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Gene Review

Tgfbr1  -  transforming growth factor, beta receptor I

Mus musculus

Synonyms: ALK5, AU017191, Alk-5, ESK2, TGF-beta receptor type I, ...
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Disease relevance of Tgfbr1


High impact information on Tgfbr1


Biological context of Tgfbr1

  • Overall, the results indicate a key role for a tumour suppressor gene(s) encoded in an approximately 3 cM segment on proximal chromosome 4 and provide an experimental basis for the further investigation of the functional role of candidate genes which include Pax5 and Tgfbr1 [10].
  • Transgenic mice expressing an active mutant of Alk5 in the mammary gland (MMTV-Alk5(T204D)) exhibited reduced apoptosis in terminal endbuds and during postlactational involution [11].
  • The Alk5(lacZ) mice will be a valuable resource in identifying the in vivo cellular targets of TGF-beta family signals mediated by Alk5, both during embryonic development as well as in diverse pathological conditions [12].
  • Furthermore HSCs from T beta RI null mice exhibit a normal cell cycle distribution and do not differ in their ability long term to repopulate primary and secondary recipient mice following bone marrow transplantation [9].
  • Hybridization of a radiolabeled fragment internal to the deletion was detected in the genomes of TGF-beta-responsive cells, but not in JK cells, indicating that they contain no wild-type TbetaR-I gene [2].

Anatomical context of Tgfbr1

  • With RT-PCR, expression of the signaling TGF-beta receptors (types II and ALK-5) was shown to be absent in isolated germ layers of 6.0-7.5 days postcoitum (dpc) embryos, whereas the type III receptor and Tsk 7L were differentially expressed at these stages [13].
  • In addition, although Alk5-null embryos exhibit a defect in the formation of vascular smooth muscle layers, the lumens of blood vessels are generated properly, which stands in contrast to the severe dilation of the vascular lumens in Alk1-null mice [12].
  • In blood vessels, contrasting to predominant Alk1 expression in arterial endothelium, Alk5 expression was localized in the medial and adventitial layers of blood vessels, but was undetectable in the intimal layer [12].
  • Overall, a high level of Alk5 expression was found in perichondria, periostea, and the mesenchymal layers underlying epithelia in the kidney, lung, and gallbladder [12].
  • BACKGROUND: In endothelial cells (EC), transforming growth factor-beta (TGF-beta) can bind to and transduce signals through ALK1 and ALK5 [14].

Associations of Tgfbr1 with chemical compounds


Physical interactions of Tgfbr1

  • Transforming growth factor-beta (TGFbeta) isoforms initiate signaling by assembling a heterotetrameric complex of paired type I (TbetaRI) and type II (TbetaRII) receptors on the cell surface [17].
  • Here, we show that the extracellular domain of TbetaRI (TbetaRI-ED) binds in vitro with high affinity to complexes of the extracellular domain of TbetaRII (TbetaRII-ED) and TGFbetas 1 or 3, but not to either ligand or receptor alone [17].

Enzymatic interactions of Tgfbr1

  • Several studies have shown that TbetaR-II acts as a primary receptor, binding TGF-beta and phosphorylating TbetaR-I, whose kinase activity then propagates the signals [18].

Regulatory relationships of Tgfbr1

  • These results suggest that TGF beta-1 regulates two key dentin proteins involved in matrix mineralization most likely mediated through the type I ALK5 receptor and transduced by Smads 2, 3, and 4 [19].
  • We here demonstrated that TGF betas and T beta R-I are expressed in hair follicle epithelium and have found a positive reactivity for LTBP and T beta R-I in ++sebocytes [20].

Other interactions of Tgfbr1

  • Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis [21].
  • Alk5 mutant embryos showed malformations in anterior-posterior patterning, including the lack of expression of the posterior determinant Hoxc10, that resemble defects found in Gdf11-null mutants [21].
  • The expression of TbetaR-III was temporo-spatially restricted to the MEE during palatal fusion, while the expression of TbetaR-I was primarily localized in all palatal epithelia, consistent with the expression patterns of TbetaR-II and TGF-beta3 (Cui et al., 1998) [22].
  • ALK-3 and ALK-5 mRNAs first decreased on day 14 and increased again on day 21 [23].
  • The TGF-(beta) type I receptor (ALK-5) and its effector Smad proteins mediate the epithelial to mesenchymal transition [24].

