Affinage

GDF11

Growth/differentiation factor 11 · UniProt O95390

Length
407 aa
Mass
45.1 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GDF11 is a TGF-β superfamily ligand that functions as a secreted morphogen governing progenitor cell competence, axial patterning, and tissue homeostasis across diverse developmental and adult contexts. It is synthesized as an inactive precursor that requires sequential proteolytic processing by the proprotein convertase PC5/6 (PCSK5) at an RSRR↓N motif and release from its latent prodomain complex by BMP1/Tolloid metalloproteinases (PMID:18378898, PMID:15988002). Mature GDF11 signals through ActRIIA/ActRIIB type II receptors and ALK4/5/7 type I receptors to phosphorylate Smad2/3, thereby directly activating Hox gene enhancers (via Smad3/4 binding) to establish rostrocaudal positional identity, and inducing cyclin-dependent kinase inhibitors p27Kip1/p57Kip2 to promote progenitor cell cycle exit in neural, retinal, and pancreatic lineages (PMID:12414726, PMID:24016758, PMID:12546816, PMID:15548585). Its bioavailability is antagonized extracellularly by follistatin, GASP-1/GASP-2, and WFIKKN2, which block type II receptor engagement, and at supraphysiological levels GDF11 drives muscle atrophy through FOXO1/Atrogin-1 upregulation and activates catabolic ubiquitin-proteasome and autophagy pathways (PMID:24019467, PMID:30814254, PMID:36094432, PMID:28647906).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 High

    Establishing GDF11 as a positional morphogen: it was unknown how caudal Hox codes are specified in motor neurons; GDF11 (with FGFs and retinoids) was shown to establish rostrocaudal Hox-c identity in the developing spinal cord, defining GDF11 as a key axial patterning signal.

    Evidence In vitro spinal cord patterning assay and Hox expression profiling in chick/mouse embryos

    PMID:11754833

    Open questions at the time
    • Receptor and intracellular signaling pathway for Hox induction not yet identified
    • Relative contributions of GDF11 vs. FGFs vs. retinoids unresolved
  2. 2002 High

    Identifying the receptor complex: GDF11 was shown to bind and signal cooperatively through both ActRIIA and ActRIIB type II receptors and to induce Smad2 phosphorylation, establishing the core receptor-Smad signaling axis.

    Evidence Genetic epistasis in double-mutant mice, biochemical binding assays, and Smad2 phosphorylation assays

    PMID:12414726

    Open questions at the time
    • Type I receptor identity not yet determined
    • Relative affinity for ActRIIA vs. ActRIIB not quantified
  3. 2003 High

    Defining a cellular mechanism: GDF11 was shown to restrain neurogenesis by inducing p27Kip1-mediated cell cycle arrest in olfactory progenitors, with follistatin acting as its physiological antagonist — establishing GDF11 as a feedback regulator of progenitor pool size.

    Evidence Gdf11 and follistatin knockout mouse genetics plus in vitro neurogenesis and cell cycle marker analysis

    PMID:12546816

    Open questions at the time
    • Whether GDF11 acts cell-autonomously on progenitors or via intermediary cells not resolved
    • Downstream transcriptional targets beyond p27 unknown
  4. 2005 High

    Elucidating proteolytic activation: two studies resolved the two-step maturation mechanism — PC5/6 cleaves the proprotein at RSRR↓N, and BMP1/Tolloid metalloproteinases subsequently cleave the latent prodomain complex to release active GDF11, explaining how GDF11 bioavailability is spatiotemporally controlled.

    Evidence In vitro reconstitution, prodomain mutagenesis, PC12 differentiation assays (2005); conditional Pcsk5 knockout mice with in vitro/ex vivo cleavage assays (2008)

    PMID:15988002 PMID:18378898

    Open questions at the time
    • Tissue-specific regulation of BMP1/Tolloid vs. PC5/6 activity not characterized
    • Whether other convertases can substitute for PC5/6 in specific tissues unclear
  5. 2005 High

    Expanding developmental roles: GDF11 was found to control retinal progenitor temporal competence by regulating Math5 expression duration, and to limit pancreatic islet progenitor (NGN3+) expansion via Smad2, broadening GDF11's role from axial patterning to a general timer of progenitor competence windows.

    Evidence Gdf11 knockout retinal and pancreatic phenotyping with molecular marker quantification

    PMID:15548585 PMID:15976303

    Open questions at the time
    • Direct transcriptional targets in retina and pancreas not identified
    • Whether p27/p57 induction underlies all these progenitor effects not tested
  6. 2006 High

    Connecting GDF11-Smad2 to Hox gene control in vivo: electroporation experiments demonstrated that GDF11 induces Smad2 phosphorylation to shift Hox expression domains and motor neuron column positions, closing the gap between ligand identity and transcriptional patterning output.

    Evidence In ovo electroporation of Gdf11 and follistatin constructs with Hox immunohistochemistry and pSmad2 assay in chick

    PMID:16790475

    Open questions at the time
    • Direct Smad binding to Hox regulatory elements not yet demonstrated
  7. 2009 High

    Placing GDF11 in a transcription factor circuit: Foxg1 was shown to promote neurogenesis by antagonizing GDF11-mediated negative feedback, with Gdf11 mutations rescuing Foxg1-null defects in a dose-dependent manner, establishing an upstream regulator of GDF11 signaling.

