April 1, 1999Journal of Biological Chemistry141 citationsOpen Access

Assignment of Transforming Growth Factor β1 and β3 and a Third New Ligand to the Type I Receptor ALK-1

ALAndreas LuxTechnische Hochschule Mannheim LALiliana AttisanoUniversity of Toronto DMDouglas A. MarchukDuke University

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Abstract

Germ line mutations in one of two distinct genes, endoglin or ALK-1, cause hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disorder of localized angiodysplasia. Both genes encode endothelial cell receptors for the transforming growth factor β (TGF-β) ligand superfamily. Endoglin has homology to the type III receptor, betaglycan, although its exact role in TGF-β signaling is unclear. Activin receptor-like kinase 1 (ALK-1) has homology to the type I receptor family, but its ligand and corresponding type II receptor are unknown. In order to identify the ligand and type II receptor for ALK-1 and to investigate the role of endoglin in ALK-1 signaling, we devised a chimeric receptor signaling assay by exchanging the kinase domain of ALK-1 with either the TGF-β type I receptor or the activin type IB receptor, both of which can activate an inducible PAI-1 promoter. We show that TGF-β1 and TGF-β3, as well as a third unknown ligand present in serum, can activate chimeric ALK-1. HHT-associated missense mutations in the ALK-1 extracellular domain abrogate signaling. The ALK-1/ligand interaction is mediated by the type II TGF-β receptor for TGF-β and most likely through the activin type II or type IIB receptors for the serum ligand. Endoglin is a bifunctional receptor partner since it can bind to ALK-1 as well as to type I TGF-β receptor. These data suggest that HHT pathogenesis involves disruption of a complex network of positive and negative angiogenic factors, involving TGF-β, a new unknown ligand, and their corresponding receptors. Germ line mutations in one of two distinct genes, endoglin or ALK-1, cause hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disorder of localized angiodysplasia. Both genes encode endothelial cell receptors for the transforming growth factor β (TGF-β) ligand superfamily. Endoglin has homology to the type III receptor, betaglycan, although its exact role in TGF-β signaling is unclear. Activin receptor-like kinase 1 (ALK-1) has homology to the type I receptor family, but its ligand and corresponding type II receptor are unknown. In order to identify the ligand and type II receptor for ALK-1 and to investigate the role of endoglin in ALK-1 signaling, we devised a chimeric receptor signaling assay by exchanging the kinase domain of ALK-1 with either the TGF-β type I receptor or the activin type IB receptor, both of which can activate an inducible PAI-1 promoter. We show that TGF-β1 and TGF-β3, as well as a third unknown ligand present in serum, can activate chimeric ALK-1. HHT-associated missense mutations in the ALK-1 extracellular domain abrogate signaling. The ALK-1/ligand interaction is mediated by the type II TGF-β receptor for TGF-β and most likely through the activin type II or type IIB receptors for the serum ligand. Endoglin is a bifunctional receptor partner since it can bind to ALK-1 as well as to type I TGF-β receptor. These data suggest that HHT pathogenesis involves disruption of a complex network of positive and negative angiogenic factors, involving TGF-β, a new unknown ligand, and their corresponding receptors. hereditary hemorrhagic telangiectasia activin receptor-like kinase 1 transforming growth factor β plasminogen activator inhibitor type I or type II TGF-β receptor type I or type II activin receptor bone morphogenetic protein type I or type II bone morphogenetic protein receptor glycine-serine domain transmembrane domain