Transforming growth factor, beta 3 explained

Transforming growth factor beta-3 is a protein that in humans is encoded by the gene.^{[1] [2]}

It is a type of protein, known as a cytokine, which is involved in cell differentiation, embryogenesis and development. It belongs to a large family of cytokines called the Transforming growth factor beta superfamily, which includes the TGF-β family, Bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), inhibins and activins.^[3]

TGF-β3 is believed to regulate molecules involved in cellular adhesion and extracellular matrix (ECM) formation during the process of palate development. Without TGF-β3, mammals develop a deformity known as a cleft palate.^{[4] [5]} This is caused by failure of epithelial cells in both sides of the developing palate to fuse. TGF-β3 also plays an essential role in controlling the development of lungs in mammals, by also regulating cell adhesion and ECM formation in this tissue,^[6] and controls wound healing by regulating the movements of epidermal and dermal cells in injured skin.^[1]

Interactions

Transforming growth factor, beta 3 has been shown to interact with TGF beta receptor 2.^{[7] [8] [9] [10]}

Clinical research

After successful phase I/II trials,^[11] human recombinant TGF-β3 (avotermin, planned trade name Juvista) failed in Phase III trials.^[12]

Further reading

• Kalluri R, Neilson EG . Epithelial-mesenchymal transition and its implications for fibrosis . The Journal of Clinical Investigation . 112 . 12 . 1776–84 . Dec 2003 . 14679171 . 297008 . 10.1172/JCI20530 .
• Arrick BA, Lee AL, Grendell RL, Derynck R . Inhibition of translation of transforming growth factor-beta 3 mRNA by its 5' untranslated region . Molecular and Cellular Biology . 11 . 9 . 4306–13 . Sep 1991 . 1875922 . 361291 . 10.1128/mcb.11.9.4306.
• ten Dijke P, Hansen P, Iwata KK, Pieler C, Foulkes JG . Identification of another member of the transforming growth factor type beta gene family . Proceedings of the National Academy of Sciences of the United States of America . 85 . 13 . 4715–9 . Jul 1988 . 3164476 . 280506 . 10.1073/pnas.85.13.4715 . 1988PNAS...85.4715T . free .
• Derynck R, Lindquist PB, Lee A, Wen D, Tamm J, Graycar JL, Rhee L, Mason AJ, Miller DA, Coffey RJ . A new type of transforming growth factor-beta, TGF-beta 3 . The EMBO Journal . 7 . 12 . 3737–43 . Dec 1988 . 3208746 . 454948 . 10.1002/j.1460-2075.1988.tb03257.x.
• Barton DE, Foellmer BE, Du J, Tamm J, Derynck R, Francke U . Chromosomal mapping of genes for transforming growth factors beta 2 and beta 3 in man and mouse: dispersion of TGF-beta gene family . Oncogene Research . 3 . 4 . 323–31 . 1989 . 3226728 .
• Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J . Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction . Nature Genetics . 11 . 4 . 415–21 . Dec 1995 . 7493022 . 10.1038/ng1295-415 . 22365206 .
• Nishida K, Sotozono C, Adachi W, Yamamoto S, Yokoi N, Kinoshita S . Transforming growth factor-beta 1, -beta 2 and -beta 3 mRNA expression in human cornea . Current Eye Research . 14 . 3 . 235–41 . Mar 1995 . 7796607 . 10.3109/02713689509033520 .
• Lin HY, Moustakas A, Knaus P, Wells RG, Henis YI, Lodish HF . The soluble exoplasmic domain of the type II transforming growth factor (TGF)-beta receptor. A heterogeneously glycosylated protein with high affinity and selectivity for TGF-beta ligands . The Journal of Biological Chemistry . 270 . 6 . 2747–54 . Feb 1995 . 7852346 . 10.1074/jbc.270.6.2747 . free .
• Rampazzo A, Nava A, Danieli GA, Buja G, Daliento L, Fasoli G, Scognamiglio R, Corrado D, Thiene G . The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome 14q23-q24 . Human Molecular Genetics . 3 . 6 . 959–62 . Jun 1994 . 7951245 . 10.1093/hmg/3.6.959 .
• Zhao Y, Chegini N, Flanders KC . Human fallopian tube expresses transforming growth factor (TGF beta) isoforms, TGF beta type I-III receptor messenger ribonucleic acid and protein, and contains [125I]TGF beta-binding sites . The Journal of Clinical Endocrinology and Metabolism . 79 . 4 . 1177–84 . Oct 1994 . 10.1210/jcem.79.4.7962292 . 7962292 .
• Hildebrand A, Romarís M, Rasmussen LM, Heinegård D, Twardzik DR, Border WA, Ruoslahti E . Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta . The Biochemical Journal . 302 . 2 . 527–34 . Sep 1994 . 8093006 . 1137259 . 10.1042/bj3020527.
• López-Casillas F, Payne HM, Andres JL, Massagué J . Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites . The Journal of Cell Biology . 124 . 4 . 557–68 . Feb 1994 . 8106553 . 2119924 . 10.1083/jcb.124.4.557 .
• Mittl PR, Priestle JP, Cox DA, McMaster G, Cerletti N, Grütter MG . The crystal structure of TGF-beta 3 and comparison to TGF-beta 2: implications for receptor binding . Protein Science . 5 . 7 . 1261–71 . Jul 1996 . 8819159 . 2143453 . 10.1002/pro.5560050705 .
• Ambros RA, Kallakury BV, Malfetano JH, Mihm MC . Cytokine, cell adhesion receptor, and tumor suppressor gene expression in vulvar squamous carcinoma: correlation with prominent fibromyxoid stromal response . International Journal of Gynecological Pathology . 15 . 4 . 320–5 . Oct 1996 . 8886879 . 10.1097/00004347-199610000-00004 .
• Djonov V, Ball RK, Graf S, Mottaz AE, Arnold AM, Flanders K, Studer UE, Merz VW . Transforming growth factor-beta 3 is expressed in nondividing basal epithelial cells in normal human prostate and benign prostatic hyperplasia, and is no longer detectable in prostate carcinoma . The Prostate . 31 . 2 . 103–9 . May 1997 . 9140123 . 10.1002/(SICI)1097-0045(19970501)31:2<103::AID-PROS5>3.0.CO;2-O . 22734222 .
• Jin L, Qian X, Kulig E, Sanno N, Scheithauer BW, Kovacs K, Young WF, Lloyd RV . Transforming growth factor-beta, transforming growth factor-beta receptor II, and p27Kip1 expression in nontumorous and neoplastic human pituitaries . The American Journal of Pathology . 151 . 2 . 509–19 . Aug 1997 . 9250163 . 1858020 .
• Lidral AC, Romitti PA, Basart AM, Doetschman T, Leysens NJ, Daack-Hirsch S, Semina EV, Johnson LR, Machida J, Burds A, Parnell TJ, Rubenstein JL, Murray JC . Association of MSX1 and TGFB3 with nonsyndromic clefting in humans . American Journal of Human Genetics . 63 . 2 . 557–68 . Aug 1998 . 9683588 . 1377298 . 10.1086/301956 .
• 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 . Jan 1999 . 9872992 . 10.1074/jbc.274.2.584 . free .
• Lux A, Attisano L, Marchuk DA . Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1 . The Journal of Biological Chemistry . 274 . 15 . 9984–92 . Apr 1999 . 10187774 . 10.1074/jbc.274.15.9984 . free .
• Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M, Nakanishi T, Takehara K . Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model . Journal of Cellular Physiology . 181 . 1 . 153–9 . Oct 1999 . 10457363 . 10.1002/(SICI)1097-4652(199910)181:1<153::AID-JCP16>3.0.CO;2-K . 21284888 .

