95,543 results match your criteria signaling domain

Short-term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain-derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety-like behaviors.

FASEB J 2021 Aug;35(8):e21767

The Fukuoka University Institute for Physical Activity, Fukuoka University, Fukuoka, Japan.

Running exercise has beneficial effects on brain health. However, the effects of relatively short-term running exercise (STEx) on behavior, and its underlying signaling pathways, are poorly understood. In this study, we evaluated the possibility that the regulation by STEx of brain-derived neurotrophic factor (BDNF) and neuronal nitric oxide synthase (nNOS, encoded by NOS1), which are important molecules for anxiety regulation, might involve mechanisms of epigenetic modification, such as DNA methylation. Read More

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NirD curtails the stringent response by inhibiting RelA activity in .

Elife 2021 Jul 29;10. Epub 2021 Jul 29.

Laboratoire de Chimie Bactérienne, Institut de Microbiologie de la Méditerranée, CNRS-Aix Marseille Univ (UMR7283), Marseille, France.

Bacteria regulate their metabolism to adapt and survive adverse conditions, in particular to stressful downshifts in nutrient availability. These shifts trigger the so-called stringent response, coordinated by the signaling molecules guanosine tetra and pentaphosphate collectively referred to as (p)ppGpp. In , accumulation of theses alarmones depends on the (p)ppGpp synthetase RelA and the bifunctional (p)ppGpp synthetase/hydrolase SpoT. Read More

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The repair gene - a potential oncogene.

Oncol Rev 2021 Feb 2;15(1):519. Epub 2021 Jul 2.

Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India.

encodes for a protein that belongs to RecQ DEAH helicase family and interacts with the BRCT repeats of . The N-terminus of functions in DNA metabolism as DNA-dependent ATPase and helicase. The C-terminus consists of BRCT domain, which interacts with and this interaction is one of the major regulator of function. Read More

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February 2021

Genotype-Specific Expression and NLR Repertoire Contribute to Phenotypic Resistance Diversity in .

Front Plant Sci 2021 12;12:675760. Epub 2021 Jul 12.

Organismal and Evolutionary Biology Research Programme, University of Helsinki, Helsinki, Finland.

High levels of phenotypic variation in resistance appears to be nearly ubiquitous across natural host populations. Molecular processes contributing to this variation in nature are still poorly known, although theory predicts resistance to evolve at specific loci driven by pathogen-imposed selection. Nucleotide-binding leucine-rich repeat (NLR) genes play an important role in pathogen recognition, downstream defense responses and defense signaling. Read More

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Necroptosis: A Novel Pathway in Neuroinflammation.

Front Pharmacol 2021 12;12:701564. Epub 2021 Jul 12.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.

Neuroinflammation is a complex inflammatory process in the nervous system that is expected to play a significant role in neurological diseases. Necroptosis is a kind of necrosis that triggers innate immune responses by rupturing dead cells and releasing intracellular components; it can be caused by Toll-like receptor (TLR)-3 and TLR-4 agonists, tumor necrosis factor (TNF), certain microbial infections, and T cell receptors. Necroptosis signaling is modulated by receptor-interacting protein kinase (RIPK) 1 when the activity of caspase-8 becomes compromised. Read More

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A genetic basis for friendship? Homophily for membrane-associated PDE11A-cAMP-CREB signaling in CA1 of hippocampus dictates mutual social preference in male and female mice.

Mol Psychiatry 2021 Jul 28. Epub 2021 Jul 28.

Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.

Although the physical and mental benefits of friendships are clear, the neurobiological mechanisms driving mutual social preferences are not well understood. Studies in humans suggest friends are more genetically similar, particularly for targets within the 3',5'-cyclic adenosine monophosphate (cAMP) cascade. Unfortunately, human studies can not provide conclusive evidence for such a biological driver of friendship given that other genetically related factors tend to co-segregate with friendship (e. Read More

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PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistance.

Cell Death Dis 2021 Jul 29;12(8):749. Epub 2021 Jul 29.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

To identify drivers of sarcoma cancer stem-like cells (CSCs), we compared gene expression using RNA sequencing between HT1080 fibrosarcoma and SK-LMS-1 leiomyosarcoma spheroids (which are enriched for CSCs) compared with the parent populations. The most overexpressed survival signaling-related gene in spheroids was phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of PI3K, which functions in tumorigenesis and metastasis. In a human sarcoma microarray, PIK3R3 was also overexpressed by 4. Read More

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Tyr Regulates Lymphocyte-Specific Tyrosine Kinase Activity in T Cells.

J Immunol 2021 Jul 28. Epub 2021 Jul 28.

Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; and

TCR signaling critically depends on the tyrosine kinase Lck (lymphocyte-specific protein tyrosine kinase). Two phosphotyrosines, the activating pTyr and the inhibitory pTyr, control Lck activity. Recently, pTyr in the Lck SH2 domain emerged as a third regulator. Read More

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Hhex inhibits cell migration via regulating RHOA/CDC42-CFL1 axis in human lung cancer cells.

Cell Commun Signal 2021 Jul 28;19(1):80. Epub 2021 Jul 28.

Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Room N8-110, 72 Binhai Road, Qingdao, 266237, China.

Background: Hhex(human hematopoietically expressed homeobox), also known as PRH, is originally considered as a transcription factor to regulate gene expression due to its homebox domain. Increasing studies show that Hhex plays a significant role in development, including anterior-posterior axis formation, vascular development and HSCs self-renewal etc. Hhex is linked to many diseases such as cancers, leukemia, and type-2 diabetes. Read More

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Targeted immune epitope prediction to HHLA2 and MAGEB5 protein variants as therapeutic approach to related viral diseases.

BMC Immunol 2021 Jul 28;22(1):49. Epub 2021 Jul 28.

PepVax, Inc., 0411 Motor City Drive, Suite #750, Bethesda, MD, 20817, USA.

Background: Targeted immunotherapy is mostly associated with cancer treatment wherein designed molecules engage signaling pathways and mutant proteins critical to the survival of the cell. One of several genetic approaches is the use of in silico methods to develop immune epitopes targeting specific antigenic regions on related mutant proteins. In a recent study we showed a functional association between the gamma retrovirus HERV-H Long Terminal Associating (HHLA1, HHLA2 and HHLA3) proteins and melanoma associated antigen of the B class proteins (MAGEB5), with a resultant decrease in expression of HLA class I and II immune variants. Read More

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The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation.

Aging (Albany NY) 2021 Jul 28;13(undefined). Epub 2021 Jul 28.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Fraxetin, a natural product isolated and purified from the bark of , has anti-inflammatory, analgesic, and anti-dysenteric activities. This study aimed to investigate the anti-tumor effects of fraxetin in pancreatic ductal adenocarcinoma (PDA). The effects of fraxetin on the malignant biological behavior of PDA were evaluated. Read More

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Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer.

Neoplasia 2021 Jul 25;23(9):898-911. Epub 2021 Jul 25.

Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy; Oncoxx Biotech, 66034 Lanciano (Chieti), Italy; Unit of Medical Genetics, Department of Biomedical Sciences - BIOMORF, University of Messina, 98125 Messina, Italy. Electronic address:

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2-driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Read More

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On the PHLPPside: Emerging roles of PHLPP phosphatases in the heart.

Cell Signal 2021 Jul 25:110097. Epub 2021 Jul 25.

Department of Pharmacology, University of California, San Diego, La Jolla, CA 92039, USA; Cardiovascular Molecular Signaling, Huntington Medical Research Institutes, Pasadena, CA 91105, USA. Electronic address:

PH domain leucine-rich repeat protein phosphatase (PHLPP) is a family of enzymes made up of two isoforms (PHLPP1 and PHLPP2), whose actions modulate intracellular activity via the dephosphorylation of specific serine/threonine (Ser/Thr) residues on proteins such as Akt. Recent data generated in our lab, supported by findings from others, implicates the divergent roles of PHLPP1 and PHLPP2 in maintaining cellular homeostasis since dysregulation of these enzymes has been linked to various pathological states including cardiovascular disease, diabetes, ischemia/reperfusion injury, musculoskeletal disease, and cancer. Therefore, development of therapies to modulate specific isoforms of PHLPP could prove to be therapeutically beneficial in several diseases especially those targeting the cardiovascular system. Read More

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Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function.

Cell Rep 2021 Jul;36(4):109446

Oncode Institute and Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands. Electronic address:

Transcription factors harbor defined regulatory intrinsically disordered regions (IDRs), which raises the question of how they mediate binding to structured co-regulators and modulate their activity. Here, we present a detailed molecular regulatory mechanism of Forkhead box O4 (FOXO4) by the structured transcriptional co-regulator β-catenin. We find that the disordered FOXO4 C-terminal region, which contains its transactivation domain, binds β-catenin through two defined interaction sites, and this is regulated by combined PKB/AKT- and CK1-mediated phosphorylation. Read More

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A bispecific decoy receptor VEGFR-EGFR/Fc binding EGF-like ligands and VEGF shows potent antitumor efficacy.

J Drug Target 2021 Jul 28:1-28. Epub 2021 Jul 28.

