GDF2

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).{{UniProt Full|Q9UK05}} 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.{{cite journal | vauthors = Mi LZ, Brown CT, Gao Y, Tian Y, Le VQ, Walz T, Springer TA | title = Structure of bone morphogenetic protein 9 procomplex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 12 | pages = 3710–5 | date = March 2015 | pmid = 25751889 | doi = 10.1073/pnas.1501303112 | pmc=4378411| bibcode = 2015PNAS..112.3710M | doi-access = free }}

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.{{cite journal | vauthors = Lopez-Coviella I, Follettie MT, Mellott TJ, Kovacheva VP, Slack BE, Diesl V, Berse B, Thies RS, Blusztajn JK | title = Bone morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 19 | pages = 6984–9 | date = May 2005 | pmid = 15870197 | pmc = 1088172 | doi = 10.1073/pnas.0502097102 | bibcode = 2005PNAS..102.6984L | doi-access = free }} GDF2 is also important for the maturation of BFCN. 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.{{cite journal | vauthors = Truksa J, Peng H, Lee P, Beutler E | title = Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 27 | pages = 10289–93 | date = Jul 2006 | pmid = 16801541 | pmc = 1502450 | doi = 10.1073/pnas.0603124103 | bibcode = 2006PNAS..10310289T | doi-access = free }} The physiological receptor of GDF2 is activin receptor-like kinase 1, ALK1 (also called ACVRL1), an endothelial-specific type I receptor of the TGF-beta receptor family.{{cite journal | vauthors = David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S | title = Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells | journal = Blood | volume = 109 | issue = 5 | pages = 1953–61 | date = Mar 2007 | pmid = 17068149 | doi = 10.1182/blood-2006-07-034124 | doi-access = free }} 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.{{cite journal | vauthors = McDonald J, Bayrak-Toydemir P, Pyeritz RE | title = Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis | journal = Genetics in Medicine | volume = 13 | issue = 7 | pages = 607–16 | date = Jul 2011 | pmid = 21546842 | doi = 10.1097/GIM.0b013e3182136d32 | doi-access = free }}

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.{{cite journal | vauthors = 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 | title = Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery | journal = Gene Therapy | volume = 11 | issue = 17 | pages = 1312–20 | date = Sep 2004 | pmid = 15269709 | doi = 10.1038/sj.gt.3302298 | s2cid = 24526533 | doi-access = }}

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.{{cite journal | vauthors = 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 | title = Hey1 basic helix-loop-helix protein plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal progenitor cells | journal = The Journal of Biological Chemistry | volume = 284 | issue = 1 | pages = 649–59 | date = Jan 2009 | pmid = 18986983 | pmc = 2610517 | doi = 10.1074/jbc.M806389200 | doi-access = free }} 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.{{cite journal | vauthors = Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, Fritz MH, Hansen NF, Durand EY, Malaspinas AS, Jensen JD, Marques-Bonet T, Alkan C, Prüfer K, Meyer M, Burbano HA, Good JM, Schultz R, Aximu-Petri A, Butthof A, Höber B, Höffner B, Siegemund M, Weihmann A, Nusbaum C, Lander ES, Russ C, Novod N, Affourtit J, Egholm M, Verna C, Rudan P, Brajkovic D, Kucan Z, Gusic I, Doronichev VB, Golovanova LV, Lalueza-Fox C, de la Rasilla M, Fortea J, Rosas A, Schmitz RW, Johnson PL, Eichler EE, Falush D, Birney E, Mullikin JC, Slatkin M, Nielsen R, Kelso J, Lachmann M, Reich D, Pääbo S | display-authors = 6 | title = A draft sequence of the Neandertal genome | journal = Science | volume = 328 | issue = 5979 | pages = 710–22 | date = May 2010 | pmid = 20448178 | doi = 10.1126/science.1188021 | pmc=5100745| bibcode = 2010Sci...328..710G }}

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.{{cite journal | vauthors = 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 | title = Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex | journal = The Journal of Biological Chemistry | volume = 287 | issue = 33 | pages = 27313–25 | date = Aug 2012 | pmid = 22718755 | pmc = 3431715 | doi = 10.1074/jbc.M112.377960 | doi-access = free }} 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.{{cite journal | vauthors = 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 | title = Crystal structure of BMP-9 and functional interactions with pro-region and receptors | journal = The Journal of Biological Chemistry | volume = 280 | issue = 26 | pages = 25111–8 | date = Jul 2005 | pmid = 15851468 | doi = 10.1074/jbc.M503328200 | doi-access = free }} 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. 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.

