Endoglin modulates cellular responses to TGF-beta 1.
Endoglin is a homodimeric membrane glycoprotein which can bind the beta 1 and beta 3 isoforms of transforming growth factor-beta (TGF-beta). We reported previously that endoglin is upregulated during monocyte differentiation. We have now observed that TGF-beta itself can stimulate the expression of endoglin in cultured human monocytes and in the U-937 monocytic line. To study the functional role of endoglin, stable transfectants of U-937 cells were generated which overexpress L- or S- endoglin isoforms, differing in their cytoplasmic domain. Inhibition of cellular proliferation and downregulation of c-myc mRNA which are normally induced by TGF-beta 1 in U-937 cells were totally abrogated in L-endoglin transfectants and much reduced in the S-endoglin transfectants. Inhibition of proliferation by TGF-beta 2 was not altered in the transfectants, in agreement with the isoform specificity of endoglin. Additional responses of U-937 cells to TGF-beta 1, including stimulation of fibronectin synthesis, cellular adhesion, platelet/endothelial cell adhesion molecule 1 (PECAM-1) phosphorylation, and homotypic aggregation were also inhibited in the endoglin transfectants. However, modulation of integrin and PECAM-1 levels and stimulation of mRNA levels for TGF-beta 1 and its receptors R-I, R-II, and betaglycan occurred normally in the endoglin transfectants. No changes in total ligand binding were observed in L-endoglin transfectants relative to mock, while a 1.5-fold increase was seen in S-endoglin transfectants. The degradation rate of the ligand was the same in all transfectants. Elucidating the mechanism by which endoglin modulates several cellular responses to TGF-beta 1 without interfering with ligand binding or degradation should increase our understanding of the complex pathways which mediate the effects of this factor.
Lastres
P
P
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
Letamendía
A
A
Zhang
H
H
Rius
C
C
Almendro
N
N
Raab
U
U
López
L A
LA
Langa
C
C
Fabra
A
A
Letarte
M
M
Bernabéu
C
C
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D000071063:Endoglin; D005353:Fibronectins / Q000096:biosynthesis; D016259:Genes, myc / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D018076:DNA, Complementary; C064206:ENG protein, human; D000071063:Endoglin; D005353:Fibronectins; D016023:Integrins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1