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growth/differentiation factor 11; GDF-11; bone morphogenetic protein 11; BMP-11 (GDF11, BMP11)

Function: - secreted signal that acts globally to specify positional identity along the anterior/posterior axis during development - role in patterning both mesodermal & neural tissues & in establishing the skeletal pattern - inhibitor of nerve tissue growth [4,5] - arrest of progenitor cell-cycle in the G1 phase - interacts with ALK4 & ALK5 to activate SMAD3-dependent genes [6] - may upregulate expression of Hoxc10 [6] - inhibits proliferation of olfactory receptor neuron progenitors to regulate the number of olfactory receptor neurons in the olfactory epithelium by inducing p27(Kip1) & reversible cell cycle arrest in progenitors [7] - controls the numbers of retinal ganglion cells, amacrine cells & photoreceptor cells during development of the retina [8] - in the retina, does not affect proliferation of progenitors - controls duration of expression of Math5, a gene that confers competence for retinal ganglion cell genesis - thus controls temporal windows for progenitor cell competence [8] - increases expression of SERCA2 in myocardium, an enzyme necessary for relaxation during diastole - negatively regulates - cardiomyocyte proliferation - neurogenesis [7] - islet cell proliferation - promotes beta-cell differentiation* - renal progenitor cell proliferation - chondrocyte proliferation - may be regulated by WFIKKN2 * perhaps in general, inhibits proliferation, promotes differentiation Structure: - homodimer; disulfide-linked (putative) - belongs to the TGF-beta family - homologous to myostatin & may play similar cellular role [4] - 90% identical in their amino acid sequence [5] - 89% homlogous to GDF8 [12] Compartment: secreted (probable) Expression: - GDF11 gene expression & protein abundance decreases with age [2,4] - GDF11 plasma levels may increase with age [11] - GDF11 plasma levels decline with age in mice, rats, horses & sheep [12] Comparative biology: - GDF11 reverses LV diastolic dysfunction in mice [1] - blood of young mice contains substances that reverse aging processes in heart muscle, skeletal muscle, & brain - one of these substances is GDF11 [3] - GDF11 inhibits muscle regeneration in mice [11] - effect may be dose-sensitive (therapeutic window) [11] - one dose may enhance muscle regeneration, but a 3-fold dose increase may inhibit muscle regeneration [11] - plasma levels of GDF11 do not decline with age [11]* - it is noted that there may be several forms of GDF11 in mice & that some forms may decline with age while others may increase [11] - plasma GDF11 & GDF11 mRNA in muscle increase with age in rats [11] - circulating levels of GDF11 decline with age in mice, rats, horses & sheep [12] - in patients with stable ischemic heart disease, higher GDF11/GDF8 (myostatin) levels are associated with lower risk of cardiovascular events & death [13]* * ref [12] claims increase in GDF11 levels with age observed in ref [11] are a result of cross-reactivity of the anti-GDF11 antibody used in ref [11] with immunoglobulin

General

bone morphogenetic protein (BMP) growth/differentiation factor (GDF) TGF-beta family protein

Properties

SIZE: entity length = 407 aa MW = 45 kD COMPARTMENT: extracellular compartment MOTIF: signal sequence {1-24} alanine-rich region {29-41} MOTIF: alanine residue (SEVERAL) N-glycosylation site {N94} glycine-rich region {210-215} cysteine residue {C313} MODIFICATION: cysteine residue {C372} cysteine residue {C341} MODIFICATION: cysteine residue {C404} cysteine residue {C345} MODIFICATION: cysteine residue {C406} cysteine residue {C371} MODIFICATION: cysteine residue {C-INTERCHAIN} cysteine residue {C372} MODIFICATION: cysteine residue {C313} cysteine residue {C404} MODIFICATION: cysteine residue {C341} cysteine residue {C406} MODIFICATION: cysteine residue {C345}

Database Correlations

OMIM 603936 UniProt O95390 PFAM correlations Entrez Gene 10220 Kegg hsa:10220

References

  1. UniProt :accession O95390
  2. Loffredo FS et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 2013 May 9; 153:828 PMID: 23663781
  3. Sinha M et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 2014 May 9; 344:649. PMID: 24797481 - Katsimpardi L et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 2014 May 9; 344:630. (http://dx.doi.org/10.1126/science.1251141) PMID: 24797482 - Villeda SA et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 2014 May 4 PMID: 24793238
  4. Wikipedia: GDF11 http://en.wikipedia.org/wiki/GDF11
  5. Recombinant Human GDF-11 http://www.peprotech.com/en-US/Pages/Product/Recombinant-Proteins/Growth-Factors-Cytokines/Recombinant_Human_GDF-11/120-11
  6. Andersson O, Reissmann E, Ibanez CF. Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis. EMBO Rep. 2006 Aug;7(8):831-7. Epub 2006 Jul 14. PMID: 16845371
  7. Wu HH, Ivkovic S, Murray RC et al Autoregulation of neurogenesis by GDF11. Neuron. 2003 Jan 23;37(2):197-207. PMID: 12546816
  8. Kim J, Wu HH, Lander AD, Lyons KM, Matzuk MM, Calof AL GDF11 controls the timing of progenitor cell competence in developing retina. Science. 2005 Jun 24;308(5730):1927-30. PMID: 15976303
  9. Harmon EB, Apelqvist AA, Smart NG, Gu X, Osborne DH, Kim SK. GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development. Development. 2004 Dec;131(24):6163-74. Epub 2004 Nov 17. PMID: 15548585
  10. Kondas K, Szlama G, Trexler M, Patthy L Both WFIKKN1 and WFIKKN2 Have High Affinity for Growth and Differentiation Factors 8 and 11. J Biol Chem. Aug 29, 2008; 283(35): 23677-23684 PMID: 18596030 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259755/#!po=73.8095
  11. Kaiser J Doubts cast on 'rejuvenating' protein. Science Daily News. May 19, 2015 http://news.sciencemag.org/biology/2015/05/doubts-cast-rejuvenating-protein
  12. Poggioli1 T, Vujic A, Yang P et al Circulating Growth Differentiation Factor 11/8 Levels Decline with Age. Circ Res. Oct 21, 2015 PMID: 26489925 http://circres.ahajournals.org/content/early/2015/10/21/CIRCRESAHA.115.307521.abstract
  13. Olson KA, Beatty AL, Heidecker B et al Association of growth differentiation factor 11/8, putative anti-ageing factor, with cardiovascular outcomes & overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts. European Heart Journal. Aug 20, 2015 PMID: 26294790 http://eurheartj.oxfordjournals.org/content/early/2015/08/20/eurheartj.ehv385