L- and S-endoglin differentially modulate TGF1 signaling mediated by ALK1 and ALK5 in L₆E₉ myoblasts

TGF regulates cellular processes by binding to type I and type II TGF receptors (TRI and TRII, respectively). In addition to these signaling receptors, endoglin is an accessory TGF receptor that regulates TGF signaling. Although there are two different alternatively spliced isoforms of endoglin, L-endoglin (L, long) and S-endoglin (S, short), little is known about the effects of S-endoglin isoform on TGF signaling. Here, we have analyzed the TGF1 signaling pathways and the effects of L- and S-endoglin in endoglin-deficient L₆E₉ cells. We found that TGF activates two distinct TRI-Smad signaling pathways: ALK1-Smad1-Id1 and ALK5-Smad2-PAI1, in these cells. Interestingly, L-endoglin enhanced the ALK1-Id1 pathway, while S-endoglin promoted the ALK5-PAI1 route. These effects on signaling are supported by biological effects on TGF1-induced collagen I expression and inhibition of cell proliferation. Thus, while L-endoglin decreased TGF1-induced collagen I and CTGF expression and increased TGF1-induced proliferation, S-endoglin strongly increased TGF1-induced collagen I and CTGF expression, and reduced TGF1-induced cell proliferation.