Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Transforming growth factor-β receptors: Role in physiology and disease

  • 26 Accesses

  • 20 Citations


Transforming growth factor-β (TGF-β) plays a pivotal role in numerous vital cellular activities, most significantly the regulation of cellular proliferation and differentiation and synthesis of extracellular matrix components. Its ubiquitous presence in different tissues and strict conservation of nucleotide sequence down through the most primitive vertebrate organisms underscore the essential nature of this family of molecules. The effects of TGF-β are mediated by a family of dedicated receptors, the TGF-β types I, II, and III receptors. It is now known that a wide variety of human pathology can be caused by aberrant expression and function of these receptors or their cognate ligands. The coding sequence of the human type II receptor appears to render it uniquely susceptible to DNA replication errors in the course of normal cell division. There are now substantial data suggesting that TGF-β type II receptor should be considered a tumor suppressor gene. High levels of mutation in the TGF-β type II receptor gene have been observed in a wide variety of primarily epithelial malignancies, including colon, gastric, and hepatic cancer. It appears likely that mutation of the TGF-β type II receptor gene represents a very critical step in the pathway of carcinogenesis.

This is a preview of subscription content, log in to check access.


  1. 1

    Aaltonen L, Peltomäki P, Leach F, Sistonen P, Pylkkanen L, Jarvinen H, Powell S, Jen J, Hamilton S, Petersen G, Kinzler K, Vogelstein B, de la Chapelle A. Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816;1993.

  2. 2

    Alexandrow M, Moses H. Transforming growth factor β and cell cycle regulation. Cancer Res 55:1452–1457;1995.

  3. 3

    Alexandrow M, Moses H. Transforming growth factor β1 inhibits mouse keratinocytes late in G1 independent of effects on gene transcription. Cancer Res 55:3928–3932;1995.

  4. 4

    Amento E, DeGuzman L, Lee W, Xu Y, McFatridge L, Beck L. The systemic administration of TGF-β1 accelerates wound healing. J Cell Biochem Suppl 15F:191;1991.

  5. 5

    Andres D, Goldstein J, Ho Y, Brown M. Mutational analysis of alpha-subunit of protein farnesyltransferase: evidence for a catalytic role. J Biol Chem 268:1383–1390;1993.

  6. 6

    Arora K, Levine M, O'Connor M. The screw gene encodes a ubiquitously expressed member of the TGF-β family required for specification of dorsal cell fates in the Drosophila embryo. Genes Dev 8:2588–2601;1994.

  7. 7

    Assoian R, Komoriya A, Heyers C, Miller D, Sporn MB. Transforming growth factor-β in human platelets. J Biol Chem 258:7155–7160;1983.

  8. 8

    Atfi A, Lepage K, Allard P, Chapdelaine A, Chevalier S. Activation of a serine/threonine kinase signaling pathway by transforming growth factor type β. Proc Natl Acad Sci USA 92:12110–12114;1995.

  9. 9

    Attisano L, Cárcamo J, Ventura F, Weis F, Massagué J, Wrana J. Identification of human activin and TGFβ type I receptors that form heteromeric kinase complexes with type II receptors. Cell 75:671–680;1993.

  10. 10

    Bae HW, Geiser AG, Kim DH, Chung MT, Burmester JK, Sporn MD, Roberts AB, Kim S-J. Characterization of the promoter region of the human transforming growth factor-β type II receptor gene. J Biol Chem 270:29460–29468;1995.

  11. 11

    Barnett J, Moustakas A, Lin W, Wang X, Lin H, Galper J, Maas R. Cloning and developmental expression of the chick type II and type III TGFβ receptors. Dev Dyn 199:12–27;1994.

  12. 12

    Bassing C, Yingling J, Howe DJ, Wang T, He WW, Gustafson ML, Shah P, Donahoe PK, Wang X-F. A transforming growth factor type I receptor that signals to activate gene expression. Science 263:87–89;1994.

  13. 13

    Beck L, DeGuzman L, Lee W, Xu Y, McFatridge L, Gillett N, Amento E. TGF-β induces bone closure of skull defects. J Bone Mineral Res 6:1257–1265;1991.

  14. 14

    Bedossa P, Peltier E, Terris B, Franco D, Poynard T. Transforming growth factor-beta 1 (TGF-β1) and TGF-β1 receptors in normal, cirrhotic, and neoplastic human livers. Hepatology 21:760–766;1995.

  15. 15

    Birchenall-Roberts M, Falk L, Kasper J, Keller J, Faltynek C, Ruscetti F. Differential expression of transforming growth factor-β1 (TGF-β1) receptors in murine myeloid cell lines transformed with oncogenes. J Biol Chem 266:9617–9621;1991.

  16. 16

    Birchenall-Roberts M, Ruscetti F, Kasper J, Lee HD, Friedman R, Geiser A, Sporn MB, Roberts AB, Kim S-J. Transcriptional regulation of the transforming growth factor-β1 promoter by v-src gene products is mediated through the AP-1 complex. Mol Cell Biol 10:4978–4983;1990.

  17. 17

    Border W, Okuda S, Languino L, Sporn MB, Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1. Nature 346:371–374;1990.