Analytical, diagnostic and therapeutic context of Tgfbr1

  • To investigate the role of TGF-beta type III receptor (TbetaR-III) in MEE transformation, we examined the expression pattern of TbetaR-III in the developing palate from E12 to E15 mice in vivo and in vitro by immunohistochemistry and compared the expression pattern to that of type I receptor (TbetaR-I) [22].
  • To define the function of TGF-beta more precisely, we inactivated the TGF-beta type I receptor (TbetaRI) gene by gene targeting [8].
  • PCR primers that flanked the deleted TbetaR-I region amplified a single band from JK cell genomic DNA that lacked the last 178 bp of exon 1 and all of the approximately 5 kb of intron 1 [2].
  • Antibody-mediated immunofluorescence co-patching of epitope-tagged receptors provides the first evidence in live cells that TbetaRI [25].
  • Velocity centrifugation of endogenous receptors suggests that ligand-bound TbetaRI and TbetaRII form a heteromeric complex that is most likely a heterotetramer [25].


  1. Concerted action of TGF-beta 1 and its type II receptor in control of epidermal homeostasis in transgenic mice. Cui, W., Fowlis, D.J., Cousins, F.M., Duffie, E., Bryson, S., Balmain, A., Akhurst, R.J. Genes Dev. (1995) [Pubmed]
  2. A deletion in the gene for transforming growth factor beta type I receptor abolishes growth regulation by transforming growth factor beta in a cutaneous T-cell lymphoma. Schiemann, W.P., Pfeifer, W.M., Levi, E., Kadin, M.E., Lodish, H.F. Blood (1999) [Pubmed]
  3. Inhibition of p38 Mitogen-Activated Protein Kinase and Transforming Growth Factor-{beta}1/Smad Signaling Pathways Modulates the Development of Fibrosis in Adriamycin-Induced Nephropathy. Li, J., Campanale, N.V., Liang, R.J., Deane, J.A., Bertram, J.F., Ricardo, S.D. Am. J. Pathol. (2006) [Pubmed]
  4. Transforming growth factor beta type I receptor acts as a potent tumor suppressor in rat bladder carcinoma. Hattori, K., Okamoto, M., Oyasu, R. Carcinogenesis (1997) [Pubmed]
  5. Photocoagulation-induced retinal gliosis is inhibited by systemically expressed soluble TGF-beta receptor type II via adenovirus mediated gene transfer. Hisatomi, T., Sakamoto, T., Yamanaka, I., Sassa, Y., Kubota, T., Ueno, H., Ohnishi, Y., Ishibashi, T. Lab. Invest. (2002) [Pubmed]
  6. Characterization of type I receptors for transforming growth factor-beta and activin. ten Dijke, P., Yamashita, H., Ichijo, H., Franzén, P., Laiho, M., Miyazono, K., Heldin, C.H. Science (1994) [Pubmed]
  7. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. Goumans, M.J., Valdimarsdottir, G., Itoh, S., Rosendahl, A., Sideras, P., ten Dijke, P. EMBO J. (2002) [Pubmed]
  8. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. Larsson, J., Goumans, M.J., Sjöstrand, L.J., van Rooijen, M.A., Ward, D., Levéen, P., Xu, X., ten Dijke, P., Mummery, C.L., Karlsson, S. EMBO J. (2001) [Pubmed]
  9. TGF-beta signaling-deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro. Larsson, J., Blank, U., Helgadottir, H., Björnsson, J.M., Ehinger, M., Goumans, M.J., Fan, X., Levéen, P., Karlsson, S. Blood (2003) [Pubmed]
  10. Analysis of loss of heterozygosity in lymphoma and leukaemia arising in F1 hybrid mice locates a common region of chromosome 4 loss. Meijne, E., Huiskamp, R., Haines, J., Moody, J., Finnon, R., Wilding, J., Spanjer, S., Bouffler, S., Edwards, A., Cox, R., Silver, A. Genes Chromosomes Cancer (2001) [Pubmed]