    Evidence Double-mutant mouse genetics (Foxg1−/−; Gdf11−/−) with neurogenesis quantification

    PMID:19297409

    Open questions at the time
    • Whether Foxg1 regulates Gdf11 transcription directly or indirectly unknown
    • Applicability beyond olfactory epithelium untested
  8. 2011 High

    Refining the progenitor cell cycle exit mechanism: GDF11 secreted by newborn neurons was shown to upregulate both p57Kip2 and p27Kip1 and downregulate Pax6 in spinal cord progenitors, establishing a feedback loop wherein differentiated neurons signal back to limit further neurogenesis.

    Evidence Gdf11 knockout mouse spinal cord analysis, neurosphere assays with recombinant GDF11

    PMID:21248112

    Open questions at the time
    • Whether Smad2/3 directly binds p57/p27 promoters not shown
    • Relative importance of p27 vs. p57 not dissected
  9. 2013 High

    Demonstrating direct Smad-Hox enhancer regulation and identifying extracellular antagonists: Smad3/4 were shown to bind directly to a Hoxd11 enhancer element, with mutagenesis abolishing activity in vivo; separately, GASP-1/GASP-2 were identified as physiological GDF11 antagonists that block ActRIIB binding, with Gasp2-null mice phenocopying GDF11 gain-of-function.

    Evidence ChIP, Smad-binding site mutagenesis, transgenic reporter mice (Hoxd11); biochemical receptor-blocking assays and Gasp1/2 knockout phenotyping (GASP antagonism)

    PMID:24016758 PMID:24019467

    Open questions at the time
    • Whether GASP-1/2 regulate GDF11 vs. myostatin differentially in specific tissues not resolved
    • Genome-wide Smad3/4 binding landscape downstream of GDF11 not mapped
  10. 2015 High

    Resolving the GDF11-muscle controversy: contradicting claims of rejuvenation, GDF11 was shown to inhibit myoblast differentiation and satellite cell expansion via Smad2/3, establishing it as an inhibitor rather than promoter of muscle regeneration.

    Evidence GDF11-specific immunoassay, in vitro myoblast differentiation, in vivo mouse muscle regeneration with satellite cell quantification

    PMID:26001423

    Open questions at the time
    • Dose-response relationship between circulating GDF11 and muscle effects not fully defined
    • Contribution of GDF11 vs. myostatin to physiological muscle homeostasis unclear
  11. 2017 High

    Structural basis for GDF11's enhanced potency: crystal structures of GDF11 (apo and in complex with follistatin-288) revealed unique type I receptor binding site features explaining GDF11's greater Smad2/3 activation potency compared to myostatin; at supraphysiological levels, GDF11 overexpression caused cardiac and skeletal muscle atrophy via Smad2/ubiquitin-proteasome activation.

    Evidence X-ray crystallography (apo-GDF11, GDF11:FS288), chimeric mutagenesis, AAV-mediated overexpression in mice with echocardiography and muscle phenotyping

    PMID:28257634 PMID:28270449

    Open questions at the time
    • Type I receptor ternary complex structure not solved
    • Threshold distinguishing physiological from pathological GDF11 levels in vivo undefined
  12. 2019 High

    Expanding the antagonist repertoire structurally: the crystal structure of the WFIKKN2 follistatin domain revealed a distinct mechanism for blocking GDF11/GDF8-ActRIIB interaction, showing that multiple extracellular antagonists use non-overlapping strategies to regulate GDF11.

    Evidence 1.39 Å crystal structure, SPR, alanine-scanning mutagenesis, native gel shift, cell-based GDF8 inhibition assay

    PMID:30814254

    Open questions at the time
    • In vivo relevance of WFIKKN2 as a GDF11 antagonist not tested genetically
    • Whether WFIKKN2 preferentially targets GDF11 vs. GDF8 in circulation unknown
  13. 2019 Medium

    Defining downstream effector pathways in adult tissues: multiple studies mapped GDF11-Smad2/3 outputs to tissue-specific effectors — FOXO1/Atrogin-1 in muscle atrophy, SMURF1/ERK1/2 in hepatic hepcidin suppression, AKT/HIF-1α in angiogenesis, and YME1L/OPA1 in mitochondrial fusion — demonstrating context-dependent pathway branching from the core Smad2/3 signal.

    Evidence iPSC-derived myocyte FOXO1 inhibition (2022); hepatocyte SMURF1 overexpression and ERK inhibitor studies (2019); EPC AKT/HIF-1α Western blot (2019); MSC Smad2/3-YME1L pathway dissection (2020)

    PMID:30026260 PMID:31418854 PMID:32515551 PMID:36094432

    Open questions at the time
    • Most effector studies from single laboratories awaiting independent replication
    • Whether these pathways operate simultaneously or are mutually exclusive in a given cell type unknown
    • Direct Smad2/3 binding to effector gene promoters not demonstrated in most cases
  14. 2022 Medium

    Identifying ID2 as an obligate downstream intermediate: GDF11 was shown to induce MMP2 and trophoblast invasion through ALK4/5-Smad2/3 activation of ID2, placing ID2 as a required transcriptional mediator in at least one GDF11-driven cellular response.