  18. 18

    Boyd J, Kaufman D. Expression of transforming growth factor β1 by human endometrial carcinoma cell lines: Inverse correlation with effects on growth rate and morphology. Cancer Res 50:3394–3399;1990.

  19. 19

    Boyd F, Massagué J. Transforming growth factor-β inhibition of epithelial cell proliferation linked to the expression of a 53-kDa membrane receptor. J Biol Chem 264:2272–2278;1989.

  20. 20

    Brand T, Schneider M. Inactive type II and type I receptors for TGF-β are dominant inhibitors of TGF-β-dependent transcription. J Biol Chem 270:8274–8284;1995.

  21. 21

    Brand T, Schneider M. The TGFβ superfamily in myocardium: Ligands, receptors, transduction, and function. J Mol Cell Cardiol 27:5–18;1995.

  22. 22

    Bronner C, Baker S, Morrison P, Warren G, Smith L, Lescoe M, Kane M, Earabino C, Lipford J, Lindblom A, Tannergånd P, Bollag R, Godwin A, Ward D, Nordenskjøld M, Fishel R, Kolodner R, Liskay RM. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368:258–261;1994.

  23. 23

    Brummel T, Twombly V, Marqués G, Wrana J, Newfeld S, Attisano L, Massagué J, O'Connor M, Gelbart WM. Characterization and relationship of dpp receptors encoded by the saxophone and thick veins genes in drosophila. Cell 78:251–261;1994.

  24. 24

    Capocasale R, Lamb R, Vonderheid EC, Fox FE, Rook AH, Nowell PC, Moore JS. Reduced surface expression of transforming growth factor β receptor type II in mitogen-activated T cells from Sézary patients. Proc Natl Acad Sci USA 92:5501–5505;1995.

  25. 25

    Cárcamo J, Zentella A, Massagué J. Disruption of transforming growth factor β signalling by a mutation that prevents transphosphorylation within the receptor complex. Mol Cell Biol 15:1573–1581;1995.

  26. 26

    Castilla A, Prieto J, Fausto N. Transforming growth factors β1 and α in chronic liver disease: Effects of interferon alfa therapy. N Engl J Med 324:923–940;1991.

  27. 27

    Centrella M, Casinghino S, Kim J, Pham T, Rosen V, Wozney J, McCarthy T. Independent changes in type I and type II receptors for transforming growth factor β induced by bone morphogenetic protein 2 parallel expression of the osteoblast phenotype. Mol Cell Biol 15:3273–3281;1995.

  28. 28

    Centrella M, McCarthy T, Canalis E. Transforming growth factor-β is a bifunctional regulator of replication and collagen synthesis in osteoblast-enriched cultures from fetal rat calvariae. J Biol Chem 262:2869–2874;1987.

  29. 29

    Cheifetz S, Hernandez H, Laiho M, tenDijke P, Iwata K, Massagué J. Distinct transforming growth factor-β (TGF-β) receptor subsets as determinants of cellular responsiveness to three TGF-β isoforms. J Biol Chem 265:20533–20538;1990.

  30. 30

    Cheifetz S, Bellón T, Calés C, Vera S, Bernabeau C, Massagué J, Letarte M. Endoglin is a component of the TGF-β receptor system in human endothelial cells. J Biol Chem 267:19027–19030;1992.

  31. 31

    Chen F, Weigberg RA. Biochemical evidence for the autophosphorylation and transphosphorylation of transforming growth factor β receptor kinases. Proc Natl Acad Sci USA 92:1565–1569;1995.

  32. 32

    Chen J, Hoshi H, McKeehan W. Transforming growth factor type β specifically stimulates synthesis of proteoglycan in human adult arterial smooth muscle cells. Proc Natl Acad Sci USA 84:5287–5291;1987.

  33. 33

    Chen R-H, Derynck R. Homomeric interactions between type II transforming growth factor-β receptors. J Biol Chem 269:22868–22874;1994.

  34. 34

    Chen R-H, Miettinen PJ, Maruoka EM, Choy L, Derynck R. A WD-domain protein that is associated with and phosphorylated by the type II TGF-β receptor. Nature 377:548–552;1995.

  35. 35

    Ciernik I, Ciernik B, Cockerell C, Minna J, Gazdar A, Carbone D. Expression of transforming growth factor β and transforming growth factor β receptors on AIDS-associated Kaposi's sarcoma. Clin Cancer Res 1:1119–1124;1995.

  36. 36

    Dallas S, Miyazono K, Skerry T, Mundy G, Bonewald L. Dual role for the latent transforming growth factor-β binding protein in storage of latent TGF-β in the extracellular matrix and as a structural matrix protein. J Cell Biol 131:539–549;1995.

  37. 37

    Damstrup L, Rygaard K, Spang-Thomsen M, Poulson H. Expression of transforming growth factor-β (TGFβ) receptors and expression of TGF-β1, TGF-β2, TGF-β3 in human small cell lung cancer cell lines. Br J Cancer 67:1015–1021;1993.

  38. 38

    Datto M, Li Y, Panus J, Howe D, Xiong Y, Wang X-F. Transforming growth factor β induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci USA 92:5545–5549;1995.

