Growth/differentiation factor 5

NameGrowth/differentiation factor 5
Synonyms
  • BMP-14
  • BMP14
  • Bone morphogenetic protein 14
  • Cartilage-derived morphogenetic protein 1
  • CDMP-1
  • CDMP1
  • GDF-5
  • LAP-4
  • Lipopolysaccharide-associated protein 4
  • LPS-associated protein 4
  • Radotermin
Gene NameGDF5
OrganismHuman
Amino acid sequence
>lcl|BSEQ0020629|Growth/differentiation factor 5
MRLPKLLTFLLWYLAWLDLEFICTVLGAPDLGQRPQGTRPGLAKAEAKERPPLARNVFRP
GGHSYGGGATNANARAKGGTGQTGGLTQPKKDEPKKLPPRPGGPEPKPGHPPQTRQATAR
TVTPKGQLPGGKAPPKAGSVPSSFLLKKAREPGPPREPKEPFRPPPITPHEYMLSLYRTL
SDADRKGGNSSVKLEAGLANTITSFIDKGQDDRGPVVRKQRYVFDISALEKDGLLGAELR
ILRKKPSDTAKPAAPGGGRAAQLKLSSCPSGRQPASLLDVRSVPGLDGSGWEVFDIWKLF
RNFKNSAQLCLELEAWERGRAVDLRGLGFDRAARQVHEKALFLVFGRTKKRDLFFNEIKA
RSGQDDKTVYEYLFSQRRKRRAPLATRQGKRPSKNLKARCSRKALHVNFKDMGWDDWIIA
PLEYEAFHCEGLCEFPLRSHLEPTNHAVIQTLMNSMDPESTPPTCCVPTRLSPISILFID
SANNVVYKQYEDMVVESCGCR
Number of residues501
Molecular Weight55410.15
Theoretical pI10.41
GO Classification
Functions
  • transforming growth factor beta receptor binding
  • identical protein binding
  • BMP binding
  • growth factor activity
  • cytokine activity
Processes
  • positive regulation of chondrocyte differentiation
  • negative regulation of epithelial cell proliferation
  • growth
  • negative regulation of chondrocyte differentiation
  • cell-cell signaling
  • chondrocyte differentiation
  • regulation of apoptotic process
  • SMAD protein signal transduction
  • cell development
  • extracellular matrix organization
  • SMAD protein import into nucleus
  • regulation of multicellular organism growth
  • embryonic limb morphogenesis
  • regulation of MAPK cascade
  • hindlimb morphogenesis
  • positive regulation of neuron differentiation
  • negative regulation of mesenchymal cell apoptotic process
  • transforming growth factor beta receptor signaling pathway
  • BMP signaling pathway
  • positive regulation of pathway-restricted SMAD protein phosphorylation
  • forelimb morphogenesis
  • negative regulation of neuron apoptotic process
  • chondroblast differentiation
  • mitophagy in response to mitochondrial depolarization
  • positive regulation of BMP signaling pathway
Components
  • intracellular
  • extracellular region
  • plasma membrane
  • extracellular space
General FunctionTransforming growth factor beta receptor binding
Specific FunctionGrowth factor involved in bone and cartilage formation. During cartilage development regulates differentiation of chondrogenic tissue through two pathways. Firstly, positively regulates differentiation of chondrogenic tissue through its binding of high affinity with BMPR1B and of less affinity with BMPR1A, leading to induction of SMAD1-SMAD5-SMAD8 complex phosphorylation and then SMAD protein signaling transduction (PubMed:24098149, PubMed:21976273, PubMed:15530414, PubMed:25092592). Secondly, negatively regulates chondrogenic differentiation through its interaction with NOG (PubMed:21976273). Required to prevent excessive muscle loss upon denervation. This function requires SMAD4 and is mediated by phosphorylated SMAD1/5/8 (By similarity). Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205).