    Evidence siRNA knockdown of ALK4, ALK5, Smad2/3, and ID2 in trophoblast cells with invasion assays

    PMID:35705978

    Open questions at the time
    • Whether ID2 is a general GDF11 mediator or context-specific to trophoblasts untested
    • Direct Smad2/3 binding to ID2 promoter not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Open question: the structural basis of GDF11's ternary complex with type I and type II receptors has not been resolved, the threshold between physiological and pathological GDF11 concentrations in adult tissues is not defined, and the genome-wide direct Smad2/3 transcriptional program downstream of GDF11 (beyond Hoxd11) remains unmapped.
  • No ternary receptor complex structure
  • Physiological vs. pathological dose thresholds not established
  • Genome-wide direct Smad target identification lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 4
Partners
ACVR2AACVR2BACVRL1FSTPCSK5SMAD2TGFBR1WFIKKN2

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GDF11 signals through activin type IIA (ActRIIA) and type IIB (ActRIIB) receptors cooperatively to pattern axial vertebrae; GDF11 binds both receptors and induces phosphorylation of Smad2, as demonstrated by genetic and biochemical studies in mice. Genetic epistasis (double-mutant mice), biochemical binding assays, Smad2 phosphorylation assays Genes & development High 12414726
2003 GDF11 inhibits olfactory epithelium neurogenesis by inducing p27(Kip1)-mediated reversible cell cycle arrest in neuronal progenitors; mice lacking GDF11 have excess progenitors and neurons, while mice lacking the GDF11 antagonist follistatin show dramatically decreased neurogenesis. Loss-of-function mouse genetics (Gdf11 knockout, follistatin knockout), in vitro neurogenesis assays, cell cycle marker analysis Neuron High 12546816
2001 Gdf11 (along with FGFs and retinoids) establishes rostrocaudal Hox-c positional identity of spinal motor neurons in the developing spinal cord; convergent activities of these signals from Hensen's node and paraxial mesoderm define motor neuron subtype identity. In vitro spinal cord patterning assay, Hox protein expression profiling in chick/mouse embryos Neuron High 11754833
2005 GDF11 forms a noncovalent latent complex with its SPC-cleaved prodomain, and this latent complex is activated by cleavage at a single specific site by BMP1/Tolloid family metalloproteinases; mutant GDF11 prodomains impervious to BMP1/Tolloid cleavage act as potent stimulators of neural differentiation in PC12 cells. In vitro reconstitution of latent complex, protease cleavage assays, mutagenesis of prodomain cleavage site, PC12 cell differentiation assay Molecular and cellular biology High 15988002
2008 The proprotein convertase PC5/6 (encoded by Pcsk5) specifically cleaves and activates GDF11 in vivo; the selectivity resides in a P1' Asn residue in the RSRR↓N cleavage motif; PC5/6-deficient embryos display Gdf11-related anteroposterior patterning defects. Conditional knockout mouse genetics, in vitro and ex vivo cleavage assays, in situ hybridization, mutagenesis of cleavage motif Proceedings of the National Academy of Sciences of the United States of America High 18378898
2005 GDF11 controls the timing of retinal progenitor cell competence by regulating the duration of Math5 expression (a gene conferring competence for retinal ganglion cell genesis), without affecting progenitor proliferation; this governs the temporal windows during which progenitors can produce distinct neural cell types. Gdf11 knockout mouse genetics, Math5 expression analysis, retinal cell-type quantification Science (New York, N.Y.) High 15976303
2004 GDF11 negatively regulates the number of NGN3+ islet progenitor cells and is required for beta-cell maturation during pancreas development; Gdf11-null mice have increased NGN3+ cells but reduced beta-cell numbers; GDF11 acts through Smad2 signaling in parallel to the Notch pathway. Gdf11 knockout mouse genetics, Smad2 knockout comparison, cell-type quantification, epistasis with Notch pathway Development (Cambridge, England) High 15548585
2006 Gdf11 induces Smad2 phosphorylation and activated Smad2 induces caudal Hox gene expression; ectopic Gdf11 in chick spinal cord causes rostral displacement of Hox expression domains and motor neuron columns, while follistatin causes the opposite, demonstrating that Gdf11 signals through Smad2 to control rostrocaudal patterning. In ovo electroporation (gain/loss of function), Hox protein immunohistochemistry, Smad2 phosphorylation assay Development (Cambridge, England) High 16790475