  39. 39

    Derynck R, Goeddel D, Ullrich A, Gutterman J, Williams R, Bringman T, Berger W. Synthesis of messenger RNAs for transforming growth factors α and β and the epidermal growth factor receptor by human tumors. Cancer Res 47:707–712;1987

  40. 40

    Derynck R. TGF-β-receptor mediated signaling. Trends Biochem Sci 19:548–553;1994.

  41. 41

    Diebold R, Eis M, Yin M, Ormsby I, Boivin G, Darrow B, Saffitz J, Doetschman T. Earlyonset multifocal inflammation in the transforming growth factor β1-null mouse is lymphocyte mediated. Proc Natl Acad Sci USA 92:12215–12219;1995.

  42. 42

    Dumont N, O'Connor-McCourt M, Philip A. Transforming growth factor-β receptors on human endometrial cells: identification of the type I, II, and III receptors and glycosylphosphatidylinositol anchored TGF-β binding proteins. Mol Cell Endocrinol 111:57–66;1995.

  43. 43

    Ebner R, Chen R, Lawler S, Ziocheck T, Derynck R. Determination of type I receptor specificity by the type II receptors for TGF-β or activin. Science 262:900–902;1993.

  44. 44

    Ebner R, Chen RH, Shum L, Lawler S, Zioncheck T, Lee A, Lopez A, Derynck R. Cloning of a type I TGF-β receptor and its effect on TGF-β binding to the type II receptor. Science 260:1344–1348;1993.

  45. 45

    Elbendary A, Berchuck A, Davis P, et al. Transforming growth factor β1 can induce CIP1/WAF1 expression independent of the p53 pathway in ovarian cells. Cell Growth Differ 5:1301–1307;1994.

  46. 46

    Eshleman J, Markowitz S. Microsatellite instability in inherited and sporadic neoplasms. Curr Opin Oncol 7:83–89;1995.

  47. 47

    Ewen M, Sluss H, Whitehouse L, Livingston D. TGF-β inhibition of Cdk4 synthesis is linked to cell cycle arrest. Cell 74:1009–1020;1993.

  48. 48

    Filmus J, Zhao J, Buick R. Overexpression of H-ras oncogene induces resistance to the growth-inhibitory action of transforming growth factor-β1 (TGF-β1) and alters the number and type of TGF-β1 receptors in rat intestinal epithelical cell clones. Oncogene 7:521–526;1992.

  49. 49

    Filmus J, Kerbel R. Development of resistance mechanisms to the growth-inhibitory effects of transforming growth factor-β during tumor progression. Curr Opin Oncol 5:123–129;1993.

  50. 50

    Fishel R, Lescoe M, Rao M, Copeland N, Jenkins N, Garber J, Kane M, Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038;1993.

  51. 51

    Flaumenhaft R, Abe M, Mignatti P, Rifkin D. Basic fibroblast growth factor-induced activation of latent transforming growth factor-β in endothelial cells: Regulation of plasminogen activator activity. J Cell Biol 118:901–909;1992.

  52. 52

    Franzén P, ten Dijke P, Ichijo H, Yamashita H, Schulz P, Heldin C-H, Miyazono K. Cloning of a TGF-β type I receptor that forms a heteromeric complex with the TGF-β type II receptor. Cell 75:681–692;1993.

  53. 53

    Frolik C, Dart L, Meyers C, Smith D, Sporn MB. Purification and initial characterization of a type beta transforming growth factor from human placenta. Proc Natl Acad Sci USA 80:3676–3680;1983.

  54. 54

    Garrigue-Antar L, Muñoz-Antonia T, Gesmonde J, Vellucci VF, Reiss M. Missense mutations of the transforming growth factor β type II receptor in human head and neck squamous carcinoma cells. Cancer Res 55:3892–3987;1995.

  55. 55

    Geiser A, Letterio J, Kulkarni A, Karlsson S, Roberts AB, Sporn MB. Transforming growth factor β1 (TGF-β1) controls expression of major histocompatibility antigen expression in the pathogenesis of the TGF-β1 null mouse phenotype. Proc Natl Acad Sci USA 90:9944–9948;1993.

  56. 56

    Geiser A, Kim SJ, Roberts AB, Sporn MB. Characterization of the mouse transforming growth factor-β1 promoter and activation by the Ha-ras oncogene. Mol Cell Biol 11:84–92;1991.

  57. 57

    Geiser A, Burmester J, Webbink R, Roberts AB, Sporn MB. Inhibition of growth by transforming growth factor-β following fusion of two nonresponsive human carcinoma cell lines. J Biol Chem 267:2588–2593;1992.

  58. 58

    Geng Y, Weinberg R. Transforming growth factor β effects on expression of G1 cyclins and cyclin-dependent protein kinases. Proc Natl Acad Sci USA 90:10315–10319;1993.

  59. 59

    Gerwin B, Spillare E, Forrester K, Lehman J, Kispart J, Welsh J, Pfeifer A, Lechner J, Baker S, Vogelstein B, Harris C. Mutant p53 can induce tumorigenic conversion of human bronchial epithelial cells and reduce their responsiveness to a negative growth factor, transforming growth factor beta. Proc Natl Acad Sci USA 89:2759–2763;1992.

  60. 60

    Gibbs J, Oliff A, Kohl N. Farnesyltransferase inhibitors: ras research yields a potential cancer therapeutic. Cell 77:175–178;1994.

