GDF11

What is GDF11 Protein?

GDF11 gene (growth differentiation factor 11) is a protein coding gene which situated on the long arm of chromosome 12 at locus 12q13. This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein plays a role in the development of the nervous and other organ systems, and may regulate aging. The GDF11 protein is consisted of 407 amino acids and GDF11 molecular weight is approximately 45.1 kDa.

What is the Function of GDF11 Protein?

GDF11 plays a key role in embryonic development, bone formation and skeletal pattern establishment. In addition, GDF11 is also considered to be a factor capable of reversing the aging process, with potential functional restoration effects. The expression of GDF11 in the adult brain is mainly concentrated in excitatory neurons and is closely related to brain aging and cognitive function. In addition, the loss of GDF11 has been associated with declines in cognitive function, including impairments in social cognition and object recognition memory. At the molecular level, the loss of GDF11 leads to the upregulation of p21 protein, a pro-aging factor whose upregulation is associated with neuronal aging and cell cycle arrest. The study also found that excitatory neuronal aging caused by GDF11 loss requires the involvement of p21, suggesting that the GDF11-P21 signaling pathway plays a key role in regulating excitatory neuronal aging and brain aging.

Fig1. Effects of GDF11 on embryogenesis and carcinogenesis. (Wojciech Król, 2023)

GDF11 Related Signaling Pathway

GDF11 can regulate the polarization of macrophage M1 and M2 by targeting TGFβR1/ MAD-2 signaling pathway, thereby improving severe acute pancreatitis (SAP). GDF11 inhibits lipogenic differentiation by activating the TGF-β/Smad signaling pathway. In breast cancer, GDF11 is involved in cancer progression by regulating SMURF1-mediated p53 and ERα signaling pathways. In the central nervous system, GDF11 is specifically highly expressed in excitatory neurons, and by inhibiting p21, it delays excitatory neuron aging and brain aging, improves cognitive aging and prolongs the lifespan of mice.

GDF11 Related Diseases

GDF11 has been implicated in a variety of diseases, with particular potential regulatory roles in neurodegenerative diseases, cognitive decline, and age-related symptoms. Decreased expression of GDF11 is associated with brain aging and cognitive decline, and its loss of function may be related to the development of neurodegenerative diseases. In addition, GDF11 plays a role in inflammatory diseases such as severe acute pancreatitis by regulating macrophage polarization, demonstrating its important role in inflammatory responses. In the field of oncology, the function of GDF11 may have a dual nature, it may promote tumor progression in some cases, while it may inhibit tumor development in others.

Bioapplications of GDF11

GDF11 has attracted attention for its potential to promote tissue regeneration, improve neurodegenerative diseases, and delay brain aging, with its applications mainly concentrated in the field of medical research and therapy. For example, GDF11 has been studied to promote repair after heart and muscle damage, improve cognitive function, and treat age-related memory decline. In addition, the regulatory role of GDF11 also shows potential applications in the treatment of inflammatory diseases and certain cancers, although it may have a complex dual role in tumor development. Therefore, GDF11-related applications are being actively explored in order to develop new therapeutic strategies and drugs.

Case Study 1: Mikako Honda, 2022

Recent studies show that in addition to MSTN, GDF11, which shares a high sequence identity with MSTN, induces muscle atrophy in vitro and in vivo at supraphysiological levels, whereas controversy regarding its roles exists. Furthermore, higher circulating GDF11 levels associate with frailty in humans. On the other hand, little is known about the effect of pathophysiological levels of GDF11 on muscle atrophy. Here this study aims to determine whether pathophysiological levels of GDF11 are sufficient to activate Smad2/Smad3 signaling and induce muscle atrophy using human iPSC-derived myocytes (hiPSC myocytes). Incubating hiPSC myocytes with pathophysiological concentrations of GDF11 significantly reduces myocyte diameters. And pathophysiological levels of GDF11 are sufficient to activate Smad2/3 signaling. Finally, pathophysiological levels of GDF11 are capable of inducing the expression of Atrogin-1, an atrophy-promoting E3 ubiquitin ligase and that FOXO1 blockage reverses the GDF11-induced Atrogin-1 expression and atrophic phenotype.

Fig1. Pathophysiological levels of GDF11 induce muscle atrophy in hiPSC myocytes.

Fig2. Smad2/3 activation by pathophysiological levels of GDF11 in hiPSC myocytes.

Case Study 2: Sharik Hernandez, 2021

The aim of the present work was to investigate the mechanism associated with the tumor-suppressive properties displayed by GDF11 in liver cancer cells. Hepatocellular carcinoma-derived cell lines were exposed to GDF11 (50 ng/ml), RNA-seq analysis in Huh7 cell line revealed that GDF11 exerted profound transcriptomic impact, which involved regulation of cholesterol metabolic process, steroid metabolic process as well as key signaling pathways, resembling endoplasmic reticulum-related functions. Cholesterol and triglycerides determination in Huh7 and Hep3B cells treated with GDF11 exhibited a significant decrement in the content of these lipids. The mTOR signaling pathway was downregulated, and this was associated with a reduction in key proteins involved in the mevalonate pathway. In addition, real-time metabolism assessed by Seahorse technology showed abridged glycolysis as well as glycolytic capacity, closely related to an impaired oxygen consumption rate and decrement in adenosine triphosphate production. Finally, transmission electron microscopy revealed mitochondrial abnormalities, such as cristae disarrangement, consistent with metabolic changes.

Fig3. Unsupervised hierarchical cluster analysis of GDF11-treated and not treated cells.

Fig4. GDF11 decreases aberrant lipogenesis. Huh7 and Hep3B cells were treated for 72 h with GDF11.

GDF11 has several biochemical functions, for example, cytokine activity,growth factor activity,transforming growth factor beta receptor binding. Some of the functions are cooperated with other proteins, some of the functions could acted by GDF11 itself. We selected most functions GDF11 had, and list some proteins which have the same functions with GDF11. You can find most of the proteins on our site.

GDF11 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with GDF11 here. Most of them are supplied by our site. Hope this information will be useful for your research of GDF11.

ACVR2B;Acvr1b;Tgfbr1;Acvr1c;WFIKKN2;WFIKKN1