2011 GDF11 secreted by newly born neurons in the developing spinal cord facilitates temporal progression of neurogenesis by upregulating cyclin-dependent kinase inhibitors p57(Kip2) and p27(Kip1) and downregulating Pax6, promoting cell cycle exit and altering progenitor differentiation potential. Gdf11 knockout mouse genetics, neurosphere assays, in vitro GDF11 addition, cell cycle marker analysis The Journal of neuroscience : the official journal of the Society for Neuroscience High 21248112
2013 GASP-1 and GASP-2 inhibit GDF11 (and myostatin) activity by blocking ligand binding to the type II receptor (ActRIIB); Gasp2-null mice show posteriorly directed axial skeletal transformations (opposite to Gdf11-null mice), confirming GASP-2 as a physiological GDF11 antagonist in vivo. Biochemical receptor-binding inhibition assays, Gasp1/Gasp2 knockout mouse phenotyping, skeletal and muscle analyses Proceedings of the National Academy of Sciences of the United States of America High 24019467
2013 Gdf11/Smad signaling directly activates a Hoxd11 axial expression enhancer via a Smad3/4 binding element within conserved region VIII; chromatin immunoprecipitation shows direct Smad2/3 binding to this enhancer, and mutation of the Smad binding motif abolishes both in vitro reporter activity and in vivo tailbud expression. Luciferase reporter assay, ChIP, Smad-binding site mutagenesis, transgenic mouse reporter analysis Developmental biology High 24016758
2015 GDF11 and myostatin both induce Smad2/3 phosphorylation and inhibit myoblast differentiation; GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion when administered to mice, indicating it acts as an inhibitor rather than a promoter of muscle regeneration. GDF11-specific immunoassay, in vitro myoblast differentiation assay, in vivo mouse muscle regeneration assay, satellite cell quantification Cell metabolism High 26001423
2017 Despite high sequence similarity, GDF11 is a more potent activator of Smad2/3 and signals more effectively through ALK4/5/7 type I receptors than GDF8 (myostatin); crystal structures of GDF11:FS288 complex, apo-GDF8, and apo-GDF11 reveal unique type I receptor binding site features of GDF11 that enhance its potency; substitution of GDF11 residues into GDF8 confers enhanced GDF8 activity. Crystal structure determination (GDF11:FS288, apo-GDF8, apo-GDF11), Smad2/3 signaling assays, receptor-binding assays, mutagenesis/chimeric protein assays BMC biology High 28257634
2017 GDF11 at supraphysiological levels activates pSmad2/3 signaling and induces comparable atrophy of differentiated myotubes in vitro; systemic AAV-mediated GDF11 overexpression in mice causes substantial atrophy of skeletal and cardiac muscle; greater cardiac expression of Tgfbr1 may explain the GDF11-specific cardiac phenotype. In vitro myoblast/myotube culture assays, AAV-mediated in vivo overexpression, muscle mass and function measurements EMBO molecular medicine High 28270449
2017 PCSK5 is the convertase responsible for processing inactive GDF11 precursor to its bioactive form in triple-negative breast cancer cells; loss of PCSK5 causes intracellular accumulation of GDF11 precursor, abolishing its tumor-suppressive activity; PCSK5 reconstitution mobilizes latent GDF11 and suppresses TNBC metastasis. PCSK5 knockdown/reconstitution, GDF11 precursor/mature protein Western blot, 3D culture invasion assay, syngeneic in vivo metastasis model Developmental cell High 29161592
2016 GDF11 inhibits osteoblastic differentiation of bone marrow mesenchymal stem cells by repressing Runx2 expression through induction of Smad2/3 phosphorylation; intraperitoneal GDF11 injection inhibits bone formation and accelerates age-related bone loss in mice without affecting osteoclast differentiation. In vitro osteoblast differentiation assays, Smad2/3 phosphorylation Western blot, in vivo injection studies with histomorphometry Calcified tissue international Medium 27395058
2017 In vivo GDF11 exposure activates SMAD2, the ubiquitin-proteasome pathway and autophagy in cardiomyocytes and skeletal muscle fibers, inducing loss of cardiac and skeletal muscle mass and function. GDF11-secreting cell injection in mice, echocardiography, SMAD2 phosphorylation analysis, ubiquitin-proteasome and autophagy pathway markers Basic research in cardiology Medium 28647906
2018 GDF11 modulates Ca2+-dependent Smad2/3 signaling to prevent cardiomyocyte hypertrophy; GDF11 induces intracellular Ca2+ release via the IP3 pathway, which is required for Smad2/3 phosphorylation and luciferase activity; Smad2/3 siRNA knockdown abolishes the anti-hypertrophic effects of GDF11. Intracellular Ca2+ imaging, IP3 pathway inhibitors (BAPTA-AM), Smad2/3 siRNA knockdown, cardiomyocyte size measurement, [3H]-leucine incorporation International journal of molecular sciences Medium 29783655