  11. Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Muraoka-Cook, R.S., Shin, I., Yi, J.Y., Easterly, E., Barcellos-Hoff, M.H., Yingling, J.M., Zent, R., Arteaga, C.L. Oncogene (2006) [Pubmed]
  12. Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development. Seki, T., Hong, K.H., Oh, S.P. Lab. Invest. (2006) [Pubmed]
  13. Expression of TGF-beta s and their receptors during implantation and organogenesis of the mouse embryo. Roelen, B.A., Lin, H.Y., Knezević, V., Freund, E., Mummery, C.L. Dev. Biol. (1994) [Pubmed]
  14. Smad7 and protein phosphatase 1alpha are critical determinants in the duration of TGF-beta/ALK1 signaling in endothelial cells. Valdimarsdottir, G., Goumans, M.J., Itoh, F., Itoh, S., Heldin, C.H., ten Dijke, P. BMC Cell Biol. (2006) [Pubmed]
  15. Kinetic characterization of novel pyrazole TGF-beta receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition. Peng, S.B., Yan, L., Xia, X., Watkins, S.A., Brooks, H.B., Beight, D., Herron, D.K., Jones, M.L., Lampe, J.W., McMillen, W.T., Mort, N., Sawyer, J.S., Yingling, J.M. Biochemistry (2005) [Pubmed]
  16. Quiescence of hematopoietic stem cells and maintenance of the stem cell pool is not dependent on TGF-beta signaling in vivo. Larsson, J., Blank, U., Klintman, J., Magnusson, M., Karlsson, S. Exp. Hematol. (2005) [Pubmed]
  17. Assembly of TbetaRI:TbetaRII:TGFbeta ternary complex in vitro with receptor extracellular domains is cooperative and isoform-dependent. Zúñiga, J.E., Groppe, J.C., Cui, Y., Hinck, C.S., Contreras-Shannon, V., Pakhomova, O.N., Yang, J., Tang, Y., Mendoza, V., López-Casillas, F., Sun, L., Hinck, A.P. J. Mol. Biol. (2005) [Pubmed]
  18. Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling. Datta, P.K., Chytil, A., Gorska, A.E., Moses, H.L. J. Biol. Chem. (1998) [Pubmed]
  19. TGF beta-1 downregulates DMP-1 and DSPP in odontoblasts. Unterbrink, A., O'Sullivan, M., Chen, S., MacDougall, M. Connect. Tissue Res. (2002) [Pubmed]
  20. Expression of transforming growth factor beta isoforms and their receptors during hair growth phases in mice. Wollina, U., Lange, D., Funa, K., Paus, R. Histol. Histopathol. (1996) [Pubmed]
  21. Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis. Andersson, O., Reissmann, E., Ibáñez, C.F. EMBO Rep. (2006) [Pubmed]
  22. The TGF-beta type III receptor is localized to the medial edge epithelium during palatal fusion. Cui, X.M., Shuler, C.F. Int. J. Dev. Biol. (2000) [Pubmed]
  23. Temporal changes in expression of transforming growth factor-beta superfamily members and their receptors during bovine preodontoblast differentiation in vitro. Toyono, T., Nakashima, M., Kuhara, S., Akamine, A. Arch. Oral Biol. (1997) [Pubmed]
  24. TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. Piek, E., Moustakas, A., Kurisaki, A., Heldin, C.H., ten Dijke, P. J. Cell. Sci. (1999) [Pubmed]
  25. Transforming growth factor-beta induces formation of a dithiothreitol-resistant type I/Type II receptor complex in live cells. Wells, R.G., Gilboa, L., Sun, Y., Liu, X., Henis, Y.I., Lodish, H.F. J. Biol. Chem. (1999) [Pubmed]
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