GDF2

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.[5] GDF2 belongs to the transforming growth factor beta superfamily.

GDF2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1ZKZ, 4FAO, 4MPL, 4YCG, 4YCI
Identifiers
Aliases	GDF2, BMP-9, BMP9, HHT5, growth differentiation factor 2
External IDs	OMIM: 605120 MGI: 1321394 HomoloGene: 32299 GeneCards: GDF2
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q11.22 Start 47,322,454 bp[1] End 47,327,588 bp[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)[2] Band 14|14 B Start 33,941,039 bp[2] End 33,947,198 bp[2]
Gene ontology Molecular function • cytokine activity • GO:0001948 protein binding • transforming growth factor beta receptor binding • growth factor activity Cellular component • extracellular exosome • extracellular • extracellular region Biological process • regulation of apoptotic process • pathway-restricted SMAD protein phosphorylation • positive regulation of endothelial cell differentiation • regulation of MAPK cascade • positive regulation of endothelial cell proliferation • blood vessel morphogenesis • negative regulation of blood vessel endothelial cell migration • cell development • SMAD protein signal transduction • ossification • positive regulation of pathway-restricted SMAD protein phosphorylation • cellular response to BMP stimulus • negative regulation of DNA replication • positive regulation of angiogenesis • negative regulation of endothelial cell migration • negative regulation of endothelial cell proliferation • vasculogenesis • positive regulation of transcription, DNA-templated • cartilage development • positive regulation of gene expression • positive regulation of osteoblast differentiation • positive regulation of cartilage development • negative regulation of cell growth • angiogenesis • osteoblast differentiation • positive regulation of interleukin-8 production • positive regulation of BMP signaling pathway • branching involved in blood vessel morphogenesis • negative regulation of angiogenesis • negative regulation of DNA biosynthetic process • positive regulation of transcription from RNA polymerase II promoter • cellular iron ion homeostasis • activin receptor signaling pathway • BMP signaling pathway • regulation of receptor activity 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	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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).[6] 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.[7]

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.[8] GDF2 is also important for the maturation of BFCN.[8] 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.[9] 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.[10] 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.[11]

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.[12]

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.[13] 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.[14]

Interactions

The signaling complex for bone morphogenetic proteins (BMP) start with a ligand binding with a high affinity 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.[15] 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.[15][16] 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.[15] 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.[15]

Associate Disease

Mutations in GDF2 have been identified in patients with a vascular disorder phenotypically overlapping with hereditary hemorrhagic telangiectasia.[17]

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.[18][19] GDF2 also triggers Smad-2/Smad-3 phosphorylation in different endothelial cell types.[20][21]

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.[21]

The transcriptional factor p38 activation induced by GDF2 has been documented in other cell types such as osteosarcoma cells,[22] human osteoclasts derived from cord blood monocytes,[23] and dental follicle stem cells.[24]

References

1. GRCh38: Ensembl release 89: ENSG00000263761 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000072625 - 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. 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.
6. Universal protein resource accession number Q9UK05 at UniProt.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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. PMC 7657113. PMID 23281849. S2CID 9890953.
19. 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.
20. 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.
21. 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.
22. 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. S2CID 29663731.
23. 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.
24. 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.

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. 150B (6): 808–16. doi:10.1002/ajmg.b.30902. PMID 19086053. S2CID 44524739.
• 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. S2CID 19584714.
• 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.