TGF beta receptor 1 explained

Transforming growth factor beta receptor I (activin A receptor type II-like kinase, 53kDa) is a membrane-bound TGF beta receptor protein of the TGF-beta receptor family for the TGF beta superfamily of signaling ligands. TGFBR1 is its human gene.

Function

See also: TGF beta signaling pathway. The protein encoded by this gene forms a heteromeric complex with type II TGF-β receptors when bound to TGF-β, transducing the TGF-β signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys–Dietz aortic aneurysm syndrome (LDS, LDAS).^[1]

Interactions

TGF beta receptor 1 has been shown to interact with:

• Caveolin 1,^[2]
• Endoglin,^{[3] [4]}
• FKBP1A,^{[5] [6]}
• FNTA,^[7]
• Heat shock protein 90kDa alpha (cytosolic), member A1^[8]
• Mothers against decapentaplegic homolog 7,^{[9] [10] [11] [12] [13] [14]}
• PPP2R2A,^[15]
• STRAP,^{[14] [16]}
• TGF beta 1,^{[17] [18]} and
• TGF beta receptor 2.^{[2] [19]}

Inhibitors

• GW-788,388
• LY-2109761
• Galunisertib (LY-2157299)
• SB-431,542
• SB-525,334
• RepSox^[20]

Animal studies

Defects are observed when the TGFBR-1 gene is either knocked-out or when a constitutively active TGFBR-1 mutant (that is active in the presence or absence of ligand) is knocked-in.

In mouse TGFBR-1 knock-out models, the female mice were sterile. They developed oviductal diverticula and defective uterine smooth muscle, meaning that uterine smooth muscle layers were poorly formed. Oviductal diverticula are small, bulging pouches located on the oviduct, which is the tube that transports the ovum from the ovary to the uterus. This deformity of the oviduct occurred bilaterally and resulted in impaired embryo development and impaired transit of the embryos to the uterus. Ovulation and fertilization still occurred in the knock-outs, however remnants of embryos were found in these oviductal diverticula.^[21]

In mouse TGFBR-1 knock-in models where a constitutively active TGFBR-1 gene is conditionally induced, the over-activation of the TGFBR-1 receptors lead to infertility, a reduction in the number of uterine glands, and hypermuscled uteri (an increased amount of smooth muscle in the uteri).^[22]

Research into how turning off the TGFBR-1 gene affects spinal cord development in mice led to the discovery that, when the gene is turned off, external genitalia instead form as two hind legs.^[23]

These experiments show that the TGFB-1 receptor plays a critical role in the function of the female reproductive tract. They also show that genetic mutations in the TGFBR-1 gene may lead to fertility issues in women.

Further reading

• Massagué J . Receptors for the TGF-beta family . Cell . 69 . 7 . 1067–70 . June 1992 . 1319842 . 10.1016/0092-8674(92)90627-O . 54268875 .
• Wrana JL . TGF-beta receptors and signalling mechanisms . Mineral and Electrolyte Metabolism . 24 . 2–3 . 120–30 . 1998 . 9525694 . 10.1159/000057359 . 84458561 .
• Josso N, di Clemente N, Gouédard L . Anti-Müllerian hormone and its receptors . Molecular and Cellular Endocrinology . 179 . 1–2 . 25–32 . June 2001 . 11420127 . 10.1016/S0303-7207(01)00467-1 . 27316217 .

External links

• GeneReviews/NIH/NCBI/UW entry on Thoracic Aortic Aneurysms and Aortic Dissections
• GeneReviews/NCBI/NIH/UW entry on Loeys-Dietz Syndrome