2009 Foxg1 promotes olfactory neurogenesis by antagonizing GDF11-mediated negative feedback; mutations in Gdf11 rescue the major neurogenic and structural defects in Foxg1-null olfactory epithelium in a gene-dosage-dependent manner, placing Foxg1 upstream of Gdf11 signaling in a negative-regulatory circuit. Double-mutant mouse genetics (Foxg1-/-;Gdf11-/- and Foxg1-/-;Gdf11+/-), neurogenesis quantification, follistatin expression analysis Development (Cambridge, England) High 19297409
2011 Activin βB (ACTβB) and GDF11 act by distinct mechanisms in the olfactory epithelium: GDF11 inhibits expansion of immediate neuronal precursors (INPs), while ACTβB inhibits expansion of stem/early progenitor cells; interplay between these two factors and follistatin determines the ratio of neuronal versus glial cell fates. Fst-/- mouse genetic analysis, in vitro neurosphere assays, lineage marker analysis, pharmacological and genetic dissection of ACTβB vs. GDF11 pathways Development (Cambridge, England) High 21852401
2019 GDF11 promotes osteogenesis by activating BMP signaling; Gdf11-null mice show reduced bone mass through impaired osteoblast and chondrocyte maturation and increased osteoclastogenesis, whereas Mstn-null mice show enhanced bone mass; deletion of Mstn upregulates Gdf11, which activates BMP signaling to enhance osteogenesis. Gdf11 and Mstn knockout mouse phenotyping, follistatin-overexpressing transgenic mice, bone histomorphometry, BMP signaling pathway analysis Proceedings of the National Academy of Sciences of the United States of America High 32071240
2013 GDF11 activates the canonical Smad2/3 signaling cascade in neural stem cells via an ActRIIB/ALK5 receptor complex and alters expression of ~4700 gene transcripts; GDF11 inhibits neural stem cell proliferation (correlating with downregulation of Cyclin D2), suppresses cytoskeletal regulatory genes (Fascin, LASP1), and inhibits cell migration. Transcriptome-wide gene expression analysis, Western blot for Smad2/3, cell proliferation and scratch wound migration assays, pharmacological inhibitors PloS one Medium 24244313
2019 GDF11 activates the TGF-β/Smad2/3 and PI3K/AKT/FoxO1 signaling pathways to protect pancreatic beta cells from glucotoxicity-induced dysfunction and apoptosis in vitro and in diabetic mouse models. Recombinant GDF11 treatment of isolated murine islets and MIN6 cells, Western blot for Smad2 and AKT/FoxO1 phosphorylation, anti-GDF11 antibody blockade, in vivo mouse diabetes models Diabetes Medium 28450417
2019 GDF11 inhibits hepatic hepcidin (HAMP) production by suppressing BMP-SMAD signaling through enhanced SMURF1 (Smad ubiquitin regulatory factor 1) expression and activation of ERK1/2 signaling; ERK1/2 signaling activation is required for GDF11-mediated or SMURF1-mediated suppression of BMP-SMAD signaling and HAMP expression. Exogenous GDF11 administration in vivo and in vitro, pathway inhibitor studies, SMURF1 overexpression, RNA and proteome sequencing British journal of haematology Medium 31418854
2019 GDF11 activates TGF-β/Smad2/3 and protein kinase B/HIF-1α pathways to rescue angiogenic function of endothelial progenitor cells (EPCs) in diabetic hindlimb ischemia; anti-GDF11 antibody impairs vascularization. Recombinant GDF11 treatment of EPCs, anti-GDF11 antibody blockade, Western blot for Smad2/3 and AKT/HIF-1α, in vivo blood flow measurements Diabetes Medium 30026260
2019 GDF11 induces kidney fibrosis and epithelial-to-mesenchymal transition (EMT) of renal tubular cells via SMAD2 phosphorylation; the EMT is SMAD3-dependent; these effects are blocked by follistatin; Gdf11 heterozygous mice show reduced renal fibrosis. In vivo GDF11 administration, renal cell line assays (fibroblast proliferation, EMT assays), Smad2/3 phosphorylation Western blot, follistatin blockade, Gdf11 heterozygous mice Surgery Medium 29731246
2017 GDF11 promotes sacral vertebrae and hindlimb positioning integration by inducing Hox gene expression in axial mesoderm and lateral plate mesoderm via secretion from posterior axial mesoderm; heterochronic shifts in the onset of Gdf11 expression account for evolutionary diversity in hindlimb positioning across tetrapods. Chick embryo electroporation (Gdf11 gain of function), comparative vertebrate embryo analysis, Hox gene expression mapping Nature ecology & evolution Medium 29046533
2019 Crystal structure of the WFIKKN2 follistatin domain (FSD) reveals it blocks GDF8 and GDF11 interactions with ActRIIB; surface-exposed residues critical for antagonism differ between WFIKKN2, follistatin, and FSTL3 FSDs, indicating mechanistically distinct ligand blocking strategies. Crystal structure (1.39 Å), native gel shift, surface plasmon resonance, alanine-scanning mutagenesis, cell-based GDF8 inhibition assay The Journal of biological chemistry High 30814254