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein IDNot Available
UniProtKB IDP43026
UniProtKB Entry NameGDF5_HUMAN
Cellular LocationSecreted
Gene sequence
>lcl|BSEQ0020630|Growth/differentiation factor 5 (GDF5)
ATGAGACTCCCCAAACTCCTCACTTTCTTGCTTTGGTACCTGGCTTGGCTGGACCTGGAA
TTCATCTGCACTGTGTTGGGTGCCCCTGACTTGGGCCAGAGACCCCAGGGGACCAGGCCA
GGATTGGCCAAAGCAGAGGCCAAGGAGAGGCCCCCCCTGGCCCGGAACGTCTTCAGGCCA
GGGGGTCACAGCTATGGTGGGGGGGCCACCAATGCCAATGCCAGGGCAAAGGGAGGCACC
GGGCAGACAGGAGGCCTGACACAGCCCAAGAAGGATGAACCCAAAAAGCTGCCCCCCAGA
CCGGGCGGCCCTGAACCCAAGCCAGGACACCCTCCCCAAACAAGGCAGGCTACAGCCCGG
ACTGTGACCCCAAAAGGACAGCTTCCCGGAGGCAAGGCACCCCCAAAAGCAGGATCTGTC
CCCAGCTCCTTCCTGCTGAAGAAGGCCAGGGAGCCCGGGCCCCCACGAGAGCCCAAGGAG
CCGTTTCGCCCACCCCCCATCACACCCCACGAGTACATGCTCTCGCTGTACAGGACGCTG
TCCGATGCTGACAGAAAGGGAGGCAACAGCAGCGTGAAGTTGGAGGCTGGCCTGGCCAAC
ACCATCACCAGCTTTATTGACAAAGGGCAAGATGACCGAGGTCCCGTGGTCAGGAAGCAG
AGGTACGTGTTTGACATTAGTGCCCTGGAGAAGGATGGGCTGCTGGGGGCCGAGCTGCGG
ATCTTGCGGAAGAAGCCCTCGGACACGGCCAAGCCAGCGGCCCCCGGAGGCGGGCGGGCT
GCCCAGCTGAAGCTGTCCAGCTGCCCCAGCGGCCGGCAGCCGGCCGCCTTGCTGGATGTG
CGCTCCGTGCCAGGCCTGGACGGATCTGGCTGGGAGGTGTTCGACATCTGGAAGCTCTTC
CGAAACTTTAAGAACTCGGCCCAGCTGTGCCTGGAGCTGGAGGCCTGGGAACGGGGCAGG
GCCGTGGACCTCCGTGGCCTGGGCTTCGACCGCGCCGCCCGGCAGGTCCACGAGAAAGCC
CTGTTCCTGGTGTTTGGCCGCACCAAGAAACGGGACCTGTTCTTTAATGAGATTAAGGCC
CGCTCTGGCCAGGACGATAAGACCGTGTATGAGTACCTGTTCAGCCAGCGGCGAAAACGG
CGGGCCCCACTGGCCACTCGCCAGGGCAAGCGACCCAGCAAGAACCTTAAGGCTCGCTGC
AGTCGGAAGGCACTGCATGTCAACTTCAAGGACATGGGCTGGGACGACTGGATCATCGCA
CCCCTTGAGTACGAGGCTTTCCACTGCGAGGGGCTGTGCGAGTTCCCATTGCGCTCCCAC
CTGGAGCCCACGAATCATGCAGTCATCCAGACCCTGATGAACTCCATGGACCCCGAGTCC
ACACCACCCACCTGCTGTGTGCCCACGCGGCTGAGTCCCATCAGCATCCTCTTCATTGAC
TCTGCCAACAACGTGGTGTATAAGCAGTATGAGGACATGGTCGTGGAGTCGTGTGGCTGC
AGGTAG
GenBank Gene IDX80915
GeneCard IDNot Available
GenAtlas IDGDF5
HGNC IDHGNC:4220
Chromosome Location20
Locus20q11.2
References
  1. Hotten G, Neidhardt H, Jacobowsky B, Pohl J: Cloning and expression of recombinant human growth/differentiation factor 5. Biochem Biophys Res Commun. 1994 Oct 28;204(2):646-52. 7980526
  2. Chang SC, Hoang B, Thomas JT, Vukicevic S, Luyten FP, Ryba NJ, Kozak CA, Reddi AH, Moos M Jr: Cartilage-derived morphogenetic proteins. New members of the transforming growth factor-beta superfamily predominantly expressed in long bones during human embryonic development. J Biol Chem. 1994 Nov 11;269(45):28227-34. 7961761
  3. Deloukas P, Matthews LH, Ashurst J, Burton J, Gilbert JG, Jones M, Stavrides G, Almeida JP, Babbage AK, Bagguley CL, Bailey J, Barlow KF, Bates KN, Beard LM, Beare DM, Beasley OP, Bird CP, Blakey SE, Bridgeman AM, Brown AJ, Buck D, Burrill W, Butler AP, Carder C, Carter NP, Chapman JC, Clamp M, Clark G, Clark LN, Clark SY, Clee CM, Clegg S, Cobley VE, Collier RE, Connor R, Corby NR, Coulson A, Coville GJ, Deadman R, Dhami P, Dunn M, Ellington AG, Frankland JA, Fraser A, French L, Garner P, Grafham DV, Griffiths C, Griffiths MN, Gwilliam R, Hall RE, Hammond S, Harley JL, Heath PD, Ho S, Holden JL, Howden PJ, Huckle E, Hunt AR, Hunt SE, Jekosch K, Johnson CM, Johnson D, Kay MP, Kimberley AM, King A, Knights A, Laird GK, Lawlor