GDF2

Growth differentiation factor 2
PDB rendering based on 1zkz.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1ZKZ​, 4FAO​, 4MPL​, 4YCG​, 4YCI​
Identifiers
Symbols	GDF2 ; BMP-9; BMP9; HHT5
External IDs	OMIM: 605120 MGI: 1321394 HomoloGene: 32299 GeneCards: GDF2 Gene
Gene ontology Molecular function • cytokine activity • transforming growth factor beta receptor binding • protein binding • growth factor activity Cellular component • extracellular space • cell • extracellular exosome Biological process • ossification • angiogenesis • patterning of blood vessels • vasculogenesis • osteoblast differentiation • negative regulation of endothelial cell proliferation • positive regulation of endothelial cell proliferation • cellular iron ion homeostasis • negative regulation of DNA replication • negative regulation of endothelial cell migration • positive regulation of pathway-restricted SMAD protein phosphorylation • negative regulation of angiogenesis • negative regulation of cell growth • BMP signaling pathway • positive regulation of BMP signaling pathway • positive regulation of interleukin-8 production • activin receptor signaling pathway • growth • regulation of apoptotic process • regulation of MAPK cascade • negative regulation of blood vessel endothelial cell migration • positive regulation of endothelial cell differentiation • positive regulation of osteoblast differentiation • positive regulation of angiogenesis • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • cell development • blood vessel morphogenesis • cartilage development • pathway-restricted SMAD protein phosphorylation • SMAD protein signal transduction • positive regulation of cartilage development • cellular response to BMP stimulus • negative regulation of DNA biosynthetic process Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2658	12165
Ensembl	ENSG00000263761	ENSMUSG00000072625
UniProt	Q9UK05	Q9WV56
RefSeq (mRNA)	NM_016204	NM_019506
RefSeq (protein)	NP_057288	NP_062379
Location (UCSC)	Chr 10: 47.32 – 47.33 Mb	Chr 14: 33.94 – 33.95 Mb
PubMed search

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.

Structure

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]

Function

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]

Interactions

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]

Signaling

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 goes in 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]

References

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. UniProt: Q9UK05
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. PMID 25751889.
4. 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/sj.gt.3302298. 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. PMID 20448178.
11. 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. 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. 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. 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. PMID 23155360.

Further reading

• Davila S, Froeling FE, Tan A, Bonnard C, Boland GJ, Snippe H, Hibberd ML, Seielstad M (Apr 2010). "New genetic associations detected in a host response study to hepatitis B vaccine". Genes and Immunity 11 (3): 232–8. doi:10.1038/gene.2010.1. PMID 20237496.
• David L, Mallet C, Keramidas M, Lamandé N, Gasc JM, Dupuis-Girod S, Plauchu H, Feige JJ, Bailly S (Apr 2008). "Bone morphogenetic protein-9 is a circulating vascular quiescence factor". Circulation Research 102 (8): 914–22. doi:10.1161/CIRCRESAHA.107.165530. PMC 2561062. PMID 18309101.
• Herrera B, van Dinther M, Ten Dijke P, Inman GJ (Dec 2009). "Autocrine bone morphogenetic protein-9 signals through activin receptor-like kinase-2/Smad1/Smad4 to promote ovarian cancer cell proliferation". Cancer Research 69 (24): 9254–62. doi:10.1158/0008-5472.CAN-09-2912. PMC 2892305. PMID 19996292.
• Upton PD, Davies RJ, Trembath RC, Morrell NW (Jun 2009). "Bone morphogenetic protein (BMP) and activin type II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells". The Journal of Biological Chemistry 284 (23): 15794–804. doi:10.1074/jbc.M109.002881. PMC 2708876. PMID 19366699.
• Grupe A, Li Y, Rowland C, Nowotny P, Hinrichs AL, Smemo S, Kauwe JS, Maxwell TJ, Cherny S, Doil L, Tacey K, van Luchene R, Myers A, Wavrant-De Vrièze F, Kaleem M, Hollingworth P, Jehu L, Foy C, Archer N, Hamilton G, Holmans P, Morris CM, Catanese J, Sninsky J, White TJ, Powell J, Hardy J, O'Donovan M, Lovestone S, Jones L, Morris JC, Thal L, Owen M, Williams J, Goate A (Jan 2006). "A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease". American Journal of Human Genetics 78 (1): 78–88. doi:10.1086/498851. PMC 1380225. PMID 16385451.
• 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.
• López-Coviella I, Berse B, Krauss R, Thies RS, Blusztajn JK (Jul 2000). "Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP-9". Science 289 (5477): 313–6. doi:10.1126/science.289.5477.313. PMID 10894782.
• 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.
• Gratacòs M, Costas J, de Cid R, Bayés M, González JR, Baca-García E, de Diego Y, Fernández-Aranda F, Fernández-Piqueras J, Guitart M, Martín-Santos R, Martorell L, Menchón JM, Roca M, Sáiz-Ruiz J, Sanjuán J, Torrens M, Urretavizcaya M, Valero J, Vilella E, Estivill X, Carracedo A (Sep 2009). "Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 150B (6): 808–16. doi:10.1002/ajmg.b.30902. PMID 19086053.
• Ye L, Kynaston H, Jiang WG (Oct 2008). "Bone morphogenetic protein-9 induces apoptosis in prostate cancer cells, the role of prostate apoptosis response-4". Molecular Cancer Research 6 (10): 1594–606. doi:10.1158/1541-7786.MCR-08-0171. PMID 18922975.
• Majumdar MK, Wang E, Morris EA (Dec 2001). "BMP-2 and BMP-9 promotes chondrogenic differentiation of human multipotential mesenchymal cells and overcomes the inhibitory effect of IL-1". Journal of Cellular Physiology 189 (3): 275–84. doi:10.1002/jcp.10025. PMID 11748585.
• Roberts KE, Kawut SM, Krowka MJ, Brown RS, Trotter JF, Shah V, Peter I, Tighiouart H, Mitra N, Handorf E, Knowles JA, Zacks S, Fallon MB (Jul 2010). "Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease". Gastroenterology 139 (1): 130–9.e24. doi:10.1053/j.gastro.2010.03.044. PMC 2908261. PMID 20346360.
• Takahashi T, Morris EA, Trippel SB (Jul 2007). "Bone morphogenetic protein-2 and -9 regulate the interaction of insulin-like growth factor-I with growth plate chondrocytes". International Journal of Molecular Medicine 20 (1): 53–7. doi:10.3892/ijmm.20.1.53. PMID 17549388.
• 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.