GDF11 forms a bone morphogenetic protein 1‐activated latent complex that can modulate nerve growth factor‐induced differentiation of PC12 cells

Ge, Gaoxiang; Hopkins, Delana R.; Greenspan, Daniel S.

doi:10.1096/fasebj.20.4.a515-a

Cited by 7 publications

(18 citation statements)

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“…In interpreting the results of these studies, it is important to keep in mind not only that GDF-11 is expressed under the control of Mstn regulatory sequences in these knock-in mice but also that GDF-11 protein is made from a hybrid precursor protein containing the MSTN propeptide. Although the MSTN propeptide and GDF-11 propeptide are each capable of binding mature GDF-11 and being cleaved by BMP-1/tolloid proteases to activate latency [37,38,40], it is possible that these propeptides have distinct properties that confer some degree of specificity with respect to the biological functions carried out by MSTN versus GDF-11. Hence, additional experiments, such as germline replacement of the MSTN propeptide with the GDF-11 propeptide or the converse germline replacement of the GDF-11 propeptide and/ or mature domain with the corresponding portions of MSTN, will be required to understand the full extent to which the various domains of these molecules are functionally equivalent.…”

Section: Table 3 Fiber Type Numbers In Gastrocnemius Musclesmentioning

confidence: 99%

“…The MSTN latent complex can be activated by proteolytic cleavage of the propeptide by members of the BMP-1/tolloid family of metalloproteases [38], which appears to be the dominant mechanism operating in vivo [39]. Similarly, the C-terminal dimer and propeptide of GDF-11 also form a latent complex that can be activated by BMP-1/tolloid proteases [40]. MSTN is regulated extracellularly by other binding proteins as well, including follistatin (FST) [36], FSTL-3 [41], GASP-1, and GASP-2 [42].…”

Section: Introductionmentioning

confidence: 99%

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Functional replacement of myostatin with GDF-11 in the germline of mice

et al. 2022

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Background Myostatin (MSTN) is a transforming growth factor-ß superfamily member that acts as a major regulator of skeletal muscle mass. GDF-11, which is highly related to MSTN, plays multiple roles during embryonic development, including regulating development of the axial skeleton, kidneys, nervous system, and pancreas. As MSTN and GDF-11 share a high degree of amino acid sequence identity, behave virtually identically in cell culture assays, and utilize similar regulatory and signaling components, a critical question is whether their distinct biological functions result from inherent differences in their abilities to interact with specific regulatory and signaling components or whether their distinct biological functions mainly reflect their differing temporal and spatial patterns of expression. Methods We generated and characterized mice in which we precisely replaced in the germline the portion of the Mstn gene encoding the mature C-terminal peptide with the corresponding region of Gdf11. Results In mice homozygous for the knock-in allele, all of the circulating MSTN protein was replaced with GDF-11, resulting in ~ 30–40-fold increased levels of circulating GDF-11. Male mice homozygous for the knock-in allele had slightly decreased muscle weights, slightly increased weight gain in response to a high-fat diet, slightly increased plasma cholesterol and HDL levels, and significantly decreased bone density and bone mass, whereas female mice were mostly unaffected. Conclusions GDF-11 appears to be capable of nearly completely functionally replacing MSTN in the control of muscle mass. The developmental and physiological consequences of replacing MSTN with GDF-11 are strikingly limited.

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Section: Table 3 Fiber Type Numbers In Gastrocnemius Musclesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional replacement of myostatin with GDF-11 in the germline of mice

et al. 2022

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“…Activation of this latent pro-GDF11 requires subsequent cleavage at a BMP1 site within the prodomain. 7 Figure 1 shows a schematic drawing of human GDF11 precursor protein summarizing its structural domains and key processing sites. The 407 amino acid transcript contains a 24 amino acid signal sequence and a pro region corresponding to amino acids 25−298.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Other studies have identified roles for GDF11 in inhibiting neurogenesis in the olfactory epithelium, preventing nerve growth factor (NGF)induced neurite outgrowth in PC12 cells, and in promoting vascular remodeling and neurogenesis. 7,13 GDF11 KO mice are perinatal lethal, preventing a more extensive assessment of GDF11 function. Although GDF11 is essential for development and has been suggested to regulate aging of multiple tissues, its roles in these aging processes have recently been the focus of intense debate.…”