polyacrylamide gel electrophoresis hemagglutinin insertion polymerase chain reaction fetal bovine serum minimal essential medium nonessential amino acids Hereditary hemorrhagic telangiectasia (HHT),1 or Osler-Rendu-Weber disease, is an autosomal dominant disorder characterized by localized angiodysplasia (1Guttmacher A.E. Marchuk D.A. White R.I. N. Engl. J. Med. 1995; 333: 918-924Crossref PubMed Scopus (896) Google Scholar). Mutations have been identified in two genes, endoglin and ALK-1 that can cause HHT (2McAllister K.A. Grogg K.M. Johnson D.W. Gallione C.J. Baldwin M.A. Jackson C.E. Helmbold E.A. Markel D.S. McKinnon W.C. Murrell J. McCormick M.K. Pericak-Vance M.A. Heutink P. Oostra B. Haitjema T. kiWesterman C.J.J. Porteous M.E. Guttmacher A.E. Letarte M. Marchuk D.A. Nat. Genet. 1994; 8: 345-351Crossref PubMed Scopus (1263) Google Scholar, 3Johnson D.W. Berg J.N. Baldwin M.A. Gallione C.J. Marondel I. Yoon S.-J. Stenzel T.T. Speer M. Pericak-Vance M.A. Diamond A. Guttmacher A.E. Jackson C.E. Attisano L. Kucherlapati R. Porteous M.E.M. Marchuk D.A. Nat. Genet. 1996; 13: 189-195Crossref PubMed Scopus (878) Google Scholar). The scope and variety of mutations identified in the endoglin gene (2McAllister K.A. Grogg K.M. Johnson D.W. Gallione C.J. Baldwin M.A. Jackson C.E. Helmbold E.A. Markel D.S. McKinnon W.C. Murrell J. McCormick M.K. Pericak-Vance M.A. Heutink P. Oostra B. Haitjema T. kiWesterman C.J.J. Porteous M.E. Guttmacher A.E. Letarte M. Marchuk D.A. Nat. Genet. 1994; 8: 345-351Crossref PubMed Scopus (1263) Google Scholar, 4McAllister K.A. Baldwin M.A. Thukkani A.K. Gallione C.J. Berg J.N. Porteous M.E. Guttmacher A.E. Marchuk D.A. Hum. Mol. Genet. 1995; 4: 1983-1985Crossref PubMed Scopus (96) Google Scholar, 5Shovlin C. Hughes J.M.B. Scott J. Seidman E. Seidman J.G. Am. J. Hum. Genet. 1997; 61: 68-79Abstract Full Text PDF PubMed Scopus (142) Google Scholar, 6Pece N. Vera S. Cymerman U. White R.I. Wrana J.L. Letarte M. J. Clin. Invest. 1997; 100: 2568-2579Crossref PubMed Scopus (132) Google Scholar, 7Yamaguchi H. Azuma H. Shigekiyo T. Inoue H. Saito S. Thromb. Haemostasis. 1997; 77: 243-247Crossref PubMed Scopus (29) Google Scholar, 8Gallione C.J. Klaus D.J. Yeh E.Y. Stenzel T.T. Xue Y. Anthony K.B. McAllister K.A. Baldwin M.A. Berg J.N. Lux A. Smith J.D. Vary C.P.H. Craigen W.J. Westermann C.J.J. Warner M.L. Miller Y.E. Jackson C.E. Guttmacher A.E. Marchuk D.A. Hum. Mutat. 1998; 11: 286-294Crossref PubMed Scopus (83) Google Scholar) and theALK-1 gene (3Johnson D.W. Berg J.N. Baldwin M.A. Gallione C.J. Marondel I. Yoon S.-J. Stenzel T.T. Speer M. Pericak-Vance M.A. Diamond A. Guttmacher A.E. Jackson C.E. Attisano L. Kucherlapati R. Porteous M.E.M. Marchuk D.A. Nat. Genet. 1996; 13: 189-195Crossref PubMed Scopus (878) Google Scholar, 9Berg J.N. Gallione C.J. Stenzel T.T. Allen W.P. Schwartz C.E. Jackson C.E. Porteous M.E. Marchuk D.A. Am. J. Hum. Genet. 1997; 61: 60-67Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 10Klaus D.J. Gallione C.J. Anthony K. Yeh E.Y. Yu J. Lux A. Johnson D.W. Marchuk D.A. Hum. Mutat. 1998; (http://journals.wiley.com/mutbr7.htm/): 1059-7794Google Scholar), as well as RNA and protein expression analyses, suggest that the majority of these represent null alleles and that the disease phenotype is the result of inherited haploinsufficiency for either endoglin or ALK-1. By sequence homologies, endoglin and ALK-1 are thought to be endothelial cell receptors for members of the TGF-β superfamily. The TGF-β superfamily (TGF-βs, activins, bone morphogenetic proteins (BMPs), and Müllerian-inhibiting substance) constitutes a family of multifunctional cytokines that regulate many aspects of cellular function such as proliferation, differentiation, adhesion, migration, and extracellular matrix