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Gene Review

TGFBR1  -  transforming growth factor, beta receptor 1

Homo sapiens

Synonyms: AAT5, ACVRLK4, ALK-5, ALK5, Activin A receptor type II-like protein kinase of 53kD, ...
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Disease relevance of TGFBR1


Psychiatry related information on TGFBR1


High impact information on TGFBR1

  • A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2 [6].
  • Thirty percent of cases were identified as high or low TGF-beta signalers based on TGFB1 and TGFBR1 genotypes [7].
  • Homozygous deletions of ALK-5 were identified in 1 of 97 pancreatic and 1 of 12 biliary adenocarcinomas [8].
  • A germ-line variant of ALK-5, presumably a polymorphism, was identified, but no somatic intragenic mutations were identified upon sequencing of all coding regions of ALK-5 [8].
  • However, SPARC silencing in SSc fibroblasts appears not to be associated with TGFBR1- and Smad3-dependent processes [9].

Chemical compound and disease context of TGFBR1


Biological context of TGFBR1


Anatomical context of TGFBR1

  • A G-->A variant 24 bp downstream of the exon/intron 7 boundary of the TGFBR1 gene (Int7G24A) was evident in patients with RCC (46.5%, n = 86) and bladder and upper urinary tract TCC (49.2%, n = 65) significantly more frequently than in age-matched controls (28.3%, n = 113, p < 0.002 by chi2 test) [1].
  • To identify target genes of ALK-1 and ALK-5 in endothelial cells, we conducted oligonucleotide microarray analysis [3].
  • Here, we deleted the TGF-beta type I receptor gene Alk5 specifically in the embryonic ectodermal and neural crest cell lineages [15].
  • ALK5 and SKR1 mRNA levels were 6.8- and 9-fold greater in the pancreatic tumors in comparison with the corresponding levels in the normal pancreas [16].
  • To determine whether the inhibition of human osteoblast growth mediated by 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)D3) occurs as a result of changes in transforming growth factor (TGF) and TGF receptor synthesis, we examined the effects of 1 alpha,25(OH)2D3 on the synthesis of TGF beta and TGF-beta receptors [17].

Associations of TGFBR1 with chemical compounds


Regulatory relationships of TGFBR1

  • The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta [21].
  • In contrast, ALK5 inhibition effectively blocked Smad2 phosphorylation [22].
  • We have used a gene transfer model of progressive TGF-beta1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of ALK5, the specific TGF-beta receptor [11].
  • Both ALK2 and ALK5 are expressed throughout the heart with ALK2 expressed abundantly in endocardial cells of the outflow tract (OFT), ventricle, and AV cushion [23].

Other interactions of TGFBR1

  • Assignment of human transforming growth factor-beta type I and type III receptor genes (TGFBR1 and TGFBR3) to 9q33-q34 and 1p32-p33, respectively [24].
  • SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7 [25].
  • We searched for TGFBR1 and TGFBR2 mutations in 41 unrelated patients fulfilling the diagnostic criteria of Ghent nosology or with the tentative diagnosis of Marfan syndrome, in whom mutations in the FBN1 coding region were not identified [26].
  • CONCLUSION: The results indicate that SB431542 is a potent inhibitor of intracellular TGFbeta signaling in normal fibroblasts through selective interference with ALK-5-mediated Smad activation and Smad-dependent transcriptional responses [27].
  • In contrast, STAT-6-mediated stimulation of collagen gene expression induced by interleukin-13 was not prevented by SB431542, indicating the specificity of blockade for ALK-5-dependent signaling [27].

Analytical, diagnostic and therapeutic context of TGFBR1

  • Another germline deletion (TGFBR1*6A) and somatic mutations in the TGFBR1 were also analyzed by PCR and single-strand conformational polymorphism.RESULTS: The Int7G24A allele was evident in 32% of patients with preinvasive neoplasms and 48% of patients with invasive breast cancers compared with 26% controls (P = 0.00008) [28].
  • Int7G24A variant of the TGFBR1 gene and cancer risk: a meta-analysis of three case-control studies [29].
  • RT-PCR analysis of LbetaT2 cells and whole adult murine pituitaries indicated that both expressed Tgfbr1 mRNA, but that Tgfbr2 was not detected in LbetaT2 cells [30].
  • Increased expression of T beta R-II and ALK-5 proteins in the developing kidney was confirmed by immunohistochemistry [31].
  • In contrast, ALK-5 was not detected in these cells by either Western blot analysis or RT-PCR at all concentrations of DHT used in this study [10].