  61. 61

    Glaser B, Michels R, Kuppermann B, Sjaarda R, Pena R. Transforming growth factor-β2 for the treatment of full-thickness macular holes. Ophthalmology 99:1162–1173;1992.

  62. 62

    Glick A, Kulkarni A, Tennenbaum T. Loss of expression of transforming growth factor β in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc Natl Acad Sci USA 90:6076–6080;1993.

  63. 63

    Glick A, Lee M, Darwiche N, Kulkarni A, Karlsson S, Yuspa S. Targeted deletion of the TGF-β1 gene causes rapid progression to squamous cell carcinoma. Genes Dev 8:2429–2440;1994.

  64. 64

    Grainger D, Kirchenlohr H, Metcalfe J, Weissberg P, Wade D, Lawn R. Proliferation of human smooth muscle cells promoted by lipoprotein (a). Science 260:1655–1658;1993.

  65. 65

    Han HJ, Yanagisawa A, Kato Y, Park JG, Nakamura Y. Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res 53:5087–5089;1993.

  66. 66

    Hancock J, Magee A, Childs J, Marshall C. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 63:133–139;1990.

  67. 67

    Hannon G, Beach D. p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 371:257–261;1994.

  68. 68

    He W, Gustafson M, Hirobe S, Donahoe P. Developmental expression of four novel serine/threonine kinase receptors homologous to the activin/transforming growth factor-β type II receptor family. Dev Dyn 196:133–142;1993.

  69. 69

    Heine U, Munoz E, Flanders K, Roberts AB, Sporn MB. Colocalization of TGF-β1 and collagen I and III, fibronectin and glycosaminoglycans during lung branching morphogenesis. Development 109:29–36;1990.

  70. 70

    Heine U, Munoz E, Flanders K, Ellingsworth L, Lam Y, Thompson N, Roberts AB, Sporn MB. Transforming growth factor-β in the development of the mouse embryo. J Cell Biol 105:2861–2876;1987.

  71. 71

    Henis YI, Moustakas A, Lin HY, Lodish HF. The types II and III transforming growth factor-β receptors form homo-oligomers. J Cell Biol 126:139–154;1994.

  72. 72

    Henriksen R, Gobl A, Wilander E, Öberg K, Miyazono K, Funa K. Expression and prognostic significance of TGF-β isotypes, latent TGF-β1 binding protein, TGF-β type I and type II receptors, and endoglin in noraml ovary and ovarian neoplasms. Lab Invest 73:213–220;1995.

  73. 73

    Hock J, Canalis E, Centrella M. Transforming growth factor β (TGFβ-1) stimulates bone matrix apposition and bone cell replication in cultured fetal rat calvariae. Endocrinology 126:421–426;1990.

  74. 74

    Howe P, Draetta G, Leof E. Transforming growth factor β1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G/S-phase growth arrest. Mol Cell Biol 11:1185–1194;1991.

  75. 75

    Huang S, Chakrabarty S. Regulation of fibronectin and laminin receptor expression, fibronectin and laminin secretion in human colon cancer cells by transforming growth factor-β1. Int J Cancer 57:742–746;1994.

  76. 76

    Inagaki M, Moustaka A, Lin HY, Lodish HF, Carr BI. Growth inhibition by transforming growth factor-β-resistant hepatoma cells after expression of TGF-β receptor type II cDNA. Proc Natl Acad Sci USA 90:5359–5363;1993.

  77. 77

    Ionov Y, Peinado M, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561;1993.

  78. 78

    Ito N, Kawata S, Tamura S, Takaishi K, Shirai Y, Kiso S, Yabuuchi I, Matsudo Y, Nishioka M, Tarui S. Elevated levels of transforming growth factor-β messenger RNA and its polypeptide in human hepatocellular carcinoma. Cancer Res 51:4080–4083;1991.

  79. 79

    Jiang W, Zhang YJ, Kahn S, Hollstein M, Santella R, Lu SH, Harris C, Montesano R, Weinstein I. Altered expression of the cyclin D1 and retinoblastoma genes in human esophageal cancer. Proc Natl Acad Sci USA 90:9026–9030;1993.

  80. 80

    Joyce M, Jingushi S, Bolander M. Transforming growth factor-β in the regulation of fracture repair. Orthop Clin North Am 21:199–209;1990.

  81. 81

    Kaartinen V, Voncken J, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J. Abnormal lung development and cleft palate in mice lacking TGF-β3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 11:415–420;1995.

  82. 82

    Kadin M, Cavaille-Coll MW, Gertz R, Massagué J, Cheifetz S, George D. Loss of receptors for transforming growth factor β in human T-cell malignancies. Proc Natl Acad Sci USA 91:6002–6006;1994.

  83. 83

    Kalter V, Brody A. Receptors for transforming growth factor-β (TGF-β) on rat lung fibroblasts have higher affinity for TGF-β1 than for TGF-β2. Am J Respir Cell Mol Biol 4:397–407;1991.

  84. 84

    Kawabata M, Imamura T, Miyazono K, Engel ME, Moses HL. Interaction of the transforming growth factor-β type I receptor with farnesylprotein transferase-α. J Biol Chem 270:29628–29631;1995.