formation (11Massagué J. Annu. Rev. Cell Biol. 1990; 6: 597-641Crossref PubMed Scopus (3004) Google Scholar, 12Sporn M.B. Roberts A.B. J. Cell Biol. 1992; 119: 1017-1021Crossref PubMed Scopus (748) Google Scholar, 13Attisano L. Wrana J.L. Lopez-Casillas F. J. 1994; PubMed Scopus Google Scholar, 1994; 8: PubMed Scopus Google Scholar). receptor of type I and type II transmembrane kinase receptors. for TGF-β and activin signaling have been by J.L. Attisano A. R. F. J. 1994; PubMed Scopus Google Scholar, K. E. 1995; PubMed Scopus Google Scholar, Mol. 1996; PubMed Scopus Google Scholar). TGF-β or activin the type II receptor, the type I receptor the II receptor The type I receptor is by the type II receptor and in its domain J.L. Attisano A. R. F. J. 1994; PubMed Scopus Google Scholar, R. Wrana J.L. J. J. 1995; PubMed Scopus Google Scholar). The type I receptor signaling such as members of the identified family in K. P. 1997; PubMed Scopus Google Scholar, L. Wrana J.L. Cell Biol. 1998; PubMed Scopus Google Scholar, M. J. 1998; 8: PubMed Scopus Google Scholar). type I receptors have been the majority of and corresponding type II receptors have been is an activin type I receptor, L. J. F. J. Wrana J.L. Full Text PDF PubMed Scopus Google Scholar, J. F. R. Wrana J.L. Attisano L. J. Mol. Biol. 1994; PubMed Google Scholar, P. H. P. P. J. H. K. 8: Google Scholar). and are the type I receptors and P. H. P. P. J. H. K. 8: Google Scholar, P. H. M. H. K. J. Biol. 1994; Full Text PDF PubMed Google Scholar). is an activin and type I receptor L. Wrana J.L. Lopez-Casillas F. J. 1994; PubMed Scopus Google H. P. M. Smith K. J. Cell Biol. 1995; PubMed Scopus Google Scholar). is the TGF-β type I receptor, P. P. H. H. P. K. Full Text PDF PubMed Scopus Google Scholar). is in the and can complex with type II receptors for both TGF-β and activin K. S. Mol. 1996; PubMed Scopus Google Scholar, M. T. H. N. I. M. T. P. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). in ligand to a The ligand and corresponding type II for ALK-1 are unknown. In the of the TGF-β type II receptor ALK-1 in the of the activin type II receptor ALK-1 activin L. J. F. J. Wrana J.L. Full Text PDF PubMed Scopus Google Scholar, P. H. H. P. M. K. 1994; PubMed Scopus Google Scholar, C.J. A. H. P. K. Cell 1996; PubMed Scopus Google Scholar). of these a as by a of an in or the to activate a gene in the cell line TGF-β and activin as ALK-1 as ALK-1 signaling by these cytokines activate cellular the of a signaling assay of ALK-1 and its role in the pathogenesis of have been devised for receptors in superfamily. In and are to TGF-β or of the which the of L. J. F. J. Wrana J.L. Full Text PDF PubMed Scopus Google Scholar, J.L. Attisano L. J. A. J. M. J. 1992; Full Text PDF PubMed Scopus Google Scholar). By chimeric have that is by the domain of a chimeric type I receptor, with the type II receptor, of the ligand of the extracellular domain M. J. K. T. R. K. Mol. Biol. 1997; 8: PubMed Scopus Google Scholar, U. S. P. K. P. J. Biol. 1997; PubMed Scopus (29) Google Scholar, K. J. 1996; PubMed Scopus Google Scholar, J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Attisano L. Wrana J.L. J. J. Biol. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We that the for the of ALK-1 with the II receptor we chimeric receptors with the ALK-1 extracellular domain and the domain of or to an ALK-1 signaling Endoglin is thought to be a TGF-β type III receptor its sequence homology to the F. S. J. J.L. J. Full Text PDF PubMed Scopus Google Scholar, E. J. Full Text PDF PubMed Scopus Google Scholar, A. H. K. 1992; PubMed Scopus Google Scholar). the to and the signaling of the type I receptor F. Wrana J.L. J. Full Text PDF PubMed Scopus Google Scholar). of its sequence homology to betaglycan, a