GDF2 contains an N-terminal TGF-beta-like pro-peptide (prodomain) (residues 56–257) and a C-terminaltransforming 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]
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]
References
↑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. PMID10849432.
↑Universal protein resource accession number Q9UK05 at UniProt.
↑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. PMID17068149.
↑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. PMID21546842.
↑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. PMID15269709.
↑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. PMID15851468.
↑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. PMID23281849.
↑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. PMID17311849.
↑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. PMID23262982.
↑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. PMID23313128.
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. PMID20237496.
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. PMID15851468.
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. PMID10894782.
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. PMID19086053.
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. PMID18922975.
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. PMID11748585.
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. PMID17549388.
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. PMID17311849.