2020 GDF11 enhanced Smad2/3 phosphorylation in MSCs, upregulating YME1L (a mitochondrial protease) to balance OPA1 processing and promote mitochondrial fusion; this pathway protects MSCs from apoptosis under hypoxia; TGF-β receptor or Smad2/3 inhibitors block these effects. Lentiviral GDF11 overexpression in MSCs, TGF-β receptor inhibitor (SB431542) and Smad2/3 inhibitor (SIS3), Western blot for Smad2/3/YME1L/OPA1, mitochondrial morphology imaging, in vivo MSC transplantation Stem cells translational medicine Medium 32515551
2022 GDF11 stimulates MMP2 expression and EVT cell invasion via ALK4/5-Smad2/3 signaling, with ID2 (inhibitor of differentiation 2) acting as an obligate intermediate; siRNA knockdown of ALK4, ALK5, Smad2/3, or ID2 each abolishes GDF11-stimulated MMP2 expression. Pharmacological inhibitors of ALK4/5, siRNA knockdown of Smad2/3 and ID2, Western blot, Matrigel invasion assay in HTR-8/SVneo and primary EVT cells Cell communication and signaling : CCS Medium 35705978
2022 GDF11 pathophysiological levels activate Smad2/3 signaling and upregulate the E3 ubiquitin ligase Atrogin-1 (via FOXO1) to induce skeletal muscle atrophy in human iPSC-derived myocytes; FOXO1 blockade reverses GDF11-induced Atrogin-1 expression and atrophic phenotype. Human iPSC-derived myocyte treatment with GDF11, Western blot for pSmad2/3, FOXO1 inhibition, Atrogin-1 mRNA and protein, myocyte diameter measurements American journal of physiology. Cell physiology Medium 36094432
2021 Endogenous GDF11 in the adult hippocampus acts as a negative regulator of hippocampal neurogenesis; conditional depletion of Gdf11 in adult mice increases neural progenitor proliferation and decreases newborn neuron numbers, indicating that endogenous brain GDF11 and circulating exogenous GDF11 have different effects on neurogenesis. Tamoxifen-inducible conditional Gdf11 knockout in adult mice, immunohistochemical quantification of neural progenitor proliferation and newborn neurons Molecular brain Medium 34488822
2019 GDF11 activates ALK5-dependent SMAD2/3 signaling in hepatocellular carcinoma cells to rapidly trigger lipid droplet accumulation; ALK5 inhibition blocks GDF11-mediated SMAD2/3 signaling and attenuates lipid accumulation; this effect is absent in primary hepatocytes. ALK5 inhibitor treatment, lipidomics (UHPLC/MS), transcriptomics, immunofluorescence for SMAD2/3 nuclear translocation, Western blot Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 33684566
2009 GDF11 (BMP-11) supports undifferentiated human embryonic stem cell self-renewal under feeder-free conditions by activating SMAD2/3 phosphorylation through the ALK4/ALK5/ALK7 type I receptors; the type I TGF-β receptor inhibitor SB431542 completely abolishes this maintenance activity. Feeder-free hESC culture with recombinant GDF11, SB431542 inhibitor treatment, Western blot for pSmad2/3, pluripotency marker analysis Cloning and stem cells Medium 19751112
2019 GDF11 activates TGF-β/Smad2/3 and AMPK signaling pathways in white adipose tissue to regulate metabolic homeostasis; GDF11 overexpression also activates PI3K/AKT/FoxO1 pathway; these mechanisms underlie GDF11-mediated improvement of insulin resistance and obesity phenotypes. Hydrodynamic gene delivery, Western blot for pathway activation, metabolic studies in HFD and STZ diabetic mice, adipose tissue gene expression analysis Journal of translational medicine Medium 31847906
2022 GDF11 inhibits adipogenesis of pre-adipocytes through ALK5-Smad2/3 activation in cooperation with the WNT/β-catenin pathway; WNT/β-catenin pathway inhibition overrides GDF11-mediated anti-adipogenic effects; GDF11 also increases adiponectin secretion and glucose uptake in mature adipocytes. Murine and human pre-adipocyte cell lines, WNT/β-catenin pathway inhibitor, Western blot for pSmad2/3, adipogenesis assays, glucose uptake measurements Cell proliferation Medium 35920128
2019 GDF11 modulates macrophage polarization from M1 to M2 via the TGFβR1/Smad2 pathway; in vitro, GDF11 treatment of Raw264.7 and THP1 cells promotes M2 and diminishes M1 markers; TGFβR1 was identified as the relevant receptor by RNA and proteome sequencing followed by pathway inhibition. In vitro macrophage polarization assays, RNA and proteome sequencing, TGFβR1 inhibition, in vivo SAP mouse/rat models International immunopharmacology Medium 35461108
2019 In triple-negative breast cancer and TNBC-related xenograft models, GDF11 promotes an epithelial, anti-invasive phenotype by sustaining expression of E-cadherin and ID2; this is mediated through PCSK5-dependent proteolytic activation of GDF11. 3D culture invasion assays, intraductal xenografts, PCSK5 reconstitution, E-cadherin/ID2 Western blot, in vivo lung metastasis model Developmental cell High 29161592