function is for We present data that endoglin is the partner for ALK-1 a role for endoglin in signaling ALK-1. cell and fetal bovine serum by a by B. in medium and in by of J. J. Biol. Full Text PDF PubMed Google Scholar, M. J. 1990; Full Text PDF PubMed Scopus Google Scholar). in minimal essential medium nonessential amino acids and cell in a endoglin and ALK-1 of the endoglin extracellular by and the ALK-1 extracellular domain for the the corresponding the expression a and in and proteins a The proteins a and The with and to The and serum in endoglin and ALK-1 in that with an endoglin or ALK-1 expression with the serum with the of the hemagglutinin in with a The the of a cell line and the The endoglin of TGF-β1 and and and the and activin with a expression the to the for an in medium and an in medium The and and in the activin The of for in medium and as a negative in the activin serum the and of the receptors and chimeric receptors the expression for have a ALK-1 one with an and one which be in the The ALK-1, and L. J. F. J. Wrana J.L. Full Text PDF PubMed Scopus Google Scholar, T. S. M. M.B. Attisano L. Wrana J.L. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The endoglin the Endoglin the of The endoglin sequence has the amino acids the transmembrane domain a and is a in the the with which the endoglin domain and in the chimeric type I receptors that in the we to a new in receptor which the amino sequence in the The receptor ALK-1, and in or The new with the for the of the the sequence in the of the The new by The with the and an that to the of the type I receptors. The and for to the chimeric receptors. These are a with the The by The chimeric the of chimeric receptors the extracellular domain of ALK-1 or and the transmembrane domain and domain of and The chimeric receptors with a of polymerase polymerase the in as in the the domain sequence as the an the of the ALK-1 extracellular with the ALK-1 by the of the transmembrane the the of the which the their with for the the an the of the extracellular with the by the of the transmembrane the the The with the or and to the extracellular domain of ALK-1 or The sequence and by in and their expression by the since have a HHT mutations in the chimeric receptor by the The with the in to The for to the with the of 1 of receptor and 1 of or in of two receptor 1 of in of 1 1 1 1 for The by in a and for The cell with of protein in for The with of or ALK-1 or of of protein for The protein in of and in of The proteins by and to a for with the with the to the expression the and with J.L. Attisano L. J. A. J. M. J. 1992; Full Text PDF PubMed Scopus Google Scholar), the receptor in or The to the for the and to to with in of medium of in the of of and 1 of of with either of type I receptors or type I 1 of and 1 of The and in In two type I receptors of receptor In the for with two receptors to be with the of receptor the receptor with of in the receptor with in for and to in The and a and for in to the to to the for in for with the of the cytokines to the with and for in of to the the assay in a The to the as J. T. Scholar). for The in the 1 the ligand and type II receptor for ALK-1 are a signaling assay for ALK-1 is We to a signaling assay involving chimeric receptors. an we chimeric receptors which we be to a is the receptor for and to a but in the we a chimeric receptor by exchanging the domain with the corresponding and two in the and and one the transmembrane In order to signaling through TGF-β the chimeric receptors one of two cell or which are for and J.L. Attisano L. J. A. J. M. J. 1992; Full Text PDF PubMed Scopus Google Scholar, J. J. Biol. Full Text PDF PubMed Google Scholar). We that in or chimeric receptors to a of with either or The in with the and activin signaling