TGF beta receptor 1

TGFBR1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1B6C, 1IAS, 1PY5, 1RW8, 1VJY, 2L5S, 2PJY, 2WOT, 2WOU, 2X7O, 3FAA, 3GXL, 3HMM, 3KCF, 3KFD, 3TZM, 4X0M, 4X2J, 4X2K, 4X2N, 4X2G, 4X2F, 5E8W, 5E8X, 5E8U, 5E8T, 5E8S, 5E90, 5E8Z
Identifiers
Aliases	TGFBR1, AAT5, ACVRLK4, ALK-5, ALK5, ESS1, LDS1, LDS1A, LDS2A, MSSE, SKR4, TGFR-1, tbetaR-I, transforming growth factor beta receptor 1, TBRI, TBR-i
External IDs	OMIM: 190181 MGI: 98728 HomoloGene: 3177 GeneCards: TGFBR1
Gene location (Human)
Chr.	Chromosome 9 (human)[1]
End	99,154,192 bp[1]
Gene location (Mouse)
Chr.	Chromosome 4 (mouse)[2]
End	47,414,931 bp[2]
Gene ontology
Molecular function	• type II transforming growth factor beta receptor binding; • I-SMAD binding; • transforming growth factor beta-activated receptor activity; • kinase activity; • receptor binding; • ATP binding; • protein kinase activity; • metal ion binding; • protein serine/threonine kinase activity; • transforming growth factor beta receptor activity, type I; • transferase activity; • growth factor binding; • transmembrane receptor protein serine/threonine kinase activity; • GO:0001948 protein binding; • SMAD binding; • nucleotide binding; • transforming growth factor beta binding; • activin binding;
Cellular component	• endosome; • membrane; • bicellular tight junction; • cell surface; • membrane raft; • integral component of membrane; • receptor complex; • cell membrane; • cell junction; • intracellular; • intracellular membrane-bounded organelle; • integral component of plasma membrane; • activin receptor complex; • cell nucleus;
Biological process	• skeletal system development; • response to cholesterol; • regulation of protein ubiquitination; • post-embryonic development; • protein phosphorylation; • negative regulation of chondrocyte differentiation; • mesenchymal cell differentiation; • angiogenesis; • transforming growth factor beta receptor signaling pathway; • positive regulation of filopodium assembly; • extracellular structure organization; • pharyngeal system development; • apoptotic process; • cellular response to transforming growth factor beta stimulus; • pathway-restricted SMAD protein phosphorylation; • positive regulation of protein kinase B signaling; • regulation of transcription, DNA-templated; • activation of MAPKK activity; • kidney development; • collagen fibril organization; • thymus development; • cell motility; • negative regulation of extrinsic apoptotic signaling pathway; • positive regulation of apoptotic signaling pathway; • in utero embryonic development; • negative regulation of transforming growth factor beta receptor signaling pathway; • positive regulation of transcription, DNA-templated; • heart development; • positive regulation of cell growth; • parathyroid gland development; • artery morphogenesis; • blastocyst development; • activin receptor signaling pathway; • palate development; • cell differentiation; • male gonad development; • phosphorylation; • skeletal system morphogenesis; • wound healing; • negative regulation of apoptotic process; • epithelial–mesenchymal transition; • regulation of gene expression; • embryonic cranial skeleton morphogenesis; • positive regulation of cellular component movement; • peptidyl-threonine phosphorylation; • GO:0007243 intracellular signal transduction; • positive regulation of endothelial cell proliferation; • positive regulation of cell migration; • regulation of epithelial to mesenchymal transition; • positive regulation of pathway-restricted SMAD protein phosphorylation; • endothelial cell activation; • negative regulation of endothelial cell proliferation; • transmembrane receptor protein serine/threonine kinase signaling pathway; • lens development in camera-type eye; • peptidyl-serine phosphorylation; • cell cycle arrest; • positive regulation of cell proliferation; • regulation of growth; • neuron fate commitment; • regulation of protein binding; • endothelial cell migration; • germ cell migration; • positive regulation of SMAD protein import into nucleus; • cardiac epithelial to mesenchymal transition; • signal transduction; • anterior/posterior pattern specification; • proepicardium development; • ventricular trabecula myocardium morphogenesis; • ventricular compact myocardium morphogenesis; • positive regulation of epithelial to mesenchymal transition; • protein deubiquitination; • positive regulation of stress fiber assembly; • regulation of cardiac muscle cell proliferation; • ventricular septum morphogenesis; • angiogenesis involved in coronary vascular morphogenesis; • coronary artery morphogenesis; • positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation; • positive regulation of occluding junction disassembly; • epicardium morphogenesis; • positive regulation of apoptotic process; • positive regulation of gene expression; • pattern specification process;
	Sources:Amigo / QuickGO
Orthologs
	7046
	21812
	ENSG00000106799
	ENSMUSG00000007613
	P36897
	Q64729
	NM_001130916; NM_001306210; NM_004612
	NM_009370; NM_001312868; NM_001312869
	NP_001124388; NP_001293139; NP_004603
	NP_001299797; NP_001299798; NP_033396
	Wikidata
View/Edit Human	View/Edit Mouse

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

Function

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).[5]

Interactions

TGF beta receptor 1 has been shown to interact with:

Inhibitors

GW-788,388
LY-2109761
Galunisertib (LY-2157299)
SB-431,542
SB-525,334

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.[24]

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).[25]

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.

