GDF2
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| Location (UCSC) | Chr 10: 47.32 – 47.33 Mb | Chr 14: 33.66 – 33.67 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
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.
Structure
GDF2 contains an
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
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 (
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
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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000263761 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000072625 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 10849432.
- ^ Universal protein resource accession number Q9UK05 at UniProt.
- PMID 25751889.
- ^ PMID 15870197.
- PMID 16801541.
- PMID 17068149.
- PMID 21546842.
- S2CID 24526533.
- PMID 18986983.
- PMID 20448178.
- ^ PMID 22718755.
- PMID 15851468.
- PMID 23972370.
- S2CID 9890953.
- PMID 23936038.
- S2CID 37306105.
- ^ PMID 23977991.
- S2CID 29663731.
- PMID 23313128.
- 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. S2CID 11183658.
- 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. S2CID 37306105.