-β signaling. Oligomerization of ALK5 and the type II TGF-β receptor (TβRII) were thoroughly investigated, both in vitro and in intact cells. However, such studies, especially in live cells, are missing for the endothelial cells coreceptor endoglin and for the ALK1 type I receptor, which enables endothelial cells to respond to TGF-β by activation of both Smad2/3 and Smad1/5/8. Here, we used IgG-mediated immobilization of one cell-surface receptor with lateral mobility studies of a coexpressed receptor by fluorescence recovery after photobleaching (FRAP) to demonstrate that endoglin forms stable homodimers that function as a scaffold for binding TβRII, ALK5 and ALK1. ALK1 and ALK5 bind to endoglin with differential dependence on TβRII, with the latter playing a major role in recruiting ALK5 to the complex. Signaling data indicate a role for the quaternary receptor complex in regulating the balance between TGF-β signaling to Smad1/5/8 and to Smad2/3. © 2015 by The American Society for Cell Biology.
    Preview · Article · Jul 2015 · Molecular biology of the cell
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    • "A number of signaling pathways control either the expression or the activity of SOX9 in chondrocytes. Bmp signaling is needed for formation of chondrogenic mesenchymal condensations and for expression or maintenance of Sox9 RNA at this step [9]. Interleukin-1 and tumor necrosis factor alpha inhibit Sox9 expression, whereas fibroblast growth factor (FGF) upregulates Sox9 through mitogen-activated protein kinase signaling. "
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    ABSTRACT: The transcription factor SOX9 plays an essential role in determining the fate of several cell types and is a master factor in regulation of chondrocyte development. Our aim was to determine which genes in the genome of chondrocytes are either directly or indirectly controlled by SOX9. We used RNA-Seq to identify genes whose expression levels were affected by SOX9 and used SOX9 ChIP-Seq to identify those genes that harbor SOX9-interaction sites. For RNA-Seq, the RNA expression profile of primary Sox9flox/flox mouse chondrocytes infected with Ad-CMV-Cre was compared with that of the same cells infected with a control adenovirus. Analysis of RNA-Seq data indicated that, when the levels of Sox9 mRNA were decreased more than 8-fold by infection with Ad-CMV-Cre, 196 genes showed a decrease in expression of at least 4-fold. These included many cartilage extracellular matrix (ECM) genes and a number of genes for ECM modification enzymes (transferases), membrane receptors, transporters, and others. In ChIP-Seq, 75% of the SOX9-interaction sites had a canonical inverted repeat motif within 100 bp of the top of the peak. SOX9-interaction sites were found in 55% of the genes whose expression was decreased more than 8-fold in SOX9-depleted cells and in somewhat fewer of the genes whose expression was reduced more than 4-fold, suggesting that these are direct targets of SOX9. The combination of RNA-Seq and ChIP-Seq has provided a fuller understanding of the SOX9-controlled genetic program of chondrocytes.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Mouse MSCs are similar to their human counterparts, except that they can lack or be heterogeneous for both CD73 and CD90 [25] [26]. CD105/endoglin is a high affinity coreceptor for transforming growth factor (TGF)-í µí»½1 and TGF-í µí»½3 [27]. Although CD105 is generally considered to be an important MSC marker [24] [28], several reports have shown that its expression varies depending upon the source of MSCs (bone marrow, adipose tissue, umbilical cord blood, or placenta), the culture time in vitro, and differentiation status [29] [30] [31] [32]. "
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    ABSTRACT: Adipose tissue-derived stromal cells, termed ASCs, play an important role in regenerative applications. They resemble mesenchymal stem cells owing to their inexhaustibility, general differentiation potential, and plasticity and display a series of cell-specific and cluster-of-differentiation (CD) marker profiles similar to those of other somatic stem cells. Variations in phenotypes or differentiation are intimately associated with CD markers. The purpose of our study was to exhibit distinct populations of ASCs with differing characteristics for osteogenic differentiation. The primary cell batch of murine-derived ASCs was extracted from subcutaneous adipose tissue and the cells were sorted for the expression of the surface protein molecules CD90 and CD105 using flow cytometry. Each cell population sorted for CD90 and CD105 was analyzed for osteogenic potency after cell culture. The results suggested that ASCs exhibit distinct populations with differing characteristics for osteogenic differentiation: unsorted ASCs stimulated comparable mineralized nodule formation as bone marrow stromal cells (BMSCs) in osteogenic medium and viral transfection for BMP2 accelerated the formation of mineralized nodules in CD90 and/or CD105 positive ASCs with observation of decrease in CD105 expression after 14 days. Future studies assessing different immunophenotypes of ASCs should be undertaken to develop cell-based tissue engineering.
    Full-text · Article · Sep 2014 · Stem cell International
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