in chimeric receptors. with the chimeric receptors or the expression of the in in cell as the and for in data the in the domain are with either or or ligand or with of medium of with an activin expression or with of medium of with the activin expression the a the we signaling with the extracellular domain of ALK-1 of the ALK-1 to a in either or the ALK-1 in the of ligand, a in in with the ALK-1 the of or signaling for the ALK-1 that are for ALK-1. We activin signaling in the a of activin to the of the receptor J. F. R. Wrana J.L. Attisano L. J. Mol. Biol. 1994; PubMed Google Scholar). of with a and the a in we activin signaling for the two ALK-1 and an of the ALK-1 the with These data that activin is a ligand for ALK-1. We the of TGF-β ligand to signaling through the ALK-1 a positive we which These to or with a of with the the a to TGF-β1 and TGF-β3, although that of the to The a although the of the to the ALK-1 extracellular domain as to of the TGF-β These that TGF-β1 and can a the ALK-1 The for the TGF-β that of endoglin S. T. C. Vera S. C. J. Letarte M. J. Biol. 1992; Full Text PDF PubMed Google Scholar), with the that endoglin and ALK-1 are in the signaling of the to of the although the chimeric protein since the kinase domain is to the kinase domain of in the of kinase and which are for the TGF-β R. 1997; PubMed Scopus Google Scholar). These suggest that the type I receptor is for the signaling and that be the of type I and II receptors in the with and U. S. P. K. P. J. Biol. 1997; PubMed Scopus (29) Google Scholar) that the chimeric receptor is to in with the chimeric receptor TGF-β but with the TGF-β type II receptor endoglin and ALK-1 show the TGF-β ligand we a receptor We ALK-1 can a complex with either or which the of for the ALK-1 in the of ligand. with endoglin and ALK-1 and with either the or The by and with the and that endoglin and ALK-1 can be in a a ALK-1, although endoglin is an by and S. Vera S. A. N. S. E.A. Letarte M. 1997; PubMed Scopus Google Scholar). be for the which be by with endoglin and or that these two type I receptors are to although these for ALK-1 for endoglin and the type II receptors and these receptors In order to identify ALK-1 with type II with of either ALK-1 and or ALK-1 and for ALK-1 both type II receptors for the type II receptors ALK-1 These that ALK-1 and these type II receptors are in a receptor complex and suggest that and can both as type II receptors for ALK-1. In an to identify a ligand for ALK-1, we serum as a of ligand in the signaling ALK-1 either or a in of which a serum In order to to TGF-β present in the serum, with or and with either TGF-β1 or serum in the or of a TGF-β1 The the of by for with TGF-β1 it the signaling of the In with to TGF-β1 with the serum with or the to the serum These data show that the with ALK-1 is to the of TGF-β, activin or in the is to present in serum, and to J. M. N. J. 1995; PubMed Scopus Google Scholar, Mol. Biol. 1997; PubMed Scopus Google Scholar, M.A. A. 1997; PubMed Scopus Google Scholar). we have that can be in a complex with ALK-1, and the activin type II receptor, the serum be by an receptor to signaling the ALK-1 the of an ALK-1 ligand in serum, we the of ALK-1 mutations that have been identified in HHT Mutations one D.J. Gallione C.J. Anthony K. Yeh E.Y. Yu J. Lux A. Johnson D.W. Marchuk D.A. Hum. Mutat. 1998; (http://journals.wiley.com/mutbr7.htm/): 1059-7794Google Scholar), and amino and J.N. Gallione C.J. Stenzel T.T. Allen W.P. Schwartz C.E. Jackson C.E. Porteous M.E. Marchuk D.A. Am. J. Hum. Genet. 1997; 61: 60-67Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 10Klaus D.J. Gallione C.J. Anthony K. Yeh E.Y. Yu J. Lux A. Johnson D.W. Marchuk D.A. Hum. Mutat. 