S, Lehvaslaiho MH, Leversha M, Lloyd C, Lloyd DM, Lovell JD, Marsh VL, Martin SL, McConnachie LJ, McLay K, McMurray AA, Milne S, Mistry D, Moore MJ, Mullikin JC, Nickerson T, Oliver K, Parker A, Patel R, Pearce TA, Peck AI, Phillimore BJ, Prathalingam SR, Plumb RW, Ramsay H, Rice CM, Ross MT, Scott CE, Sehra HK, Shownkeen R, Sims S, Skuce CD, Smith ML, Soderlund C, Steward CA, Sulston JE, Swann M, Sycamore N, Taylor R, Tee L, Thomas DW, Thorpe A, Tracey A, Tromans AC, Vaudin M, Wall M, Wallis JM, Whitehead SL, Whittaker P, Willey DL, Williams L, Williams SA, Wilming L, Wray PW, Hubbard T, Durbin RM, Bentley DR, Beck S, Rogers J: The DNA sequence and comparative analysis of human chromosome 20. Nature. 2001 Dec 20-27;414(6866):865-71. 11780052
  4. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  5. Thomas JT, Lin K, Nandedkar M, Camargo M, Cervenka J, Luyten FP: A human chondrodysplasia due to a mutation in a TGF-beta superfamily member. Nat Genet. 1996 Mar;12(3):315-7. 8589725
  6. Triantafilou K, Triantafilou M, Dedrick RL: A CD14-independent LPS receptor cluster. Nat Immunol. 2001 Apr;2(4):338-45. 11276205
  7. Bai X, Xiao Z, Pan Y, Hu J, Pohl J, Wen J, Li L: Cartilage-derived morphogenetic protein-1 promotes the differentiation of mesenchymal stem cells into chondrocytes. Biochem Biophys Res Commun. 2004 Dec 10;325(2):453-60. 15530414
  8. Seemann P, Brehm A, Konig J, Reissner C, Stricker S, Kuss P, Haupt J, Renninger S, Nickel J, Sebald W, Groppe JC, Ploger F, Pohl J, Schmidt-von Kegler M, Walther M, Gassner I, Rusu C, Janecke AR, Dathe K, Mundlos S: Mutations in GDF5 reveal a key residue mediating BMP inhibition by NOGGIN. PLoS Genet. 2009 Nov;5(11):e1000747. doi: 10.1371/journal.pgen.1000747. Epub 2009 Nov 26. 19956691
  9. Schwaerzer GK, Hiepen C, Schrewe H, Nickel J, Ploeger F, Sebald W, Mueller T, Knaus P: New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): mutation within the GDF5 knuckle epitope causes noggin-resistance. J Bone Miner Res. 2012 Feb;27(2):429-42. doi: 10.1002/jbmr.532. 21976273
  10. Degenkolbe E, Konig J, Zimmer J, Walther M, Reissner C, Nickel J, Ploger F, Raspopovic J, Sharpe J, Dathe K, Hecht JT, Mundlos S, Doelken SC, Seemann P: A GDF5 point mutation strikes twice--causing BDA1 and SYNS2. PLoS Genet. 2013;9(10):e1003846. doi: 10.1371/journal.pgen.1003846. Epub 2013 Oct 3. 24098149
  11. Stange K, Thieme T, Hertel K, Kuhfahl S, Janecke AR, Piza-Katzer H, Penttinen M, Hietala M, Dathe K, Mundlos S, Schwarz E, Seemann P: Molecular analysis of two novel missense mutations in the GDF5 proregion that reduce protein activity and are associated with brachydactyly type C. J Mol Biol. 2014 Sep 23;426(19):3221-31. doi: 10.1016/j.jmb.2014.07.029. Epub 2014 Aug 1. 25092592
  12. Gutierrez-Amavizca BE, Brambila-Tapia AJ, Juarez-Vazquez CI, Holder-Espinasse M, Manouvrier-Hanu S, Escande F, Barros-Nunez P: A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum. Eur J Med Genet. 2012 Nov;55(11):611-4. doi: 10.1016/j.ejmg.2012.07.004. Epub 2012 Jul 22. 22828468