Mutations in GDF2 gene have been identified in patients with vascular disorders that phenotypically overlap predominantly with pulmonary arterial hypertension (PAH), and occasionally with congenital heart diseases{{Cite journal |last=Grynblat |first=Julien |last2=Bogaard |first2=Harm Jan |last3=Eyries |first3=Mélanie |last4=Meyrignac |first4=Olivier |last5=Savale |first5=Laurent |last6=Jaïs |first6=Xavier |last7=Ghigna |first7=Maria-Rosa |last8=Celant |first8=Lucas |last9=Meijboom |first9=Lilian |last10=Houweling |first10=Arjan C. |last11=Levy |first11=Marilyne |last12=Antigny |first12=Fabrice |last13=Chaouat |first13=Ari |last14=Cottin |first14=Vincent |last15=Guignabert |first15=Christophe |date=April 2024 |title=Pulmonary vascular phenotype identified in patients with GDF2 ( BMP9 ) or BMP10 variants: an international multicentre study |url=https://publications.ersnet.org/lookup/doi/10.1183/13993003.01634-2023 |journal=European Respiratory Journal |language=en |volume=63 |issue=4 |pages=2301634 |doi=10.1183/13993003.01634-2023 |issn=0903-1936|url-access=subscription }} and more rarely with hereditary hemorrhagic telangiectasia.{{cite journal | vauthors = 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 | title = BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia | journal = American Journal of Human Genetics | volume = 93 | issue = 3 | pages = 530–7 | date = Sep 2013 | pmid = 23972370 | pmc = 3769931 | doi = 10.1016/j.ajhg.2013.07.004 }} Pathogenic variants in GDF2 were identified in 1.3% of patients PAH. In this series, PAH onset occurred at a median age of 30 years and showed a female predominance. Congenital heart disease was present in 15.4% of cases and hemoptysis appeared to be more frequent than typically observed in other forms of PAH. Most patients exhibited severe functional impairment and marked haemodynamic compromise.

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.{{cite journal | vauthors = 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 | title = Bone morphogenetic protein-9 induces epithelial to mesenchymal transition in hepatocellular carcinoma cells | journal = Cancer Science | volume = 104 | issue = 3 | pages = 398–408 | date = Mar 2013 | pmid = 23281849 | doi = 10.1111/cas.12093 | s2cid = 9890953 | pmc = 7657113 }}{{cite journal | vauthors = Herrera B, García-Álvaro M, Cruz S, Walsh P, Fernández M, Roncero C, Fabregat I, Sánchez A, Inman GJ | title = BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells | journal = PLOS ONE | volume = 8 | issue = 7 | pages = e69535 | date = July 2013 | pmid = 23936038 | doi = 10.1371/journal.pone.0069535 | pmc=3720667| bibcode = 2013PLoSO...869535H | doi-access = free }} GDF2 also triggers Smad-2/Smad-3 phosphorylation in different endothelial cell types.{{cite journal | vauthors = Scharpfenecker M, van Dinther M, Liu Z, van Bezooijen RL, Zhao Q, Pukac L, Löwik CW, ten Dijke P | title = BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis | journal = Journal of Cell Science | volume = 120 | issue = Pt 6 | pages = 964–72 | date = Mar 2007 | pmid = 17311849 | doi = 10.1242/jcs.002949 | s2cid = 37306105 | doi-access = }}{{cite journal | vauthors = 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 | title = Activation of JNKs is essential for BMP9-induced osteogenic differentiation of mesenchymal stem cells | journal = BMB Reports | volume = 46 | issue = 8 | pages = 422–7 | date = Aug 2013 | pmid = 23977991 | doi = 10.5483/BMBRep.2013.46.8.266 | pmc=4133909}}

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.

The transcriptional factor p38 activation induced by GDF2 has been documented in other cell types such as osteosarcoma cells,{{cite journal | vauthors = Park H, Drevelle O, Daviau A, Senta H, Bergeron E, Faucheux N | title = Preventing MEK1 activation influences the responses of human osteosarcoma cells to bone morphogenetic proteins 2 and 9 | journal = Anti-Cancer Drugs | volume = 24 | issue = 3 | pages = 278–90 | date = Mar 2013 | pmid = 23262982 | doi = 10.1097/CAD.0b013e32835cbde7 | s2cid = 29663731 }} human osteoclasts derived from cord blood monocytes,{{cite journal | vauthors = Fong D, Bisson M, Laberge G, McManus S, Grenier G, Faucheux N, Roux S | title = Bone morphogenetic protein-9 activates Smad and ERK pathways and supports human osteoclast function and survival in vitro | journal = Cellular Signalling | volume = 25 | issue = 4 | pages = 717–28 | date = Apr 2013 | pmid = 23313128 | doi = 10.1016/j.cellsig.2012.12.003 }} and dental follicle stem cells.{{cite journal | vauthors = Li C, Yang X, He Y, Ye G, Li X, Zhang X, Zhou L, Deng F | title = Bone morphogenetic protein-9 induces osteogenic differentiation of rat dental follicle stem cells in P38 and ERK1/2 MAPK dependent manner | journal = International Journal of Medical Sciences | volume = 9 | issue = 10 | pages = 862–71 | date = 2012 | pmid = 23155360 | doi = 10.7150/ijms.5027 | pmc=3498751}}

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{{refend}}

{{TGF beta signaling}}

{{TGFβ receptor superfamily modulators}}

Category:Developmental genes and proteins

Category:TGFβ domain