  85. 85

    Kim IY, Ahn H-J, Zelner DJ, Shaw JW, Sensibar JA, Kim J-H, Kato M, Lee C. Genetic change in transforming growth factor β (TGF-β) receptor type I gene correlates with insensitivity to TGF-β1 in human prostate cancer cells. Cancer Res 56:44–48;1996.

  86. 86

    Kim S-J, Angel P, Lafyatis R, Hattori K, Kim KY, Sporn MB, Karin M, Roberts AB. Autoinduction of transforming growth factor-β1 is mediated by the AP-1 complex. Mol Cell Biol 10:1492–1497;1990.

  87. 87

    Kim S-J, Kehrl J, Burton J, Tendler C, Jeang K, Danielpour D, Thevenin C, Kim KY, Sporn MB, Roberts AB. Transactivation of the transforming growth factor β1 (TGFβ1) gene by human T lymphotrophic virus type 1 tax: A potential mechanism for increased production of TGFβ1 in adult T cell leukemia. J Exp Med 172:121–129;1990.

  88. 88

    Kim S-J, Romeo D, Yoo Y, Park K. Transforming growth factor-β: expression in normal and pathological conditions. Horm Res 42:5–8;1994.

  89. 89

    Kimchi A, Wang X-F, Weinberg R, Cheifetz S, Massagué J. Absence of TGF-β receptors and growth inhibitory responses in retinoblastoma cells. Science 240:196–199;1988.

  90. 90

    Kingsley D. The TGF-β superfamily: new members, new receptors, and new genetic tests of function in different organisms. Gen Dev 8:133–146;1994.

  91. 91

    Kloen P, Jennings C, Gebhardt M, Springfield D, Mankin H. Expression of transforming growth factor-beta (TGF-β) receptors, TGF-β1 and TGF-β2 production and autocrine growth control in osteosarcoma cells. Int J Cancer 58:440–445;1994.

  92. 92

    Kohl N, Wilson F, Mosser S, Giulani E, deSolms S, Conner M, Anthony N, Holtz W, Gomez R, Lee TJ, Smith R, Graham S, Hartman G, Gibbs J, Oliff A. Protein farnesyltransferase inhibitors block the growth of rasdependent tumors in nude mice. Proc Natl Acad Sci USA 91:9141–9145;1994.

  93. 93

    Kossman T, Manthey C, Brandes M, Morganti-Kossman M, Ohura K, Allen J, Mergenhagen S, Wahl S. Kupffer cells express type I TGF-β receptors, migrate to TGF-β and participate in streptococcal cell wall induced hepatic granuloma formation. Growth Factors 7:73–83;1992.

  94. 94

    Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 90:770–774;1993.

  95. 95

    Lafyatis R, Thompson N, Remmers E, Flanders K, Roche N, Kim SJ, Case J, Sporn MB, Roberts AB, Wilder R. Transforming growth factor-β production by synovial tissues from rheumatoid patients and streptococcal cell wall arthritic rats: Studies on secretion by synovial fibroblast-like cells and immunohistologic localization. J Immunol 143:1142–1148;1989.

  96. 96

    Laiho M, Weis F, Massagué J. Concomitant loss of transforming growth factor (TGF)-β receptor types I and II in TGF-β-resistant cell mutants implicates both receptor types in signal transduction. J Biol Chem 265:18518–18524;1990.

  97. 97

    Laiho M, Weis F, Boyd F, Ignotz R, Massagué J. Responsiveness to transforming growth factor-β restored by genetic complementation between cells defective in TGF-β receptors I and II. J Biol Chem 266:9108–9112;1991.

  98. 98

    Leach F, Nicolaides N, Papadopulos N, Liu B, Jen J, Parsons R, Peltomäki P, Sistonen P, Aaltonen L, Nyström-Lahti M, Guan XY, Fournier R, Todd S, Lewis T, Leach R, Naylor S, Weissenbach J, Mecklin JP, Järvinen H, Petersen G, Hamilton S, Green J, Jass J, Watson P, Lynch H, Ttrent J, de la Chapelle A, Kinzler K, Vogelstein B. Mutations of a MutS homolog in hereditary non-polyposis colorectal cancer. Cell 75:1215–1225;1993.

  99. 99

    Letterio J, Geiser A, Kulkarni A, Roche N, Sporn MB, Roberts AB. Maternal rescue of transforming growth factor-β1 null mice. Science 264:1936–1938;1994.

  100. 100

    Li C-Y, Suardet L, Little J. Potential role of WAF/Cip/p21 as a mediator of TGF-β cytoinhibitory effect. J Biol Chem 270:4971–4974;1994.

  101. 101

    Lin H, Moustakas A. TGF-β receptors: Structure and function. Cell Mol Biol 40(3):337–349;1994.

  102. 102

    Lin H, Wang X-F, Ng-Eaton E, Weinberg R, Lodish H. Expression cloning of the TGF-β type II receptor a functional transmembrane serine/threonine kinase. Cell 68:775–785;1992.

  103. 103

    Lin H, Wang X. Expression cloning of TGF-β receptors. Mol Reprod Dev 32:105–110;1992.

  104. 104

    Lin JK, Chou CK. In vitro apoptosis in the human hepatoma cell line induced by transforming growth factor β1. Cancer Res 52:385–388;1992.

