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Growth differentiation factor 2 (GDF2) also known as bone morphogenetic protein (BMP)-9 is a protein that in humans is encoded by the GDF2 gene.[1] GDF2 belongs to the transforming growth factor beta superfamily.


GDF2 contains an N-terminal TGF-beta-like pro-peptide (prodomain) (residues 56–257) and a C-terminal transforming growth factor beta superfamily domain (325–428).[2] GDF2 (BMP9) is secreted as a pro-complex consisting of the BMP9 growth factor dimer non-covalently bound to two BMP9 prodomain molecules in an open-armed conformation.[3]


GDF2 has a role in inducing and maintaining the ability of embryonic basal forebrain cholinergic neurons (BFCN) to respond to a neurotransmitter called acetylcholine; BFCN are important for the processes of learning, memory and attention.[4] GDF2 is also important for the maturation of BFCN.[4] Another role of GDF2 has been recently suggested. GDF2 is a potent inducer of hepcidin (a cationic peptide that has antimicrobial properties) in liver cells (hepatocytes) and can regulate iron metabolism.[5] The physiological receptor of GDF2 is thought to be activin receptor-like kinase 1, ALK1 (also called ACVRL1), an endothelial-specific type I receptor of the TGF-beta receptor family.[6] Endoglin, a type I membrane glycoprotein that forms the TGF-beta receptor complex, is a co-receptor of ALK1 for GDF2/BMP-9 binding. Mutations in ALK1 and endoglin cause hereditary hemorrhagic telangiectasia (HHT), a rare but life-threatening genetic disorder that leads to abnormal blood vessel formation in multiple tissues and organs of the body.[7]

GDF2 is one of the most potent BMPs to induce orthotopic bone formation in vivo. BMP3, a blocker of most BMPs seems not to affect GDF2.[8]

GDF2 induces the differentiation of mesenchymal stem cells (MSCs) to an osteoblast lineage. The Smad signaling pathway of GDF2 target HEY1 inducing the differentiation by up regulating it.[9] Augmented expression of HEY1 increase the mineralization of the cells. RUNX2 is another factor who's up regulate by GDF2. This factor is known to be essential for osteoblastic differentiation.[10]


The signaling complex for bone morphogenetic proteins (BMP) start with a ligand binding with a high affinty type I receptor (ALK1-7) followed by the recruitment of a type II receptor(ActRIIA, ActRIIB, BMPRII). The first receptor kinase domain is then trans-phosphorylated by the apposed, activating type II receptor kinase domain.[11] GDF2 binds ALK1 and ActRIIB with the highest affinity in the BMPs, it also binds, with a lower affinity ALK2, also known has Activin A receptor, type I (ACVR1), and the other type II receptors BMPRII and ActRIIA.[11][12] GDF2 and BMP10 are the only ligands from the TGF-β superfamily that can bind to both type I and II receptors with equally high affinity.[11] This non-discriminative formation of the signaling complex open the possibility of a new mechanism. In cell type with low expression level of ActRIIB, GDF2 might still signal due to its affinity to ALK1, then form complex with type II receptors.[11]

Associate Disease

Mutations in GDF2 have been identified in patients with a vascular disorder phenotypically overlapping with hereditary hemorrhagic telangiectasia.[13]


Like other BMPs, GDF2 binding to its receptors triggers the phosphorylation of the R-Smads, Smad1,5,8. The activation of this pathway has been documented in all cellular types analyzed up to date, including hepatocytes and HCC cells.[14][15] GDF2 also triggers Smad-2/Smad-3 phosphorylation in different endothelial cell types.[16][17]

Another pathway for GDF2 is the induced non-canonical one. Little is known about this type of pathway in GDF2. GDF2 activate JNK in osteogenic differentiation of mesenchymal progenitor cells (MPCs). GDF2 also triggers p38 and ERK activation who will modulate de Smad pathway, p38 increase the phosphorylation of Smad 1,5,8 by GDF2 whereas ERK has the opposite effect.[17]

The transcriptional factor p38 activation induced by GDF2 has been documented in other cell types such as osteosarcoma cells,[18] human osteoclasts derived from cord blood monocytes,[19] and dental follicle stem cells.[20]