  13. Kotzsch A, Nickel J, Seher A, Sebald W, Muller TD: Crystal structure analysis reveals a spring-loaded latch as molecular mechanism for GDF-5-type I receptor specificity. EMBO J. 2009 Apr 8;28(7):937-47. doi: 10.1038/emboj.2009.37. Epub 2009 Feb 19. 19229295
  14. Thomas JT, Kilpatrick MW, Lin K, Erlacher L, Lembessis P, Costa T, Tsipouras P, Luyten FP: Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat Genet. 1997 Sep;17(1):58-64. 9288098
  15. Faiyaz-Ul-Haque M, Ahmad W, Zaidi SH, Haque S, Teebi AS, Ahmad M, Cohn DH, Tsui LC: Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome). Clin Genet. 2002 Jun;61(6):454-8. 12121354
  16. Schwabe GC, Turkmen S, Leschik G, Palanduz S, Stover B, Goecke TO, Mundlos S: Brachydactyly type C caused by a homozygous missense mutation in the prodomain of CDMP1. Am J Med Genet A. 2004 Feb 1;124A(4):356-63. 14735582
  17. Szczaluba K, Hilbert K, Obersztyn E, Zabel B, Mazurczak T, Kozlowski K: Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene. Am J Med Genet A. 2005 Nov 1;138(4):379-83. 16222676
  18. Seemann P, Schwappacher R, Kjaer KW, Krakow D, Lehmann K, Dawson K, Stricker S, Pohl J, Ploger F, Staub E, Nickel J, Sebald W, Knaus P, Mundlos S: Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. J Clin Invest. 2005 Sep;115(9):2373-81. Epub 2005 Aug 25. 16127465
  19. Dawson K, Seeman P, Sebald E, King L, Edwards M, Williams J 3rd, Mundlos S, Krakow D: GDF5 is a second locus for multiple-synostosis syndrome. Am J Hum Genet. 2006 Apr;78(4):708-12. Epub 2006 Feb 24. 16532400
  20. Wang X, Xiao F, Yang Q, Liang B, Tang Z, Jiang L, Zhu Q, Chang W, Jiang J, Jiang C, Ren X, Liu JY, Wang QK, Liu M: A novel mutation in GDF5 causes autosomal dominant symphalangism in two Chinese families. Am J Med Genet A. 2006 Sep 1;140A(17):1846-53. 16892395
  21. Miyamoto Y, Mabuchi A, Shi D, Kubo T, Takatori Y, Saito S, Fujioka M, Sudo A, Uchida A, Yamamoto S, Ozaki K, Takigawa M, Tanaka T, Nakamura Y, Jiang Q, Ikegawa S: A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat Genet. 2007 Apr;39(4):529-33. Epub 2007 Mar 25. 17384641
  22. Douzgou S, Lehmann K, Mingarelli R, Mundlos S, Dallapiccola B: Compound heterozygosity for GDF5 in Du Pan type chondrodysplasia. Am J Med Genet A. 2008 Aug 15;146A(16):2116-21. doi: 10.1002/ajmg.a.32435. 18629880
  23. Ploger F, Seemann P, Schmidt-von Kegler M, Lehmann K, Seidel J, Kjaer KW, Pohl J, Mundlos S: Brachydactyly type A2 associated with a defect in proGDF5 processing. Hum Mol Genet. 2008 May 1;17(9):1222-33. doi: 10.1093/hmg/ddn012. Epub 2008 Jan 18. 18203755
  24. Yang W, Cao L, Liu W, Jiang L, Sun M, Zhang D, Wang S, Lo WH, Luo Y, Zhang X: Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism. J Hum Genet. 2008;53(4):368-74. doi: 10.1007/s10038-008-0253-7. Epub 2008 Feb 19. 18283415
  25. Byrnes AM, Racacho L, Nikkel SM, Xiao F, MacDonald H, Underhill TM, Bulman DE: Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat. 2010 Oct;31(10):1155-62. doi: 10.1002/humu.21338. 20683927
  26. Al-Qattan MM, Al-Motairi MI, Al Balwi MA: Two novel homozygous missense mutations in the GDF5 gene cause brachydactyly type C. Am J Med Genet A. 2015 Jul;167(7):1621-6. doi: 10.1002/ajmg.a.37040. Epub 2015 Mar 28. 25820810