Department of Clinical immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) represent two clinically validated targets for a variety of human cancers, and dual inhibition of EGFR and VEGF(R) has demonstrated superior activity to single EGFR inhibitors. This study was to construct a novel bispecific decoy receptor VEGFR-EGFR/Fc that contains Fc portion of human IgG1 acted as molecular scaffold, and the immunoglobulin-like domain 1-3 of VEGFR1 and extracellular domain of EGFR fused to the N-terminal and C-terminal of Fc, respectively, aiming at capturing the EGF-like ligands and VEGF. ELISA showed that VEGFR-EGFR/Fc bound to EGF, TGF-α, and VEGF with high affinity. Read More

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Structural basis of the effect of activating mutations on the EGF receptor.

Elife 2021 Jul 28;10. Epub 2021 Jul 28.

Department of Chemistry, University College London, London, United Kingdom.

Mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are common oncogenic driver events in non-small cell lung cancer. Although the activation of EGFR in normal cells is primarily driven by growth-factor-binding-induced dimerization, mutations on different exons of the kinase domain of the receptor have been found to affect the equilibrium between its active and inactive conformations giving rise to growth-factor-independent kinase activation. Using molecular dynamics simulations combined with enhanced sampling techniques, we compare here the conformational landscape of the monomers and homodimers of the wild-type and mutated forms of EGFR ΔELREA and L858R, as well as of two exon 20 insertions, D770-N771insNPG, and A763-Y764insFQEA. Read More

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Growth Hormone Receptor (Ghr) 6ω Pseudoexon Activation: A Novel Cause Of Severe Growth Hormone Insensitivity (Ghi).

J Clin Endocrinol Metab 2021 Jul 28. Epub 2021 Jul 28.

Centre for Endocrinology, William Harvey Research Institute: Barts and The London School of Medicine and Dentistry William Harvey Research Institute.

Context: Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies.

Objective: Identification of the genetic cause of growth failure in 3 'classical' GHI subjects.

Design: A novel intronic GHR variant was identified, and in vitro splicing assays confirmed aberrant splicing. Read More

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Cryo-EM structure of human Wntless in complex with Wnt3a.

Nat Commun 2021 07 27;12(1):4541. Epub 2021 Jul 27.

Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.

Wntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas aberrant Wnt signaling is tightly associated with many human diseases including cancers. Here, we report the cryo-EM structure of human WLS in complex with Wnt3a, the most widely studied Wnt, at 2. Read More

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Mol Pharmacol 2021 Jul 27. Epub 2021 Jul 27.

Imperial College London, United Kingdom

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor and mainstay therapeutic target for the treatment of type 2 diabetes and obesity. Recent reports have highlighted how biased agonism at the GLP-1R affects sustained glucose-stimulated insulin secretion through avoidance of desensitisation and downregulation. A number of GLP-1R agonists (GLP-1RAs) feature a fatty acid moiety to prolong their pharmacokinetics via increased albumin binding, but the potential for these chemical changes to influence GLP-1R function has rarely been investigated beyond potency assessments for cyclic adenosine monophosphate (cAMP). Read More

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RtNAC100 involved in the regulation of ROS, Na accumulation and induced salt-related PCD through MeJA signal pathways in recretohalophyte Reaumuria trigyna.

Plant Sci 2021 Sep 15;310:110976. Epub 2021 Jun 15.

State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, PR China; Key Laboratory of Herbage and Endemic Crop Biotechnology, and College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China. Electronic address:

NAM, ATAF1/2, and CUC2 (NAC) proteins regulate plant responses to salt stress. However, the molecular mechanisms by which NAC proteins regulate salt-induced programmed cell death (PCD) are unclear. We identified 56 NAC genes, 35 of which had complete open reading frames with complete NAM domain, in the R. Read More

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September 2021

A new layer of phosphoinositide-mediated allosteric regulation uncovered for SHIP2.

FASEB J 2021 08;35(8):e21815

Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas, Spanish National Research Council (CSIC), Madrid, Spain.

The Src homology 2 containing inositol 5-phosphatase 2 (SHIP2) is a large multidomain enzyme that catalyzes the dephosphorylation of the phospholipid phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P ) to form PI(3,4)P . PI(3,4,5)P is a key lipid second messenger controlling the recruitment of signaling proteins to the plasma membrane, thereby regulating a plethora of cellular events, including proliferation, growth, apoptosis, and cytoskeletal rearrangements. SHIP2, alongside PI3K and PTEN, regulates PI(3,4,5)P levels at the plasma membrane and has been heavily implicated in serious diseases such as cancer and type 2 diabetes; however, many aspects of its regulation mechanism remain elusive. Read More

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PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity.

Proc Natl Acad Sci U S A 2021 Aug;118(31)

National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", 20122 Milan, Italy;

Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5 to PtdIns(4,5) They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Read More

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Mol Pharmacol 2021 Jul 26. Epub 2021 Jul 26.