References

GRCh38: Ensembl release 89: ENSG00000106799 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000007613 - Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Entrez Gene: TGFBR1 transforming growth factor, beta receptor I (activin A receptor type II-like kinase, 53kDa)".
Razani B, Zhang XL, Bitzer M, von Gersdorff G, Böttinger EP, Lisanti MP (March 2001). "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. doi:10.1074/jbc.M008340200. PMID 11102446.
Guerrero-Esteo M, Sanchez-Elsner T, Letamendia A, Bernabeu C (August 2002). "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. doi:10.1074/jbc.M111991200. PMID 12015308.
Barbara NP, Wrana JL, Letarte M (January 1999). "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. doi:10.1074/jbc.274.2.584. PMID 9872992.
Wang T, Donahoe PK, Zervos AS (July 1994). "Specific interaction of type I receptors of the TGF-beta family with the immunophilin FKBP-12". Science. 265 (5172): 674–6. doi:10.1126/science.7518616. PMID 7518616.
Liu F, Ventura F, Doody J, Massagué J (July 1995). "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. doi:10.1128/mcb.15.7.3479. PMC 230584. PMID 7791754.
Kawabata M, Imamura T, Miyazono K, Engel ME, Moses HL (December 1995). "Interaction of the transforming growth factor-beta type I receptor with farnesyl-protein transferase-alpha". The Journal of Biological Chemistry. 270 (50): 29628–31. doi:10.1074/jbc.270.50.29628. PMID 8530343.
Wrighton KH, Lin X, Feng XH (July 2008). "Critical regulation of TGFbeta signaling by Hsp90". Proceedings of the National Academy of Sciences of the United States of America. 105 (27): 9244–9. doi:10.1073/pnas.0800163105. PMC 2453700. PMID 18591668.
Mochizuki T, Miyazaki H, Hara T, Furuya T, Imamura T, Watabe T, Miyazono K (July 2004). "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. doi:10.1074/jbc.M313977200. PMID 15148321.
Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K (January 2004). "Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts". The Journal of Clinical Investigation. 113 (2): 253–64. doi:10.1172/JCI16269. PMC 310747. PMID 14722617.
Koinuma D, Shinozaki M, Komuro A, Goto K, Saitoh M, Hanyu A, Ebina M, Nukiwa T, Miyazawa K, Imamura T, Miyazono K (December 2003). "Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7". The EMBO Journal. 22 (24): 6458–70. doi:10.1093/emboj/cdg632. PMC 291827. PMID 14657019.
Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL (December 2000). "Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation". Molecular Cell. 6 (6): 1365–75. doi:10.1016/s1097-2765(00)00134-9. PMID 11163210.
Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA, Wrana JL, Falb D (June 1997). "The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling". Cell. 89 (7): 1165–73. doi:10.1016/s0092-8674(00)80303-7. PMID 9215638. S2CID 16552782.
Datta PK, Moses HL (May 2000). "STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling". Molecular and Cellular Biology. 20 (9): 3157–67. doi:10.1128/mcb.20.9.3157-3167.2000. PMC 85610. PMID 10757800.
Griswold-Prenner I, Kamibayashi C, Maruoka EM, Mumby MC, Derynck R (November 1998). "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. doi:10.1128/mcb.18.11.6595. PMC 109244. PMID 9774674.
Datta PK, Chytil A, Gorska AE, Moses HL (December 1998). "Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling". The Journal of Biological Chemistry. 273 (52): 34671–4. doi:10.1074/jbc.273.52.34671. PMID 9856985.
Ebner R, Chen RH, Lawler S, Zioncheck T, Derynck R (November 1993). "Determination of type I receptor specificity by the type II receptors for TGF-beta or activin". Science. 262 (5135): 900–2. doi:10.1126/science.8235612. PMID 8235612.
Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E (March 2000). "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. doi:10.1073/pnas.97.6.2626. PMC 15979. PMID 10716993.
Kawabata M, Chytil A, Moses HL (March 1995). "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. doi:10.1074/jbc.270.10.5625. PMID 7890683.
Li Q, Agno JE, Edson MA, Nagaraja AK, Nagashima T, Matzuk MM (October 2011). "Transforming growth factor β receptor type 1 is essential for female reproductive tract integrity and function". PLOS Genetics. 7 (10): e1002320. doi:10.1371/journal.pgen.1002320. PMC 3197682. PMID 22028666.
Gao Y, Duran S, Lydon JP, DeMayo FJ, Burghardt RC, Bayless KJ, Bartholin L, Li Q (February 2015). "Constitutive activation of transforming growth factor Beta receptor 1 in the mouse uterus impairs uterine morphology and function". Biology of Reproduction. 92 (2): 34. doi:10.1095/biolreprod.114.125146. PMC 4435420. PMID 25505200.