1998; (http://journals.wiley.com/mutbr7.htm/): 1059-7794Google Scholar). These mutations the extracellular domain of the and their the signaling The as a negative as it a in the extracellular to a of that the and mutations both signaling The signaling for the and mutations with a serum for of the the of for the ALK-1 to the of The and amino for of the The signaling of these ALK-1 These data are the that of the ALK-1 missense mutations identified in HHT have for ALK-1 signaling. ALK-1 and bind TGF-β1 and and can a complex with activate the genes L. J. F. J. Wrana J.L. Full Text PDF PubMed Scopus Google Scholar, P. H. M. H. K. J. Biol. 1994; Full Text PDF PubMed Google Scholar, C.J. A. H. P. K. Cell 1996; PubMed Scopus Google Scholar). we that ALK-1 have an TGF-β signaling through In order to ALK-1 signaling of TGF-β we a of ALK-1. type I the of either or for a in the kinase domain a type I receptor to ligand or corresponding type II receptor R. Wrana J.L. J. J. 1995; PubMed Scopus Google Scholar, T. S. M. M.B. Attisano L. Wrana J.L. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). we an of ALK-1 by with the in ALK-1 The of the ALK-1 receptor in the assay of and ALK-1 a of signaling in to is both for TGF-β1 and ALK-1 is with signaling is by in to receptors with the as the receptor by ligand, we ALK-1 have a signaling through with and ALK-1 and with either TGF-β1 or TGF-β1 The signaling data with with of with TGF-β1 and serum a in signaling with TGF-β1 be to serum that bind to TGF-β1 and it or its The ALK-1 and a in TGF-β1 the TGF-β1 serum in a in signaling These data that in ALK-1 signaling the is signaling or the is for of the such as The autosomal dominant disorder HHT is characterized by the of localized have that HHT can be by mutations in one of two genes, endoglin or ALK-1. Endoglin is a and protein the of endothelial and ALK-1 is a type I TGF-β superfamily receptor the of endothelial the role of these receptors in the pathogenesis of HHT is unclear. TGF-β is to a role in or Rev. 1997; 8: PubMed Scopus Google Scholar, S. J. Cell Biol. 1997; PubMed Scopus Google Scholar, R. L. 1996; PubMed Scopus Google Scholar). In the of the TGF-β1 and the suggest a role in and T. A. P. C. M. Vera S. S. J. Letarte M. C. J. PubMed Scopus Google M. H. Biol. 1996; PubMed Scopus Google Scholar). the in the TGF-β1 null to the in HHT A.B. S. 1995; PubMed Google Scholar). ALK-1 expression in the that of TGF-β1 M.A. 1997; PubMed Scopus Google Scholar), and ALK-1 are to in and The data these mutations suggest that ALK-1 and endoglin in the angiogenic involving data suggest to and in through the PAI-1 ALK-1 in a or activin L. J. F. J. Wrana J.L. Full Text PDF PubMed Scopus Google Scholar). ALK-1 such as growth or expression of extracellular matrix proteins J. F. R. Wrana J.L. Attisano L. J. Mol. Biol. 1994; PubMed Google P. H. M. H. K. J. Biol. 1994; Full Text PDF PubMed Google Scholar, C.J. A. H. P. K. Cell 1996; PubMed Scopus Google Scholar). These data suggest distinct for and signaling. the of a chimeric receptor signaling assay the inducible PAI-1 we have that activin and are to activate ALK-1 signaling. The negative result for activin since activin to ALK-1 in the of the activin type II receptor L. J. F. J. Wrana J.L. Full Text PDF PubMed Scopus Google Scholar), and data and that of P. H. M. H. K. J. Biol. 1994; Full Text PDF PubMed Google Scholar, C.J. A. H. P. K. Cell 1996; PubMed Scopus Google Scholar) show ALK-1 and present in a we two distinct ALK-1 either the or kinase and of signaling in a positive an signaling the activin type I receptor we that activin is a signaling ligand for ALK-1. The ALK-1 show signaling TGF-β1 and but with ligand that of endoglin S. T. C. Vera S. C. J. Letarte M. J. Biol. 1992; Full Text PDF PubMed Google Scholar). Both ALK-1 and endoglin are in of