Pharmacology, University of Texas Southwestern Medical Center, United States

The WNK (with-no lysine (K)) kinases and their downstream effector kinases, OSR1 (oxidative stress responsive 1) and SPAK (SPS/STE20-related proline-alanine rich kinase), have well-established functions in the maintenance of cell volume and ion homeostasis. Mutations in these kinases have been linked to an inherited form of hypertension, neurological defects, and other pathologies. A rapidly expanding body of evidence points to the involvement of WNKs in regulating multiple diverse cellular processes as well as the progression of some forms of cancer. Read More

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Therapeutic effect of modulating the NLRP3-regulated transforming growth factor-β signaling pathway on interstitial cystitis/bladder pain syndrome.

Biomed Pharmacother 2021 Jun 1;138:111522. Epub 2021 Apr 1.

Integrative Research Centre for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address:

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder with complex pathogenesis and lacks effective treatment. Chronic inflammation is the main pathogenesis of Hunner-type IC/BPS. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome-related transforming growth factor-β (TGF-β)/Smad signaling pathway plays a crucial role in inflammation-related tissue fibrosis. Read More

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Discovery of Cyclic Peptidomimetic Ligands Targeting the Extracellular Domain of EGFR.

J Med Chem 2021 Jul 23. Epub 2021 Jul 23.

Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, Florida 33620, United States.

It is very promising to target the extracellular domain of epidermal growth factor receptor (EGFR) for developing novel and selective anticancer therapies. Herein, we report the discovery of a novel small molecule, , from a one-bead-two-compound (OBTC) cyclic γ-AApeptide library. The molecule was found to bind tightly to the extracellular domain of EGFR. Read More

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The role of Bag3 in cell signaling.

J Cell Biochem 2021 Jul 23. Epub 2021 Jul 23.

Department of Biochemistry, Boston University, Boston, Massachusetts, USA.

Bag3 has been implicated in a wide variety of physiological processes from autophagy to aggresome formation and from cell transformation to survival. We argue that involvement of Bag3 in many of these processes is due to its distinct function in cell signaling. The structure of Bag3 suggests that it can serve as a scaffold that links molecular chaperones Hsp70 and small Hsps with components of a variety of signaling pathways. Read More

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Screening of hub genes and evaluation of the growth regulatory role of CD44 in metastatic prostate cancer.

Oncol Rep 2021 Sep 23;46(3). Epub 2021 Jul 23.

Department of Urology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China.

Prostate cancer (PCa) is the most common cancer type in men worldwide. Currently, the management of metastatic PCa (mPCa) remains a challenge to urologists. The analysis of hub genes and pathways may facilitate the understanding of the molecular mechanism of PCa. Read More

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September 2021

Sacubitril/valsartan (LCZ696) reduces myocardial injury following myocardial infarction by inhibiting NLRP3‑induced pyroptosis via the TAK1/JNK signaling pathway.

Mol Med Rep 2021 Sep 23;24(3). Epub 2021 Jul 23.

Department of Geriatric Cardiology, The First Affiliated Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China.

The present study aimed to investigate the protective effects of sacubitril/valsartan (LCZ696) on ventricular remodeling in myocardial infarction (MI) and the effects of the inflammasome‑mediated inflammatory response. First, a rat model was established. Animals were then treated with LCZ696 so that the histopathological changes associated with ventricular remodeling could be investigated. Read More

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September 2021

14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains.

Commun Biol 2021 Jul 22;4(1):899. Epub 2021 Jul 22.

Department of Structural Biology of Signaling Proteins, Division BIOCEV, Institute of Physiology of the Czech Academy of Sciences, Vestec, Czech Republic.

Neural precursor cell expressed developmentally down-regulated 4 ligase (Nedd4-2) is an E3 ubiquitin ligase that targets proteins for ubiquitination and endocytosis, thereby regulating numerous ion channels, membrane receptors and tumor suppressors. Nedd4-2 activity is regulated by autoinhibition, calcium binding, oxidative stress, substrate binding, phosphorylation and 14-3-3 protein binding. However, the structural basis of 14-3-3-mediated Nedd4-2 regulation remains poorly understood. Read More

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EGFL6 regulates angiogenesis and osteogenesis in distraction osteogenesis via Wnt/β-catenin signaling.

Stem Cell Res Ther 2021 Jul 22;12(1):415. Epub 2021 Jul 22.

Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, PR China.

Background: Osteogenesis is tightly coupled with angiogenesis during bone repair and regeneration. However, the underlying mechanisms linking these processes remain largely undefined. The present study aimed to test the hypothesis that epidermal growth factor-like domain-containing protein 6 (EGFL6), an angiogenic factor, also functions in bone marrow mesenchymal stem cells (BMSCs), playing a key role in the interaction between osteogenesis and angiogenesis. Read More

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