  1. An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder. Chen, T., Jackson, C., Costello, B., Singer, N., Colligan, B., Douglass, L., Pemberton, J., Deddens, J., Graff, J.R., Carter, J.H. Int. J. Cancer (2004) [Pubmed]
  2. Aneurysm syndromes caused by mutations in the TGF-beta receptor. Loeys, B.L., Schwarze, U., Holm, T., Callewaert, B.L., Thomas, G.H., Pannu, H., De Backer, J.F., Oswald, G.L., Symoens, S., Manouvrier, S., Roberts, A.E., Faravelli, F., Greco, M.A., Pyeritz, R.E., Milewicz, D.M., Coucke, P.J., Cameron, D.E., Braverman, A.C., Byers, P.H., De Paepe, A.M., Dietz, H.C. N. Engl. J. Med. (2006) [Pubmed]
  3. Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells. Ota, T., Fujii, M., Sugizaki, T., Ishii, M., Miyazawa, K., Aburatani, H., Miyazono, K. J. Cell. Physiol. (2002) [Pubmed]
  4. FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited. Adès, L.C., Sullivan, K., Biggin, A., Haan, E.A., Brett, M., Holman, K.J., Dixon, J., Robertson, S., Holmes, A.D., Rogers, J., Bennetts, B. Am. J. Med. Genet. A (2006) [Pubmed]
  5. Id: a target of BMP signaling. Miyazono, K., Miyazawa, K. Sci. STKE (2002) [Pubmed]
  6. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Loeys, B.L., Chen, J., Neptune, E.R., Judge, D.P., Podowski, M., Holm, T., Meyers, J., Leitch, C.C., Katsanis, N., Sharifi, N., Xu, F.L., Myers, L.A., Spevak, P.J., Cameron, D.E., De Backer, J., Hellemans, J., Chen, Y., Davis, E.C., Webb, C.L., Kress, W., Coucke, P., Rifkin, D.B., De Paepe, A.M., Dietz, H.C. Nat. Genet. (2005) [Pubmed]
  7. Combined genetic assessment of transforming growth factor-beta signaling pathway variants may predict breast cancer risk. Kaklamani, V.G., Baddi, L., Liu, J., Rosman, D., Phukan, S., Bradley, C., Hegarty, C., McDaniel, B., Rademaker, A., Oddoux, C., Ostrer, H., Michel, L.S., Huang, H., Chen, Y., Ahsan, H., Offit, K., Pasche, B. Cancer Res. (2005) [Pubmed]
  8. Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Goggins, M., Shekher, M., Turnacioglu, K., Yeo, C.J., Hruban, R.H., Kern, S.E. Cancer Res. (1998) [Pubmed]
  9. Attenuation of collagen production with small interfering RNA of SPARC in cultured fibroblasts from the skin of patients with scleroderma. Zhou, X., Tan, F.K., Guo, X., Arnett, F.C. Arthritis Rheum. (2006) [Pubmed]
  10. The conventional transforming growth factor-beta (TGF-beta) receptor type I is not required for TGF-beta 1 signaling in a human prostate cancer cell line, LNCaP. Kim, I.Y., Zelner, D.J., Lee, C. Exp. Cell Res. (1998) [Pubmed]
  11. Progressive Transforming Growth Factor {beta}1-induced Lung Fibrosis Is Blocked by an Orally Active ALK5 Kinase Inhibitor. Bonniaud, P., Margetts, P.J., Kolb, M., Schroeder, J.A., Kapoun, A.M., Damm, D., Murphy, A., Chakravarty, S., Dugar, S., Higgins, L., Protter, A.A., Gauldie, J. Am. J. Respir. Crit. Care Med. (2005) [Pubmed]
  12. Role of TGF-beta in cancer and the potential for therapy and prevention. Kaklamani, V.G., Pasche, B. Expert review of anticancer therapy. (2004) [Pubmed]
  13. Altered expression of TGFB receptors and mitogenic effects of TGFB in pancreatic carcinomas. Jonson, T., Albrechtsson, E., Axelson, J., Heidenblad, M., Gorunova, L., Johansson, B., Höglund, M. Int. J. Oncol. (2001) [Pubmed]
  14. The chromosome 9q genes TGFBR1, TSC1, and ZNF189 are rarely mutated in bladder cancer. van Tilborg, A.A., de Vries, A., Zwarthoff, E.C. J. Pathol. (2001) [Pubmed]
  15. Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion. Dudas, M., Kim, J., Li, W.Y., Nagy, A., Larsson, J., Karlsson, S., Chai, Y., Kaartinen, V. Dev. Biol. (2006) [Pubmed]