  105. 105

    Liu B, Nicolaides N, Markowitz S, Willson JK, Parsons R, Jen J, Papadopoulos N, Peltomäki P, de la Chapelle A, Hamilton S, Kinzler K, Vogelstein B. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet 9:48–53;1995.

  106. 106

    Liu B, Parsons R, Hamilton S, Petersen G, Lynch H, Watson P, Markowitz S, Willson JKV, Green J, de la Chapelle A, Kinzler K, Vogelstein B. hMSH2 mutations in hereditary non-polyposis colorectal cancer kindreds. Cancer Res 54:4590–4594;1994.

  107. 107

    López-Casillas F, Payne H, Andres J, Massagué J. Betaglycan can act as a dual modulator of TGF-β access to signaling receptors: mapping of ligand binding and GAG attachment sites. J Cell Biol 124:557–568;1994.

  108. 108

    López-Casillas F, Cheifetz S, Doody J, Andres JL, Lane WS, Massagué J. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-β receptor. Cell 67:785–795;1991.

  109. 109

    López-Casillas F, Wrana J, Massagué J. Beta-glycan presents ligand to the TGF-β signaling receptor. Cell 73:1435–1444;1993.

  110. 110

    MacKay S, Yaswen L, Tarnuzzer R, Moldawer L, Bland K, Copeland E, Schutz G. Colon cancer cells that are not growth inhibited by TGF-β lack functional type I and type II TGF-β receptors. Ann Surg 221:767–777;1995.

  111. 111

    Manne V, Yan N, Carboni J, Tuomari A, Ricca C, Brown J, Andahazy M, Schmidt R, Patel D, Zahler R, Weinmann R, Der C, Cox A, Hunt J, Gordon E, Barbacid M, Seizinger B, Bisubstrate inhibitors of farnesyltransferase: a novel class of specific inhibitors of ras transformed cells. Oncogene 10:1763–1779;1995.

  112. 112

    Manning A, Williams A, Game S, Paraskeva C. Differential sensitivity of human colonic adenoma and carcinoma cells to transforming growth factor β (TGF β): Conversion of an adenoma cell line to a tumorigenic phenotype is accompanied by a reduced response to the inhibitory effects of TGF-β. Oncogene 6:1471–1476;1991.

  113. 113

    Markowitz S, Wang J, Myeroff L, Parsons R, Sun LZ, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B, Brattain MG, Willson JKV. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science 268:1336–1338;1995.

  114. 114

    Markowitz S, Myeroff L, Cooper M, Traicoff J, Kochera M, Lutterbaugh J, Swiriduk M, Willson JKV. A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-β independence without inactivating the p53 tumor suppressor gene. J Clin Invest 93;1005–1013;1994.

  115. 115

    Martikainen P, Kyprianou N, Isaacs J. Effect of transforming growth factor-β on proliferation and death of rat prostatic cells. Endocrinology 127:2963–2968;1990.

  116. 116

    Massagué J. The transforming growth factor-β family. Annu Rev Cell Biol 6:597–641;1990.

  117. 117

    Massagué J. Receptors for the TGF-β family. Cell 69:1067–1070;1992.

  118. 118

    Massagué J, Attisano L, Wrana J. The TGF-β family and its composite receptors. Trends Cell Biol 4:172–178;1994.

  119. 119

    Massagué J, Andres J, Attisano L, Cheifetz S, López-Casillas F, Ohtsuki M, Wrana J. TGF-β receptors. Mol Reprod Dev 32:99–104;1992.

  120. 120

    Matzuk M, Finegold M, Su JG, Hsueh A, Bradley A. Alpha-inhibin is a tumor suppressor gene with gonadal specificity in mice. Nature 360:313–319;1992.

  121. 121

    Miettinen P, Ebner R, Lopez A, Derynck R. TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 127:2021–2036;1994.

  122. 122

    Missero C, Filvaroff E, Dotto GP. Induction of transforming growth factor-β1 resistance by the E1A oncogene requires binding to a specific set of cellular proteins. Proc Natl Acad Sci USA 88:3489–3493;1991.

  123. 123

    Miyazono K, Ichijo H, Heldin C. Transforming growth factor-β: latent forms, binding proteins and receptors. Growth Factors 8:11–22;1993.

  124. 124

    Moses H, Yang E, Pietenpol J. TGF-β stimulation and inhibition of cell proliferation: New mechanistic insights. Cell 63:245–247;1990.

  125. 125

    Moustakas A, Lin H, Henist Y, Plamondon J, O'Connor-McCourt M, Lodish H. The transforming growth factor β receptors types I, II, and III form hetero-oligomeric complexes in the presence of ligand. J Biol Chem 268:22215–22218;1993.

  126. 126

    Myeroff LL, Parsons R, Kim S-J, Hedrick L, Cho KR, Orth K, Mathis M, Kinzler KW, Lutterbaugh J, Park K, Bamg Y-J, Lee HY, Park J-G, Lynch HT, Roberts AB, Vogelstein B, Markowitz SD. A transforming growth factor β receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res 55:5545–5547;1995.

  127. 127

    Nicolaides N, Papadopoulos N, Liu B, Wei YF, Carter K, Ruben S, Rosen C, Haseltine W, Fleischmann R, Fraser C, Adams M, Venter JC, Dunlop M, Hamilton S, Petersen G, de la Chapelle A, Vogelstein B, Kinzler K. Mutations in two PMS homologous in hereditary nonpolyposis colon cancer. Nature 371:75–80;1994.