External links

• GeneReviews/NCBI/NIH/UW entry on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
• OMIM entries on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant

Notes and References

1. Bandyopadhyay B, Fan J, Guan S, Li Y, Chen M, Woodley DT, Li W . A "traffic control" role for TGFbeta3: orchestrating dermal and epidermal cell motility during wound healing . The Journal of Cell Biology . 172 . 7 . 1093–105 . Mar 2006 . 16549496 . 2063766 . 10.1083/jcb.200507111 .
2. Web site: Entrez Gene: TGFB3 transforming growth factor, beta 3.
3. Herpin A, Lelong C, Favrel P . Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans . Developmental and Comparative Immunology . 28 . 5 . 461–85 . May 2004 . 15062644 . 10.1016/j.dci.2003.09.007 .
4. Taya Y, O'Kane S, Ferguson MW . Pathogenesis of cleft palate in TGF-beta3 knockout mice . Development . 126 . 17 . 3869–79 . Sep 1999 . 10.1242/dev.126.17.3869 . 10433915 .
5. Dudas M, Nagy A, Laping NJ, Moustakas A, Kaartinen V . Tgf-beta3-induced palatal fusion is mediated by Alk-5/Smad pathway . Developmental Biology . 266 . 1 . 96–108 . Feb 2004 . 14729481 . 10.1016/j.ydbio.2003.10.007 .
6. Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J . Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction . Nature Genetics . 11 . 4 . 415–21 . Dec 1995 . 7493022 . 10.1038/ng1295-415 . 22365206 .
7. De Crescenzo G, Pham PL, Durocher Y, O'Connor-McCourt MD . Transforming growth factor-beta (TGF-beta) binding to the extracellular domain of the type II TGF-beta receptor: receptor capture on a biosensor surface using a new coiled-coil capture system demonstrates that avidity contributes significantly to high affinity binding . Journal of Molecular Biology . 328 . 5 . 1173–83 . May 2003 . 12729750 . 10.1016/S0022-2836(03)00360-7 .
8. Hart PJ, Deep S, Taylor AB, Shu Z, Hinck CS, Hinck AP . Crystal structure of the human TbetaR2 ectodomain--TGF-beta3 complex . Nature Structural Biology . 9 . 3 . 203–8 . Mar 2002 . 11850637 . 10.1038/nsb766 . 13322593 .
9. 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 . Jan 1999 . 9872992 . 10.1074/jbc.274.2.584 . free .
10. Rotzer D, Roth M, Lutz M, Lindemann D, Sebald W, Knaus P . Type III TGF-beta receptor-independent signalling of TGF-beta2 via TbetaRII-B, an alternatively spliced TGF-beta type II receptor . The EMBO Journal . 20 . 3 . 480–90 . Feb 2001 . 11157754 . 133482 . 10.1093/emboj/20.3.480 .
11. Ferguson MW, Duncan J, Bond J, Bush J, Durani P, So K, Taylor L, Chantrey J, Mason T, James G, Laverty H, Occleston NL, Sattar A, Ludlow A, O'Kane S . Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies . Lancet . 373 . 9671 . 1264–74 . Apr 2009 . 19362676 . 10.1016/S0140-6736(09)60322-6 . 35671002 .
12. http://www.thepharmaletter.com/file/102058/renovo-shares-plummet-75-as-scar-revision-product-juvista-fails-to-meet-study-endpoints.html Renovo shares plummet 75% as scar revision product Juvista fails to meet study endpoints