  16. Attenuated ALK5 receptor expression in human pancreatic cancer: correlation with resistance to growth inhibition. Baldwin, R.L., Friess, H., Yokoyama, M., Lopez, M.E., Kobrin, M.S., Büchler, M.W., Korc, M. Int. J. Cancer (1996) [Pubmed]
  17. 1 alpha,25-Dihydroxyvitamin D3 increases transforming growth factor and transforming growth factor receptor type I and II synthesis in human bone cells. Wu, Y., Haugen, J.D., Zinsmeister, A.R., Kumar, R. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  18. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Laping, N.J., Grygielko, E., Mathur, A., Butter, S., Bomberger, J., Tweed, C., Martin, W., Fornwald, J., Lehr, R., Harling, J., Gaster, L., Callahan, J.F., Olson, B.A. Mol. Pharmacol. (2002) [Pubmed]
  19. Isolation and molecular characterization of the porcine transforming growth factor beta type I receptor (TGFBR1) gene. Chen, K., Rund, L.A., Beever, J.E., Schook, L.B. Gene (2006) [Pubmed]
  20. Matrix contraction by dermal fibroblasts requires transforming growth factor-beta/activin-linked kinase 5, heparan sulfate-containing proteoglycans, and MEK/ERK: insights into pathological scarring in chronic fibrotic disease. Chen, Y., Shi-Wen, X., van Beek, J., Kennedy, L., McLeod, M., Renzoni, E.A., Bou-Gharios, G., Wilcox-Adelman, S., Goetinck, P.F., Eastwood, M., Black, C.M., Abraham, D.J., Leask, A. Am. J. Pathol. (2005) [Pubmed]
  21. The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Tojo, M., Hamashima, Y., Hanyu, A., Kajimoto, T., Saitoh, M., Miyazono, K., Node, M., Imamura, T. Cancer Sci. (2005) [Pubmed]
  22. TGF beta-induced focal complex formation in epithelial cells is mediated by activated ERK and JNK MAP kinases and is independent of Smad4. Imamichi, Y., Waidmann, O., Hein, R., Eleftheriou, P., Giehl, K., Menke, A. Biol. Chem. (2005) [Pubmed]
  23. Activin receptor-like kinase 2 and Smad6 regulate epithelial-mesenchymal transformation during cardiac valve formation. Desgrosellier, J.S., Mundell, N.A., McDonnell, M.A., Moses, H.L., Barnett, J.V. Dev. Biol. (2005) [Pubmed]
  24. Assignment of human transforming growth factor-beta type I and type III receptor genes (TGFBR1 and TGFBR3) to 9q33-q34 and 1p32-p33, respectively. Johnson, D.W., Qumsiyeh, M., Benkhalifa, M., Marchuk, D.A. Genomics (1995) [Pubmed]
  25. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. DaCosta Byfield, S., Major, C., Laping, N.J., Roberts, A.B. Mol. Pharmacol. (2004) [Pubmed]
  26. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Singh, K.K., Rommel, K., Mishra, A., Karck, M., Haverich, A., Schmidtke, J., Arslan-Kirchner, M. Hum. Mutat. (2006) [Pubmed]
  27. Selective inhibition of activin receptor-like kinase 5 signaling blocks profibrotic transforming growth factor beta responses in skin fibroblasts. Mori, Y., Ishida, W., Bhattacharyya, S., Li, Y., Platanias, L.C., Varga, J. Arthritis Rheum. (2004) [Pubmed]
  28. Int7G24A variant of transforming growth factor-beta receptor type I is associated with invasive breast cancer. Chen, T., Jackson, C.R., Link, A., Markey, M.P., Colligan, B.M., Douglass, L.E., Pemberton, J.O., Deddens, J.A., Graff, J.R., Carter, J.H. Clin. Cancer Res. (2006) [Pubmed]
  29. Int7G24A variant of the TGFBR1 gene and cancer risk: a meta-analysis of three case-control studies. Zhang, H.T. Lung Cancer (2005) [Pubmed]
  30. Differential regulation of follicle stimulating hormone by activin A and TGFB1 in murine gonadotropes. Gore, A.J., Philips, D.P., Miller, W.L., Bernard, D.J. Reprod. Biol. Endocrinol. (2005) [Pubmed]
  31. Differential expression of transforming growth factor-beta receptors in rat kidney development. Choi, M.E., Liu, A., Ballermann, B.J. Am. J. Physiol. (1997) [Pubmed]
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