  128. 128

    Noda M, Rodan G. Type-β transforming growth factor inhibits proliferation and expression of alkaline phosphatase in murine osteoblast-like cells. Biochem Biophys Res Commun 140:56–65;1986.

  129. 129

    Norgaard P, Damstrup L, Rygaard K, Spang-Thomsen M, Skovgaard H. Growth suppression transforming growth factor-β1 of human small-cell lung cancer cell lines is associated with expression of the type II receptor. Br J Cancer 69:802–808;1994.

  130. 130

    Oberhammer F, Pavelka M, Sharma S, Tiefenbacher R, Purchio A, Bursch W, Schulte-Hermann R. Induction of apoptosis in cultured hepatocytes and in regression liver by transforming growth factor β1. Proc Natl Acad Sci USA 89:5408–5412;1992.

  131. 131

    Okamoto A, Jiang W, Kim S-J, Spillare EA, Stoner GD, Weinstein IB, Harris CC. Overexpression of human cyclin D1 reduces the transforming growth factor β (TGF-β) type II receptor and growth inhibition by TGF-β1 in an immortalized human esophageal epithelial cell line. Proc Natl Acad Sci USA 91:11576–11580;1994.

  132. 132

    Ong G, Sikora K, Gullick W. Inactivation of the retinoblastoma gene does not lead to loss of TGF-β receptors or response to TGF-β in breast cancer cell lines. Oncogene 6:761–763;1991.

  133. 133

    Papadopoulos N, Nicolaides N, Wei Y, Ruben S, Carter K, Rosen C, Haseltine W, Fleischmann R, Fraser C, Adams M, Venter JC, Hamilton S, Petersen G, Watson P, Lynch H, Peltomäki P, Mecklin JP, de la Chapelle A, Kinzler K, Vogelstein B. Mutations of a mutL homolog in hereditary colon cancer. Science 263:1625–1629;1194.

  134. 134

    Park K, Kim S-J, Bang Y-J, Park J-G, Kim NK, Roberts AB, Sporn MB. Genetic changes in the transforming growth factor β (TGF-β) type II receptor gene in human gastric cancer cells: Correlation with sensitivity to growth inhibition by TGF-β. Proc Natl Acad Sci USA 91:8772–8776;1994.

  135. 135

    Parsons R, Myeroff LL, Liu BL, Willson JKV, Markowitz SD, Kinzler KW, Vogelstein B. Microsatellite instability and mutations of the transforming growth factor β type II receptor gene in colorectal cancer. Cancer Res 55:5548–5550;1995.

  136. 136

    Pierce D, Gorska A, Chtil A, Miese K, Page D, Coffey R, Moses H. Mammary tumor suppression by transforming growth factor β1 transgene expression. Proc Natl Acad Sci USA 92:4254–4258;1995.

  137. 137

    Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts J, Tempst P, Massagué J. Cloning of p27kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78:59–66;1994.

  138. 138

    Prendergast G, Davide J, deSolms S, Giulani E, Graham S, Gibbs J, Oliff A, Kohl. Farne-syltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton. N Mol Cell Biol 14:4194–4202;1994.

  139. 139

    Proetzel G, Pawlowski S, Wiles M, Yin M, Boivin G, Howles P, Ding J, Ferguson M, Doetschman T. Transforming growth factor-β3 is required for secondary palate fusion. Nat Genet 11:409–414;1195.

  140. 140

    Reiss M, Sartorelli A. Regulation of growth and differentiation of human keratinocytes by type β transforming growth factor and epidermal growth factor. Cancer Res 47:6705–6709;1987.

  141. 141

    Risinger J, Berchuck A, Kohler M, Watson P, Lynch H, Boyd J. Genetic instability of microsatellites in endometrial carcinoma. Cancer Res 53:5100–5103;1993.

  142. 142

    Roberts AB, Sporn MB. In: AB Robert and MB Sporn (eds), Peptide Growth Factors and Their Receptors. Handbook of Experimental Pharmacology. Heidelberg, Springer-Verlag: pp 419–472;1990.

  143. 143

    Roberts AB, Rosa F, Roche N, Coligan J, Garfield M, Rebbert M, Kondaiah P, Danielpour D, Kehrl J, Wahl S, Dawid I, Sporn MB. Isolation and characterization of TGF-β2 and TGF-β5 from medium conditioned by Xenopus XTC cells. Growth Factors 3:277–286;1990.

  144. 144

    Roberts AB, Anzano M, Meyers C, Wideman J, Blacher R, Pan YC, Stein S, Lehrman S, Smith J, Lamb L, Sporn MB. Purification and properties of a type beta transforming growth factor from bovine kidney. Biochemistry 22:5692–5698;1983.

  145. 145

    Robinson S, Silberstein G, Roberts AB, Flanders K, Daniel C. Regulated expression and growth inhibitory effects of transforming growth factor-beta isoforms in mouse mammary gland development. Development 113:867–878;1991.

  146. 146

    Roelen B, Lin H, Knezevic V, Freund E, Mummery C. Expression of TGF-βs and their receptors during implantation and organogenesis of the mouse embryo. Dev Biol 166:716–728;1994.