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science (New York, N.Y.) 672 24797481
2015 GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration. Cell metabolism 439 26001423
2003 Autoregulation of neurogenesis by GDF11. Neuron 276 12546816
2001 Assigning the positional identity of spinal motor neurons: rostrocaudal patterning of Hox-c expression by FGFs, Gdf11, and retinoids. Neuron 247 11754833
2005 GDF11 controls the timing of progenitor cell competence in developing retina. Science (New York, N.Y.) 190 15976303
2016 Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation. Circulation research 168 27034275
2002 Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning. Genes & development 164 12414726
2004 GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development. Development (Cambridge, England) 134 15548585
2005 GDF11 forms a bone morphogenetic protein 1-activated latent complex that can modulate nerve growth factor-induced differentiation of PC12 cells. Molecular and cellular biology 127 15988002
2017 Supraphysiological levels of GDF11 induce striated muscle atrophy. EMBO molecular medicine 101 28270449
2010 METABOLIC FUNCTIONS OF MYOSTATIN AND GDF11. Immunology, endocrine & metabolic agents in medicinal chemistry 99 21197386
2018 The GDF11-FTO-PPARγ axis controls the shift of osteoporotic MSC fate to adipocyte and inhibits bone formation during osteoporosis. Biochimica et biophysica acta. Molecular basis of disease 96 30279140
2017 Structural basis for potency differences between GDF8 and GDF11. BMC biology 95 28257634
2017 Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting. Basic research in cardiology 94 28647906
2016 GDF11 Protects against Endothelial Injury and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice. Molecular therapy : the journal of the American Society of Gene Therapy 92 27502608
2015 Reduced Circulating GDF11 Is Unlikely Responsible for Age-Dependent Changes in Mouse Heart, Muscle, and Brain. Endocrinology 92 26372181
2011 Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate. Development (Cambridge, England) 91 21852401
2008 In vivo functions of the proprotein convertase PC5/6 during mouse development: Gdf11 is a likely substrate. Proceedings of the National Academy of Sciences of the United States of America 85 18378898
2020 Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling. Molecular therapy. Nucleic acids 83 33230465
2013 Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2. Proceedings of the National Academy of Sciences of the United States of America 83 24019467
2006 The function of growth/differentiation factor 11 (Gdf11) in rostrocaudal patterning of the developing spinal cord. Development (Cambridge, England) 83 16790475
2016 Targeted myocardial delivery of GDF11 gene rejuvenates the aged mouse heart and enhances myocardial regeneration after ischemia-reperfusion injury. Basic research in cardiology 82 28004242
2002 Induction of dental pulp stem cell differentiation into odontoblasts by electroporation-mediated gene delivery of growth/differentiation factor 11 (Gdf11). Gene therapy 75 12040463
2001 Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb. Developmental biology 71 11203700
2017 Tumor-Suppressor Inactivation of GDF11 Occurs by Precursor Sequestration in Triple-Negative Breast Cancer. Developmental cell 69 29161592
2016 Lack of evidence for GDF11 as a rejuvenator of aged skeletal muscle satellite cells. Aging cell 66 27139744
2009 Foxg1 promotes olfactory neurogenesis by antagonizing Gdf11. Development (Cambridge, England) 66 19297409
2020 GDF11 inhibits cardiomyocyte pyroptosis and exerts cardioprotection in acute myocardial infarction mice by upregulation of transcription factor HOXA3. Cell death & disease 65 33100331
2004 Stimulation of reparative dentin formation by ex vivo gene therapy using dental pulp stem cells electrotransfected with growth/differentiation factor 11 (Gdf11). Human gene therapy 65 15610605
2017 GDF11 Attenuates Development of Type 2 Diabetes via Improvement of Islet β-Cell Function and Survival. Diabetes 63 28450417
2022 GDF11 promotes wound healing in diabetic mice via stimulating HIF-1ɑ-VEGF/SDF-1ɑ-mediated endothelial progenitor cell mobilization and neovascularization. Acta pharmacologica Sinica 62 36347996
2019 Exogenous GDF11 attenuates non-canonical TGF-β signaling to protect the heart from acute myocardial ischemia-reperfusion injury. Basic research in cardiology 61 30900023
2011 Gdf11 facilitates temporal progression of neurogenesis in the developing spinal cord. The Journal of neuroscience : the official journal of the Society for Neuroscience 59 21248112
2020 GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone. Proceedings of the National Academy of Sciences of the United States of America 58 32071240
2015 Growth and differentiation factor 11 (GDF11): Functions in the regulation of erythropoiesis and cardiac regeneration. Pharmacology & therapeutics 58 26523637
2016 GDF11 improves tubular regeneration after acute kidney injury in elderly mice. Scientific reports 56 27703192
2018 GDF11 Improves Angiogenic Function of EPCs in Diabetic Limb Ischemia. Diabetes 54 30026260
2019 The role of GDF11 in aging and skeletal muscle, cardiac and bone homeostasis. Critical reviews in biochemistry and molecular biology 49 31144559
2016 GDF11/BMP11 activates both smad1/5/8 and smad2/3 signals but shows no significant effect on proliferation and migration of human umbilical vein endothelial cells. Oncotarget 47 26919250
2005 The isolation, characterization, and expression of a novel GDF11 gene and a second myostatin form in zebrafish, Danio rerio. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 45 15886039
2018 GDF11 Rejuvenates Cerebrovascular Structure and Function in an Animal Model of Alzheimer's Disease. Journal of Alzheimer's disease : JAD 42 29480172
2017 Anatomical integration of the sacral-hindlimb unit coordinated by GDF11 underlies variation in hindlimb positioning in tetrapods. Nature ecology & evolution 38 29046533
2019 The influence of GDF11 on brain fate and function. GeroScience 36 30729414
2016 GDF11 Inhibits Bone Formation by Activating Smad2/3 in Bone Marrow Mesenchymal Stem Cells. Calcified tissue international 36 27395058
2019 Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction-like phenotype in aged mice. Aging cell 35 31637864
2011 Growing backwards: an inverted role for the shrimp ortholog of vertebrate myostatin and GDF11. The Journal of experimental biology 35 21795562
2021 GDF11 alleviates secondary brain injury after intracerebral hemorrhage via attenuating mitochondrial dynamic abnormality and dysfunction. Scientific reports 33 33597668
2019 Gdf11 gene transfer prevents high fat diet-induced obesity and improves metabolic homeostasis in obese and STZ-induced diabetic mice. Journal of translational medicine 33 31847906
2018 GDF11 antagonizes TNF-α-induced inflammation and protects against the development of inflammatory arthritis in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 30407878