Notes and References

1. Web site: Entrez Gene: TGFBR1 transforming growth factor, beta receptor I (activin A receptor type II-like kinase, 53kDa).
2. Razani B, Zhang XL, Bitzer M, von Gersdorff G, Böttinger EP, Lisanti MP . Caveolin-1 regulates transforming growth factor (TGF)-beta/SMAD signaling through an interaction with the TGF-beta type I receptor . The Journal of Biological Chemistry . 276 . 9 . 6727–38 . March 2001 . 11102446 . 10.1074/jbc.M008340200 . free .
3. Guerrero-Esteo M, Sanchez-Elsner T, Letamendia A, Bernabeu C . Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II . The Journal of Biological Chemistry . 277 . 32 . 29197–209 . August 2002 . 12015308 . 10.1074/jbc.M111991200 . free . 10261/167807 . free .
4. Barbara NP, Wrana JL, Letarte M . Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily . The Journal of Biological Chemistry . 274 . 2 . 584–94 . January 1999 . 9872992 . 10.1074/jbc.274.2.584 . free .
5. Wang T, Donahoe PK, Zervos AS . Specific interaction of type I receptors of the TGF-beta family with the immunophilin FKBP-12 . Science . 265 . 5172 . 674–6 . July 1994 . 7518616 . 10.1126/science.7518616 . 1994Sci...265..674W .
6. Liu F, Ventura F, Doody J, Massagué J . Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs . Molecular and Cellular Biology . 15 . 7 . 3479–86 . July 1995 . 7791754 . 230584 . 10.1128/mcb.15.7.3479 .
7. Kawabata M, Imamura T, Miyazono K, Engel ME, Moses HL . Interaction of the transforming growth factor-beta type I receptor with farnesyl-protein transferase-alpha . The Journal of Biological Chemistry . 270 . 50 . 29628–31 . December 1995 . 8530343 . 10.1074/jbc.270.50.29628 . free .
8. Wrighton KH, Lin X, Feng XH . Critical regulation of TGFbeta signaling by Hsp90 . Proceedings of the National Academy of Sciences of the United States of America . 105 . 27 . 9244–9 . July 2008 . 18591668 . 2453700 . 10.1073/pnas.0800163105 . 2008PNAS..105.9244W . free .
9. Mochizuki T, Miyazaki H, Hara T, Furuya T, Imamura T, Watabe T, Miyazono K . Roles for the MH2 domain of Smad7 in the specific inhibition of transforming growth factor-beta superfamily signaling . The Journal of Biological Chemistry . 279 . 30 . 31568–74 . July 2004 . 15148321 . 10.1074/jbc.M313977200 . free .
10. Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K . Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts . The Journal of Clinical Investigation . 113 . 2 . 253–64 . January 2004 . 14722617 . 310747 . 10.1172/JCI16269 .
11. Koinuma D, Shinozaki M, Komuro A, Goto K, Saitoh M, Hanyu A, Ebina M, Nukiwa T, Miyazawa K, Imamura T, Miyazono K . Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7 . The EMBO Journal . 22 . 24 . 6458–70 . December 2003 . 14657019 . 291827 . 10.1093/emboj/cdg632 .
12. Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL . Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation . Molecular Cell . 6 . 6 . 1365–75 . December 2000 . 11163210 . 10.1016/s1097-2765(00)00134-9 . free .
13. Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA, Wrana JL, Falb D . The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling . Cell . 89 . 7 . 1165–73 . June 1997 . 9215638 . 10.1016/s0092-8674(00)80303-7 . 16552782 . free .
14. Datta PK, Moses HL . STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling . Molecular and Cellular Biology . 20 . 9 . 3157–67 . May 2000 . 10757800 . 85610 . 10.1128/mcb.20.9.3157-3167.2000 .
15. Griswold-Prenner I, Kamibayashi C, Maruoka EM, Mumby MC, Derynck R . Physical and functional interactions between type I transforming growth factor beta receptors and Balpha, a WD-40 repeat subunit of phosphatase 2A . Molecular and Cellular Biology . 18 . 11 . 6595–604 . November 1998 . 9774674 . 109244 . 10.1128/mcb.18.11.6595 .
16. Datta PK, Chytil A, Gorska AE, Moses HL . Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling . The Journal of Biological Chemistry . 273 . 52 . 34671–4 . December 1998 . 9856985 . 10.1074/jbc.273.52.34671 . free .
17. Ebner R, Chen RH, Lawler S, Zioncheck T, Derynck R . Determination of type I receptor specificity by the type II receptors for TGF-beta or activin . Science . 262 . 5135 . 900–2 . November 1993 . 8235612 . 10.1126/science.8235612 . 1993Sci...262..900E .
18. Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E . Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis . Proceedings of the National Academy of Sciences of the United States of America . 97 . 6 . 2626–31 . March 2000 . 10716993 . 15979 . 10.1073/pnas.97.6.2626 . 2000PNAS...97.2626O . free .
19. Kawabata M, Chytil A, Moses HL . Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor . The Journal of Biological Chemistry . 270 . 10 . 5625–30 . March 1995 . 7890683 . 10.1074/jbc.270.10.5625 . free .
20. Mishra . Tarun . Bhardwaj . Vipin . Ahuja . Neha . Gadgil . Pallavi . Ramdas . Pavitra . Shukla . Sanjeev . Chande . Ajit . Improved loss-of-function CRISPR-Cas9 genome editing in human cells concomitant with inhibition of TGF-β signaling . Molecular Therapy - Nucleic Acids . June 2022 . 28 . 202–218 . 10.1016/j.omtn.2022.03.003. 35402072 . 8961078 . 247355285 .
21. Li Q, Agno JE, Edson MA, Nagaraja AK, Nagashima T, Matzuk MM . Transforming growth factor β receptor type 1 is essential for female reproductive tract integrity and function . PLOS Genetics . 7 . 10 . e1002320 . October 2011 . 22028666 . 3197682 . 10.1371/journal.pgen.1002320 . free .
22. Gao Y, Duran S, Lydon JP, DeMayo FJ, Burghardt RC, Bayless KJ, Bartholin L, Li Q . Constitutive activation of transforming growth factor Beta receptor 1 in the mouse uterus impairs uterine morphology and function . Biology of Reproduction . 92 . 2 . 34 . February 2015 . 25505200 . 10.1095/biolreprod.114.125146 . 4435420.
23. Reardon . Sara . 2024-03-28 . Scientists made a six-legged mouse embryo — here’s why . Nature . en . 10.1038/d41586-024-00943-7.