  147. 147

    Rogers S, Ryan G, Purchio A, Hammerman M. Metanephric transforming growth factor-β1 regulates nephrogenesis in vitro. Am J Physiol 264:F996–1002;1993.

  148. 148

    Rorke E, Jacobberger J. Transforming growth factor-β1 (TGFβ1) enhances apoptosis in human papillomavirus type 16-immortalized human ectocervical epithelial cells. Exp Cell Res 216:65–72;1995.

  149. 149

    Schlunneger M, Grutter M. An unusual feature by the crystal structure at 2.2 Å resolution of human transforming growth factorbeta 2. Nature 358:430–434;1992.

  150. 150

    Segarini P. TGF-β receptors: A complicated system of multiple binding proteins. Biochim Biophys Acta 1155:269–275;1995.

  151. 151

    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, Annunizata N, Doetschman T. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359:693–699;1992.

  152. 152

    Siepl C, Malpiero U, Fontana A. Transforming growth factor-β (TGF-β)-resistant helper T lymphocyte clones show a concomitant loss of all three types of TGF-β receptors. J Immunol 146:3063–3067;1991.

  153. 153

    Silberstein G, Daniel C. Reversible inhibition of mammary gland growth by transforming growth factor-β1. Science 237:291–293;1987.

  154. 154

    Sporn MB, Roberts AB. Autocrine growth factors and cancer. Nature 313:747–749;1985.

  155. 155

    Sun L, Wu G, Willson JKV, Zborowska E, Yang J, Rajkarunanayake I, Wang J, Gentry LE, Wang X-F, Brattain MG. Expression of transforming growth factor β type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells. J Biol Chem 269:26449–26455;1994.

  156. 156

    Takeuchi Y, Fukumoto, Matsumoto T. Relationship between actions of transforming growth factor (TGF)-β and cell surface expression of its receptors in clonal osteoblastic cells. J Cell Phys 162:315–321;1995.

  157. 157

    Thibodeau S, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 260:816–819;1993.

  158. 158

    Unsal H, Cengiz Y, Marcais C, Kew M, Volkmann M, Zentgraf H, Isselbacher K, Ozurk M. Genetic heterogeneity of hepatocellular carcinoma. Proc Natl Acad Sci USA 91:822–826;1994.

  159. 159

    Wang C, Eshleman J, Willson J, Markowitz S. TGF-β and substrate release are both inducers of apoptosis in a human colon adenoma cell line. Cancer Res 55:5101–5105;1995.

  160. 160

    Wang J, Sun L, Myeroff LL, Wang X, Gentry LE, Yang J, Liang J, Zborowska E, Markowitz S, Willson JKV, Brattain MG. Demonstration that mutation of the type II transforming growth factor β receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J Biol Chem 270:22044–22049;1995.

  161. 161

    Wang T, Donahoe PK, Zervos AS. Specific interaction of type I receptors of the TGF-β family with the immunophilin FKBP-12. Science 265:674–676;1994.

  162. 162

    Wang X-F, Lin H, Ng-Eaton E, Downward J, Lodish H, Weinberg R. Expression cloning and characterization of the TGF-β type III receptor. Cell 67:797–805;1991.

  163. 163

    Watson P, Lynch H. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71:677–685;1993.

  164. 164

    Wieser R, Attisano L, Wrana J, Massagué J. Signalling activity of transforming growth factor β type II receptors lacking specific domains in the cytoplasmic region. Mol Cell Biol 13:7239–7247;1993.

  165. 165

    Wieser R, Wrana J, Massagué J. GS domain mutations that constitutively activate TβR-1, the downstream signalling component in the TGF-β receptor complex. EMBO J 14:2199–2208;1995.

  166. 166

    Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang X-F, Massagué J. TGF-β signals through a heteromeric protein kinase receptor complex. Cell 71:1003–1014;1992.

  167. 167

    Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J. Mechanism of activation of the TGF-β receptor. Nature 370:341–347;1994.

  168. 168

    Wu S, Theodorescu D, Kerbel R, Willson JKV, Mulder K, Humphrey L, Brattain M. TGF-β1 is an autocrine-negative growth regulator of human colon carcinoma FET cells in vivo as revealed by transfection of an antisense expression vector. J Cell Biol 116:187–196;1992.

  169. 169

    Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Sishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K. Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science 270:2008–2011;1995.

  170. 170

    Yanagihara K, Tsumuraya M. Transforming growth factor β1 induces apoptotic cell death in cultured human gastric carcinoma cells. Cancer Res 52:4042–4045;1992.

  171. 171

    Yoo YD, Ueda H, Park K, Flanders KC, Lee Y, Jay G, Kim S-J. Regulation of transforming growth factor-β1 expression by the hepatitis B virus (HBV) X transcactivator. JCI 97:388–395;1996.

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kim, D.H., Kim, S. Transforming growth factor-β receptors: Role in physiology and disease. J Biomed Sci 3, 143–158 (1996). https://doi.org/10.1007/BF02253095

Download citation

Key words

  • Transforming growth factor-β
  • Tumorigenesis
  • Mutation
  • Tumor suppressor gene
  • Receptor
  • Microsatellite instability
  • Transcription