  1. Miller AF, Harvey SA, Thies RS, Olson MS (Jun 2000). "Bone morphogenetic protein-9. An autocrine/paracrine cytokine in the liver". The Journal of Biological Chemistry. 275 (24): 17937–45. doi:10.1074/jbc.275.24.17937. PMID 10849432.
  2. Universal protein resource accession number Q9UK05 at UniProt.
  3. Mi LZ, Brown CT, Gao Y, Tian Y, Le VQ, Walz T, Springer TA (March 2015). "Structure of bone morphogenetic protein 9 procomplex". Proceedings of the National Academy of Sciences of the United States of America. 112 (12): 3710–5. doi:10.1073/pnas.1501303112. PMC 4378411. PMID 25751889.
  4. 4.0 4.1 Lopez-Coviella I, Follettie MT, Mellott TJ, Kovacheva VP, Slack BE, Diesl V, Berse B, Thies RS, Blusztajn JK (May 2005). "Bone morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons". Proceedings of the National Academy of Sciences of the United States of America. 102 (19): 6984–9. doi:10.1073/pnas.0502097102. PMC 1088172. PMID 15870197.
  5. Truksa J, Peng H, Lee P, Beutler E (Jul 2006). "Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6". Proceedings of the National Academy of Sciences of the United States of America. 103 (27): 10289–93. doi:10.1073/pnas.0603124103. PMC 1502450. PMID 16801541.
  6. David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S (Mar 2007). "Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells". Blood. 109 (5): 1953–61. doi:10.1182/blood-2006-07-034124. PMID 17068149.
  7. McDonald J, Bayrak-Toydemir P, Pyeritz RE (Jul 2011). "Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis". Genetics in Medicine. 13 (7): 607–16. doi:10.1097/GIM.0b013e3182136d32. PMID 21546842.
  8. Kang Q, Sun MH, Cheng H, Peng Y, Montag AG, Deyrup AT, Jiang W, Luu HH, Luo J, Szatkowski JP, Vanichakarn P, Park JY, Li Y, Haydon RC, He TC (Sep 2004). "Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery". Gene Therapy. 11 (17): 1312–20. doi:10.1038/ PMID 15269709.
  9. Sharff KA, Song WX, Luo X, Tang N, Luo J, Chen J, Bi Y, He BC, Huang J, Li X, Jiang W, Zhu GH, Su Y, He Y, Shen J, Wang Y, Chen L, Zuo GW, Liu B, Pan X, Reid RR, Luu HH, Haydon RC, He TC (Jan 2009). "Hey1 basic helix-loop-helix protein plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal progenitor cells". The Journal of Biological Chemistry. 284 (1): 649–59. doi:10.1074/jbc.M806389200. PMC 2610517. PMID 18986983.
  10. Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, et al. (May 2010). "A draft sequence of the Neandertal genome". Science. 328 (5979): 710–22. doi:10.1126/science.1188021. PMC 5100745. PMID 20448178.
  11. 11.0 11.1 11.2 11.3 Townson SA, Martinez-Hackert E, Greppi C, Lowden P, Sako D, Liu J, Ucran JA, Liharska K, Underwood KW, Seehra J, Kumar R, Grinberg AV (Aug 2012). "Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex". The Journal of Biological Chemistry. 287 (33): 27313–25. doi:10.1074/jbc.M112.377960. PMC 3431715. PMID 22718755.
  12. Brown MA, Zhao Q, Baker KA, Naik C, Chen C, Pukac L, Singh M, Tsareva T, Parice Y, Mahoney A, Roschke V, Sanyal I, Choe S (Jul 2005). "Crystal structure of BMP-9 and functional interactions with pro-region and receptors". The Journal of Biological Chemistry. 280 (26): 25111–8. doi:10.1074/jbc.M503328200. PMID 15851468.
  13. Wooderchak-Donahue WL, McDonald J, O'Fallon B, Upton PD, Li W, Roman BL, Young S, Plant P, Fülöp GT, Langa C, Morrell NW, Botella LM, Bernabeu C, Stevenson DA, Runo JR, Bayrak-Toydemir P (Sep 2013). "BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia". American Journal of Human Genetics. 93 (3): 530–7. doi:10.1016/j.ajhg.2013.07.004. PMC 3769931. PMID 23972370.
  14. Li Q, Gu X, Weng H, Ghafoory S, Liu Y, Feng T, Dzieran J, Li L, Ilkavets I, Kruithof-de Julio M, Munker S, Marx A, Piiper A, Augusto Alonso E, Gretz N, Gao C, Wölfl S, Dooley S, Breitkopf-Heinlein K (Mar 2013). "Bone morphogenetic protein-9 induces epithelial to mesenchymal transition in hepatocellular carcinoma cells". Cancer Science. 104 (3): 398–408. doi:10.1111/cas.12093. PMID 23281849.
  15. Herrera B, García-Álvaro M, Cruz S, Walsh P, Fernández M, Roncero C, Fabregat I, Sánchez A, Inman GJ (July 2013). "BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells". PLOS ONE. 8 (7): e69535. doi:10.1371/journal.pone.0069535. PMC 3720667. PMID 23936038.
  16. Scharpfenecker M, van Dinther M, Liu Z, van Bezooijen RL, Zhao Q, Pukac L, Löwik CW, ten Dijke P (Mar 2007). "BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis". Journal of Cell Science. 120 (Pt 6): 964–72. doi:10.1242/jcs.002949. PMID 17311849.
  17. 17.0 17.1 Zhao YF, Xu J, Wang WJ, Wang J, He JW, Li L, Dong Q, Xiao Y, Duan XL, Yang X, Liang YW, Song T, Tang M, Zhao D, Luo JY (Aug 2013). "Activation of JNKs is essential for BMP9-induced osteogenic differentiation of mesenchymal stem cells". BMB Reports. 46 (8): 422–7. doi:10.5483/BMBRep.2013.46.8.266. PMC 4133909. PMID 23977991.
  18. Park H, Drevelle O, Daviau A, Senta H, Bergeron E, Faucheux N (Mar 2013). "Preventing MEK1 activation influences the responses of human osteosarcoma cells to bone morphogenetic proteins 2 and 9". Anti-Cancer Drugs. 24 (3): 278–90. doi:10.1097/CAD.0b013e32835cbde7. PMID 23262982.
  19. Fong D, Bisson M, Laberge G, McManus S, Grenier G, Faucheux N, Roux S (Apr 2013). "Bone morphogenetic protein-9 activates Smad and ERK pathways and supports human osteoclast function and survival in vitro". Cellular Signalling. 25 (4): 717–28. doi:10.1016/j.cellsig.2012.12.003. PMID 23313128.
  20. Li C, Yang X, He Y, Ye G, Li X, Zhang X, Zhou L, Deng F (2012). "Bone morphogenetic protein-9 induces osteogenic differentiation of rat dental follicle stem cells in P38 and ERK1/2 MAPK dependent manner". International Journal of Medical Sciences. 9 (10): 862–71. doi:10.7150/ijms.5027. PMC 3498751. PMID 23155360.

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