GDF2 contains anN-terminal TGF-beta-like pro-peptide (prodomain) (residues 56–257) and aC-terminaltransforming 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]
GDF2 has a role in inducing and maintaining the ability of embryonicbasal forebrain cholinergicneurons (BFCN) to respond to aneurotransmitter calledacetylcholine; BFCN are important for the processes oflearning,memory andattention.[8] GDF2 is also important for the maturation of BFCN.[8] Another role of GDF2 has been recently suggested. GDF2 is a potent inducer ofhepcidin (acationic peptide that hasantimicrobial properties) inliver cells (hepatocytes) and can regulateiron metabolism.[9] Thephysiological receptor of GDF2 is activin receptor-like kinase 1, ALK1 (also called ACVRL1), anendothelial-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 causehereditary 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 formationin vivo.BMP3, a blocker of most BMPs seems not to affect GDF2.[12]
GDF2 induces the differentiation ofmesenchymal stem cells (MSCs) to an osteoblast lineage. TheSmad signaling pathway of GDF2 targetHEY1 inducing the differentiation by up regulating it.[13] Augmented expression ofHEY1 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]
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 bindsALK1 andActRIIB 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 receptorsBMPRII andActRIIA.[15][16] GDF2 andBMP10 are the only ligands from theTGF-β superfamily that can bind to both type I and II receptors with equally highaffinity.[15] This non-discriminative formation of the signaling complex open the possibility of a new mechanism. In cell type with low expression level ofActRIIB, GDF2 might still signal due to its affinity toALK1, then form complex with type II receptors.[15]
Like otherBMPs, 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 triggersSmad-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 activateJNK in osteogenic differentiation of mesenchymal progenitor cells (MPCs). GDF2 also triggersp38 andERK activation who will modulate deSmad 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 asosteosarcoma cells,[22] human osteoclasts derived from cord bloodmonocytes,[23] and dental follicle stem cells.[24]
^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.S2CID24526533.
^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.S2CID37306105.
^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.S2CID29663731.
^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.
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