Regulation of TGF-β receptor hetero-oligomerization and signaling by endoglin

Abstract

Endoglin is a modulator of TGF-β signaling in endothelial cells. We show that it forms stable homodimers serving as a scaffold for binding TβRII, ALK5, and ALK1. ALK1 and ALK5 bind endoglin differentially, with TβRII recruiting ALK5. Signaling data indicate a role for this receptor complex in balancing TGF-β signaling between Smad1/5/8 and Smad2/3.

Compound genetically engineered mouse models of cancer reveal dual targeting of ALK1 and endoglin as a synergistic opportunity to impinge on angiogenic TGF-β signaling

“…Conversely, during conditions of reduced EndMT and impaired systemic dissemination (targeting of ALK1), ALK5 target genes exhibit a reduced expression. A recent study demonstrated stable complex formation between ALK1, endoglin and the TGF-β type II receptor, even in the absence of any ligand [22]. Interestingly, endoglin was shown to promote ALK1-dependent Smad1/5 signaling, consistent with our finding that reduced levels of endoglin shifts the balance towards the ALK5-induced Smad2/3 pathway and with previous studies demonstrating a requirement of endoglin for BMP9-induced ALK1 signaling [23].…”

ITIH5 induces a shift in TGF‐β superfamily signaling involving Endoglin and reduces risk for breast cancer metastasis and tumor death

“…As a result of the ITIH5‐ENG expression axis, we observed a shift in TGF‐β superfamily signaling in our basal‐type MDA‐MB‐231 breast cancer model. It is known that ENG controls TGF‐β1‐receptor pathways by altering the balance between the activation of ALK1‐dependet (Smad1/5/9) and ALK‐5‐dependent (Smad2/3) signaling in favor of Smad1/5/9 . As a mutual consequence the ALK‐5 driven plasminogen activator inhibitor type 1 (PAI‐1) protein, whose increased expression has been associated with poor prognosis, was only inducible by TGF‐β1 in cells lacking ITIH5/ENG expression.…”

“…It is known that ENG controls TGF-β1-receptor pathways by altering the balance between the activation of ALK1-dependet (Smad1/5/9) and ALK-5-dependent (Smad2/3) signaling in favor of Smad1/5/9. 35 As a mutual consequence the ALK-5 driven plasminogen activator inhibitor type 1 (PAI-1) protein, whose increased expression has been associated with poor prognosis, 61 was only inducible by TGF-β1 in cells lacking ITIH5/ENG expression. This corresponds to suppression of PAI-1 by overexpression in MDA-MB-231 cells.…”

“…According to its pivotal role, TGF‐β1‐receptor signaling is tightly controlled, for example, by the TGF‐β type III receptors betaglycan and Endoglin (ENG, CD105) . ENG directly interacts with type I and type II TGF‐β‐receptors, thereby modulating both the ALK1‐Smad1,5,8 and the ALK5‐Smad2,3 signaling pathways . Recent studies suggested a tumor suppressive function of ENG in epithelial carcinogenesis, as shown for prostate, breast, lung, and skin cancer; however, its precise role in breast cancer is still controversially discussed.…”

“…30 ENG directly interacts with type I and type II TGFβ-receptors, thereby modulating both the ALK1-Smad1,5,8 and the ALK5-Smad2,3 signaling pathways. [31][32][33][34][35] Recent studies suggested a tumor suppressive function of ENG in epithelial carcinogenesis, as shown for prostate, breast, lung, and skin cancer 33,36-40 ; however, its precise role in breast cancer is still controversially discussed. In 2008, Oxmann and colleagues proposed a proinvasive role of ENG in MDA-MB-231 cells.…”