Section: ■ Introductionmentioning

confidence: 99%

A Prodomain Fragment from the Proteolytic Activation of Growth Differentiation Factor 11 Remains Associated with the Mature Growth Factor and Keeps It Soluble

et al. 2017

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Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β (TGF-β) family, plays diverse roles in mammalian development. It is synthesized as a large, inactive precursor protein containing a prodomain, pro-GDF11, and exists as a homodimer. Activation requires two proteolytic processing steps that release the prodomains and transform latent pro-GDF11 into active mature GDF11. In studying proteolytic activation in vitro, we discovered that a 6-kDa prodomain peptide containing residues 60-114, PDP, remained associated with the mature growth factor. Whereas the full-length prodomain of GDF11 is a functional antagonist, PDP had no impact on activity. The specific activity of the GDF11/PDP complex (EC = 1 nM) in a SMAD2/3 reporter assay was identical to that of mature GDF11 alone. PDP improved the solubility of mature GDF11 at neutral pH. As the growth factor normally aggregates/precipitates at neutral pH, PDP can be used as a solubility-enhancing formulation. Expression of two engineered constructs with PDP genetically fused to the mature domain of GDF11 through a 2x or 3x G4S linker produced soluble monomeric products that could be dimerized through redox reactions. The construct with a 3x G4S linker retained 10% activity (EC = 10 nM), whereas the construct connected with a 2x G4S linker could only be activated (EC = 2 nM) by protease treatment. Complex formation with PDP represents a new strategy for stabilizing GDF11 in an active state that may translate to other members of the TGF-β family that form latent pro/mature domain complexes.

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“…As members of the activin subclass of TGFβ, both GDF8 and GDF11 signal through the type I receptors ALK4, ALK5 and ALK7 (Walker et al, 2017; Rebbapragada et al, 2003; Andersson et al, 2006). Molecularly, they are synthesized as precursors that remain in an inactive, latent complex until a Tolloid-like (TLD) protease cleaves the ligand prodomain to relieve the mature domain from inhibition (Rebbapragada et al, 2003; Wolfman et al, 2003; Ge et al, 2005; McFarlane et al, 2005; Lee & McPherron, 2001; Anderson et al, 2008). Mature GDF11 and mature GDF8 each consist of two monomers linked by disulfide bonds to form a homodimer of propeller-like shape ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Functional substitutions of amino acids that differ between GDF11 and GDF8 impact skeletal development and skeletal muscle

Lian

Walker

D'Amico

et al. 2022

Preprint

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Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGFβ family proteins that interact with nearly identical signaling receptors and antagonist proteins. However, GDF11 appears to activate SMAD2/3 in vitro and in vivo more potently than GDF8. The ligands possess divergent structural properties, whereby substituting unique GDF11 amino acids into GDF8 enhanced activity of the resulting chimeric GDF8. We investigated potentially distinct endogenous activities of GDF11 and GDF8 in vivo by genetically modifying their mature signaling domains. Full recoding of the GDF8 mature domain to that of GDF11 yielded mice lacking GDF8, with GDF11 levels ∼50-fold higher than normal, and exhibiting modestly decreased muscle mass, with no apparent negative impacts on health or survival to adulthood. Substitution of two specific amino acids in the fingertip region of GDF11 with the corresponding GDF8 residues resulted in prenatal axial skeletal transformations, consistent with Gdf11-deficient mice, without apparent perturbation of skeletal or cardiac muscle development or homeostasis. These experiments uncover distinctive features between the GDF11 and GDF8 mature domains in vivo and identify specific requirement for GDF11 in early-stage skeletal development.Summary StatementReplacement of amino acids unique to GDF11 and GDF8 into the native locus of the other ligand yields measurable, differential skeletal and muscle phenotypes, revealing distinct features between the ligands.

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GDF11 forms a bone morphogenetic protein 1‐activated latent complex that can modulate nerve growth factor‐induced differentiation of PC12 cells

Cited by 7 publications

References 0 publications

Functional replacement of myostatin with GDF-11 in the germline of mice

Functional replacement of myostatin with GDF-11 in the germline of mice

A Prodomain Fragment from the Proteolytic Activation of Growth Differentiation Factor 11 Remains Associated with the Mature Growth Factor and Keeps It Soluble

Functional substitutions of amino acids that differ between GDF11 and GDF8 impact skeletal development and skeletal muscle

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