External links

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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000106799 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000007613 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] "Entrez Gene: TGFBR1 transforming growth factor, beta receptor I (activin A receptor type II-like kinase, 53kDa)".

[pmid11102446-6] Razani B, Zhang XL, Bitzer M, von Gersdorff G, Böttinger EP, Lisanti MP (March 2001). "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. doi:10.1074/jbc.M008340200. PMID 11102446.

[pmid12015308-7] Guerrero-Esteo M, Sanchez-Elsner T, Letamendia A, Bernabeu C (August 2002). "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. doi:10.1074/jbc.M111991200. PMID 12015308.

[pmid9872992-8] Barbara NP, Wrana JL, Letarte M (January 1999). "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. doi:10.1074/jbc.274.2.584. PMID 9872992.

[pmid7518616-9] Wang T, Donahoe PK, Zervos AS (July 1994). "Specific interaction of type I receptors of the TGF-beta family with the immunophilin FKBP-12". Science. 265 (5172): 674–6. doi:10.1126/science.7518616. PMID 7518616.

[pmid7791754-10] Liu F, Ventura F, Doody J, Massagué J (July 1995). "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. doi:10.1128/mcb.15.7.3479. PMC 230584. PMID 7791754.

[pmid8530343-11] Kawabata M, Imamura T, Miyazono K, Engel ME, Moses HL (December 1995). "Interaction of the transforming growth factor-beta type I receptor with farnesyl-protein transferase-alpha". The Journal of Biological Chemistry. 270 (50): 29628–31. doi:10.1074/jbc.270.50.29628. PMID 8530343.

[pmid18591668-12] Wrighton KH, Lin X, Feng XH (July 2008). "Critical regulation of TGFbeta signaling by Hsp90". Proceedings of the National Academy of Sciences of the United States of America. 105 (27): 9244–9. doi:10.1073/pnas.0800163105. PMC 2453700. PMID 18591668.

[pmid15148321-13] Mochizuki T, Miyazaki H, Hara T, Furuya T, Imamura T, Watabe T, Miyazono K (July 2004). "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. doi:10.1074/jbc.M313977200. PMID 15148321.

[pmid14722617-14] Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K (January 2004). "Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts". The Journal of Clinical Investigation. 113 (2): 253–64. doi:10.1172/JCI16269. PMC 310747. PMID 14722617.

[pmid14657019-15] Koinuma D, Shinozaki M, Komuro A, Goto K, Saitoh M, Hanyu A, Ebina M, Nukiwa T, Miyazawa K, Imamura T, Miyazono K (December 2003). "Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7". The EMBO Journal. 22 (24): 6458–70. doi:10.1093/emboj/cdg632. PMC 291827. PMID 14657019.

[pmid11163210-16] Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL (December 2000). "Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation". Molecular Cell. 6 (6): 1365–75. doi:10.1016/s1097-2765(00)00134-9. PMID 11163210.

[pmid9215638-17] Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA, Wrana JL, Falb D (June 1997). "The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling". Cell. 89 (7): 1165–73. doi:10.1016/s0092-8674(00)80303-7. PMID 9215638. S2CID 16552782.

[pmid10757800-18] Datta PK, Moses HL (May 2000). "STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling". Molecular and Cellular Biology. 20 (9): 3157–67. doi:10.1128/mcb.20.9.3157-3167.2000. PMC 85610. PMID 10757800.

[pmid9774674-19] Griswold-Prenner I, Kamibayashi C, Maruoka EM, Mumby MC, Derynck R (November 1998). "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. doi:10.1128/mcb.18.11.6595. PMC 109244. PMID 9774674.

[pmid9856985-20] Datta PK, Chytil A, Gorska AE, Moses HL (December 1998). "Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling". The Journal of Biological Chemistry. 273 (52): 34671–4. doi:10.1074/jbc.273.52.34671. PMID 9856985.

[pmid8235612-21] Ebner R, Chen RH, Lawler S, Zioncheck T, Derynck R (November 1993). "Determination of type I receptor specificity by the type II receptors for TGF-beta or activin". Science. 262 (5135): 900–2. doi:10.1126/science.8235612. PMID 8235612.

[pmid10716993-22] Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E (March 2000). "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. doi:10.1073/pnas.97.6.2626. PMC 15979. PMID 10716993.

[pmid7890683-23] Kawabata M, Chytil A, Moses HL (March 1995). "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. doi:10.1074/jbc.270.10.5625. PMID 7890683.

[24] Li Q, Agno JE, Edson MA, Nagaraja AK, Nagashima T, Matzuk MM (October 2011). "Transforming growth factor β receptor type 1 is essential for female reproductive tract integrity and function". PLOS Genetics. 7 (10): e1002320. doi:10.1371/journal.pgen.1002320. PMC 3197682. PMID 22028666.

[25] Gao Y, Duran S, Lydon JP, DeMayo FJ, Burghardt RC, Bayless KJ, Bartholin L, Li Q (February 2015). "Constitutive activation of transforming growth factor Beta receptor 1 in the mouse uterus impairs uterine morphology and function". Biology of Reproduction. 92 (2): 34. doi:10.1095/biolreprod.114.125146. PMC 4435420. PMID 25505200.