P. A. H. C. N. U. C. A. Letarte M. C. J. Cell Biol. 1996; PubMed Scopus Google Scholar, I. Letarte M. 1997; PubMed Scopus Google Scholar). These data and and suggest that ALK-1 and endoglin are of a TGF-β signaling receptor The ALK-1 signaling in is that of the be to a of ALK-1 to TGF-β or to the of two type II receptor for ALK-1. The type II receptor be to ALK-1 in signaling serum and data show that ALK-1 is to two type II both present in but for the of endoglin is by K. M. In Biol. 1996; PubMed Scopus Google Scholar), type III and I TGF-β receptors and type II and I receptors but type III and II which we of type as well and type but for or type the of the receptor complex TGF-β and an in and to complex an of for The transmembrane and domain of endoglin is and homology to the corresponding of the TGF-β type III receptor F. S. J. J.L. J. Full Text PDF PubMed Scopus Google Scholar, E. J. Full Text PDF PubMed Scopus Google Scholar, A. H. K. 1992; PubMed Scopus Google Scholar, S. T. C. Vera S. C. J. Letarte M. J. Biol. 1992; Full Text PDF PubMed Google Scholar, H. H. S. A. P. K. J. Biol. 1994; Full Text PDF PubMed Google Scholar, S. Cymerman U. N. Letarte M. 1994; PubMed Scopus Google Scholar). The data suggest that type III receptors or type I receptor signaling. TGF-β in endothelial and have endoglin in a complex with and P. J. C. C. J. 1994; PubMed Scopus Google Scholar, H. A. Letarte M. J. 1996; Scholar). In both the with either an or TGF-β1 and in the of a protein of the for a type I receptor. The that the TGF-β type I receptor. since ALK-1 is in endothelial the type I receptor in endothelial have been ALK-1. is that ALK-1 and are of which for and to has been by Yu Am. J. 1996; Google Scholar). that the ALK-1 is in is and that the two receptors are in the fetal it is that of the well endothelial to TGF-β Rev. 1997; 8: PubMed Scopus Google Scholar, S. J. Cell Biol. 1997; PubMed Scopus Google Scholar, R. L. 1996; PubMed Scopus Google Scholar) are to signaling through ALK-1 and of serum, which to be one of the TGF-β family can as a third signaling ligand for ALK-1. and ALK-1 signaling signaling by the since signaling ALK-1 in either or with for type II receptors identify type II receptor in endothelial Johnson and A. the serum ligand through we unknown these data suggest and are the type II receptors for ALK-1. The of a third unknown ligand for ALK-1 of the function of ALK-1 in endothelial have that ALK-1 growth or expression of extracellular matrix proteins such as or PAI-1 TGF-β J. F. R. Wrana J.L. Attisano L. J. Mol. Biol. 1994; PubMed Google Scholar). We have that ALK-1 signaling is to although we is a of ALK-1 signaling the PAI-1 or the and ALK-1 and for signaling In of TGF-β signaling, it be to ALK-1 signaling, in that both receptors. We are a the of ALK-1 and endoglin in and their role in the pathogenesis of the data suggest a for the role of the two receptors in these the endothelial cell in a is The of is thought to be by negative the negative and positive is and positive have that TGF-β can be either a positive or negative in Rev. 1997; 8: PubMed Scopus Google Scholar). of TGF-β is TGF-β L. R. Cell PubMed Scopus Google Scholar). endothelial to TGF-β be C. M. J. Cell Biol. PubMed Scopus Google Scholar). be by the of two receptors such as and ALK-1, which have for Endoglin be as a for both type I receptors in order to the negative and positive of is by the of a third unknown ligand. ALK-1 be by the ligand ALK-1 signaling ligand result in angiogenic that are are to identify the ligand present in serum and to the signaling and its role in and the pathogenesis of We Klaus for T. Stenzel for the endoglin B. for the of the cell and H. for the of the A. F. through the and

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