2021 GDF-11 Protects the Traumatically Injured Spinal Cord by Suppressing Pyroptosis and Necroptosis via TFE3-Mediated Autophagy Augmentation. Oxidative medicine and cellular longevity 32 34712387
2019 GDF11 exhibits tumor suppressive properties in hepatocellular carcinoma cells by restricting clonal expansion and invasion. Biochimica et biophysica acta. Molecular basis of disease 32 30890427
2019 A GDF11/myostatin inhibitor, GDF11 propeptide-Fc, increases skeletal muscle mass and improves muscle strength in dystrophic mdx mice. Skeletal muscle 32 31133057
2022 GDF11 ameliorates severe acute pancreatitis through modulating macrophage M1 and M2 polarization by targeting the TGFβR1/SMAD-2 pathway. International immunopharmacology 31 35461108
2020 Anti-Aging Effects of GDF11 on Skin. International journal of molecular sciences 31 32283613
2019 GDF11 Antagonizes Psoriasis-like Skin Inflammation via Suppression of NF-κB Signaling Pathway. Inflammation 31 30259241
2020 GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing. Stem cells translational medicine 30 32515551
2014 Effective RNA-silencing strategy of Lv-MSTN/GDF11 gene and its effects on the growth in shrimp, Litopenaeus vannamei. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 29 25246367
2013 Direct activation of a mouse Hoxd11 axial expression enhancer by Gdf11/Smad signalling. Developmental biology 29 24016758
2021 GDF11 Alleviates Pathological Myocardial Remodeling in Diabetic Cardiomyopathy Through SIRT1-Dependent Regulation of Oxidative Stress and Apoptosis. Frontiers in cell and developmental biology 28 34262905
2018 GDF11 Modulates Ca2+-Dependent Smad2/3 Signaling to Prevent Cardiomyocyte Hypertrophy. International journal of molecular sciences 28 29783655
2020 Hypoxia-induced miR-1260b regulates vascular smooth muscle cell proliferation by targeting GDF11. BMB reports 27 31818357
2013 cDNA cloning and expression analysis of myostatin/GDF11 in shrimp, Litopenaeus vannamei. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 27 23402749
2013 Transcriptional basis for the inhibition of neural stem cell proliferation and migration by the TGFβ-family member GDF11. PloS one 27 24244313
2021 PPARα Targeting GDF11 Inhibits Vascular Endothelial Cell Senescence in an Atherosclerosis Model. Oxidative medicine and cellular longevity 25 33728018
2020 Candidate rejuvenating factor GDF11 and tissue fibrosis: friend or foe? GeroScience 25 33025411
2019 GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies. Frontiers in oncology 25 31681577
2007 Characterization of amphioxus GDF8/11 gene, an archetype of vertebrate MSTN and GDF11. Development genes and evolution 25 17551751
2023 Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans. Cardiovascular research 23 37742057
2021 GDF11 rapidly increases lipid accumulation in liver cancer cells through ALK5-dependent signaling. Biochimica et biophysica acta. Molecular and cell biology of lipids 23 33684566
2019 Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans. Human mutation 23 31215115
2018 GDF11 expression in the adult rat central nervous system. Journal of chemical neuroanatomy 23 29448002
2018 GDF11 restrains tumor growth by promoting apoptosis in pancreatic cancer. OncoTargets and therapy 22 30568460
2009 BMP-11 and myostatin support undifferentiated growth of human embryonic stem cells in feeder-free cultures. Cloning and stem cells 22 19751112
2022 GDF11 inhibits adipogenesis and improves mature adipocytes metabolic function via WNT/β-catenin and ALK5/SMAD2/3 pathways. Cell proliferation 21 35920128
2019 Neuroprotective potential of GDF11 in experimental intracerebral hemorrhage in elderly rats. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 21 30827882
2018 GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure. Surgery 21 29731246
2020 Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice. Scientific reports 20 32165710
2018 Late-onset administration of GDF11 extends life span and delays development of age-related markers in the annual fish Nothobranchius guentheri. Biogerontology 20 30519861
2011 PCSK5 and GDF11 expression in the hindgut region of mouse embryos with anorectal malformations. European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie 20 21480163
2022 GDF-11 promotes human trophoblast cell invasion by increasing ID2-mediated MMP2 expression. Cell communication and signaling : CCS 19 35705978
2022 GDF11 inhibits abnormal adipogenesis of condylar chondrocytes in temporomandibular joint osteoarthritis. Bone & joint research 19 35787089
2021 Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11. Genetics in medicine : official journal of the American College of Medical Genetics 19 34113007
2019 Growth differentiation factor 11 (GDF11) has pronounced effects on skin biology. PloS one 19 31181098
2018 GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway. PeerJ 19 30202652
2016 Questions and Answers About Myostatin, GDF11, and the Aging Heart. Circulation research 19 26837737
2020 Chondrocyte suppression is mediated by miR-129-5p via GDF11/SMAD3 signaling in developmental dysplasia of the hip. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 18 32396235
2020 GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells. Journal of cellular physiology 18 33174245
2019 Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11. International journal of cancer 18 30889293
2019 Analysis of Cre-mediated genetic deletion of Gdf11 in cardiomyocytes of young mice. American journal of physiology. Heart and circulatory physiology 18 31125255
2019 GDF11 contributes to hepatic hepcidin (HAMP) inhibition through SMURF1-mediated BMP-SMAD signalling suppression. British journal of haematology 18 31418854
2016 Elevated GDF11 Is a Risk Factor for Age-Related Frailty and Disease in Humans. Cell metabolism 18 27411004
2023 Hydrogen sulfide antagonizes formaldehyde-induced ferroptosis via preventing ferritinophagy by upregulation of GDF11 in HT22 cells. Toxicology 17 37105376
2022 Pathophysiological levels of GDF11 activate Smad2/Smad3 signaling and induce muscle atrophy in human iPSC-derived myocytes. American journal of physiology. Cell physiology 17 36094432
2020 GDF11 induces mild hepatic fibrosis independent of metabolic health. Aging 17 33126224
2024 GDF11 OVEREXPRESSION ALLEVIATES SEPSIS-INDUCED LUNG MICROVASCULAR ENDOTHELIAL BARRIER DAMAGE BY ACTIVATING SIRT1/NOX4 SIGNALING TO INHIBIT FERROPTOSIS. Shock (Augusta, Ga.) 16 38920138
2021 GDF11 prevents the formation of thoracic aortic dissection in mice: Promotion of contractile transition of aortic SMCs. Journal of cellular and molecular medicine 16 33764670
2019 MiR-92a regulates endothelial progenitor cells (EPCs) by targeting GDF11 via activate SMAD2/3/FAK/Akt/eNOS pathway. Annals of translational medicine 16 31807544
2021 GDF11 expressed in the adult brain negatively regulates hippocampal neurogenesis. Molecular brain 15 34488822
2019 Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11. The Journal of biological chemistry 15 30814254
2017 Modulation of GDF11 expression and synaptic plasticity by age and training. Oncotarget 14 28938532