Yuehai Ke's research while affiliated with Zhejiang Medical University and other places
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Publications (104)
Tumor‐associated thrombus (TAT) accounts for a high proportion of venous thromboembolism. Traditional thrombolysis and anticoagulation methods are not effective due to various complications and contraindications, which can easily lead to patients dying from TAT rather than the tumor itself. These clinical issues demonstrate the need to research div...
Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron‐mediated, pathogenic anemia‐inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed tha...
Background
Macrophages have versatile roles in atherosclerosis. SHP2 (Src homology 2 containing protein tyrosine phosphatase 2) has been demonstrated to play a critical role in regulating macrophage activation. However, the mechanism of SHP2 regulation of macrophage function in an atherosclerotic microenvironment remains unknown.
Methods
APOE (apo...
As a hallmark for inflammatory bowel disease (IBD), elevated intestinal epithelial cell (IEC) death compromises the gut barrier, activating inflammatory response and triggering more IEC death. However, the precise intracellular machinery that prevents IEC death and break this vicious feedback remains largely unknown. Here, we report that Gab1 expre...
Mannose is a naturally occurring sugar widely consumed in the daily diet; however, mechanistic insights into how mannose metabolism affects intestinal inflammation remain lacking. Herein, we reported that mannose supplementation ameliorated colitis development and promoted colitis recovery. Macrophage-secreted inflammatory cytokines, particularly T...
Despite the promising antitumor activity of RAF/MEK inhibitors for RAS-driven cancers, not all patients respond to these therapies. Adaptive resistance has been reported as a major culprit in non-responders, which can be reversed by SHP2 inhibitors (SHP2is) in multiple cancer cells, however the underlying mechanisms remain unknown. In this study, w...
Anaplastic thyroid carcinoma (ATC) represents an undifferentiated, aggressive and highly metastatic form of thyroid cancer with high mortality. GAB1, through direct interaction with the kinase PI3K and phosphatase SHP2, is tightly involved in the activation of oncogenic signals; however, the role of GAB1 in ATC remains unclear. GAB1 was significant...
Radiation-induced lung injury is a common late side-effect of thoracic radiotherapy. Endothelial dysfunction following leukocytes infiltration is a prominent feature in this process. Here, we established a clinical-mimicking mouse model of radiation-induced lung injury and found the activity of phosphatase Shp2 was elevated in endothelium after inj...
Oxidative stress contributes to the pathogenesis of acute lung injury. Protein S-glutathionylation plays an important role in cellular antioxidant defense. Here we report that the expression of deglutathionylation enzyme Grx1 is decreased in the lungs of acute lung injury mice. The acute lung injury induced by hyperoxia or LPS is significantly reli...
SHP2 mediates the activities of multiple receptor tyrosine kinase signaling and its function in endothelial processes has been explored extensively. However, genetic studies on the role of SHP2 in tumor angiogenesis have not been conducted. Here, we show that SHP2 is activated in tumor endothelia. Shp2 deletion and pharmacological inhibition reduce...
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing unremitting extracellular matrix deposition. Transforming growth factor-β (TGF-β) superfamily involves bone morphogenetic proteins (BMPs) and TGF-β, and the balance between the activation of TGF-β-dependent SMADs (Smad2/3) and BMP-dependent SMADs (Smad1/5/8) is essential for...
As novel mediators of cell‐to‐cell signalling, small extracellular vesicles (sEVs) play a critical role in physiological and pathophysiological processes. To date, the molecular mechanisms that support sEV generation are incompletely understood. Many kinases are reported for their roles in sEV generation or composition, whereas the involvement of p...
Radiation-induced lung injury (RILI), including acute radiation pneumonitis and chronic radiation-induced pulmonary fibrosis (RIPF), is a side effect of radiotherapy for lung cancer and esophageal cancer. Pulmonary macrophages, as a kind of natural immune cells maintaining lung homeostasis, play a key role in the whole pathological process of RILI....
Transforming growth factor β (TGFβ) signaling plays an important role in regulating tumor malignancy, including in non-small cell lung cancer (NSCLC). The major biological responses of TGFβ signaling are determined by the effector proteins SMAD2 and SMAD3. However, the regulators of TGFβ-SMADs signaling are not completely revealed yet. Here, we sho...
OBJECTIVE: A decrease in nitric oxide, leading to vascular smooth muscle cell proliferation, is a common pathological feature of vascular proliferative diseases. Nitric oxide synthesis by eNOS (endothelial nitric oxide synthase) is precisely regulated by protein kinases including AKT1. ENH (enigma homolog protein) is a scaffolding protein for multi...
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) are common lung disorders characterized by alveolar-capillary barrier disruption and dyspnea, which can cause substantial morbidity and mortality. Currently, a cluster of acute respiratory illnesses, known as novel coronavirus (2019-nCoV)-infected pneumonia...
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Atherosclerosis is a main pathological basis for cardiovascular diseases. Macrophages, featured in phenotypic and functional plasticity, play critical roles in initiation, progression, and regression of atherosclerosis. Our previously studies have shown that protein tyrosine phosphatase SHP2 regulates macrophage polarization, the immune homeostasis...
Objective
A decrease in nitric oxide, leading to vascular smooth muscle cell proliferation, is a common pathological feature of vascular proliferative diseases. Nitric oxide synthesis by eNOS (endothelial nitric oxide synthase) is precisely regulated by protein kinases including AKT1. ENH (enigma homolog protein) is a scaffolding protein for multip...
Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase Shp2, cause Noonan syndrome and LEOPARD syndrome, inherited multifaceted diseases including cardiac and vascular defects. However, the function of Shp2 in blood vessels, especially in vascular smooth muscle cells (VSMCs), remains largely unknown. We generated mice in which...
Background
We previously reported that Hook1 inhibits the phosphatase activity of SHP2 in the regulation of the epithelial-mesenchymal transition (EMT) in lung cancer. In this study, we performed a comprehensive analysis of SHP2 and Hook1 expression and relationships with the prognosis of patients with non-small cell lung cancer (NSCLC).
Materials...
Protein phosphatase 2A (PP2A) is one main serine/threonine phosphatase in eukaryotes, and its activation changes have been linked to modulation of numerous pathological processes, such as cancer, inflammation, fibrosis, and neurodegenerative diseases. Acute respiratory distress syndrome (ARDS), the major cause of respiratory failure, remains with l...
Cellular senescence is a key factor driving age-related diseases. Recent studies have revealed that senescence-associated secretory phenotype, telomere attrition, epigenetic changes, and mitochondrial autophagy damage may mediate the pathogenesis of senescence-related idiopathic pulmonary fibrosis (IPF). Reducing the level of cellular senescence or...
Inflammatory cytokines produced by activated macrophages largely contribute to the pathological signs of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is the predominant anti-inflammatory cytokine in the intestine, and its therapeutic efficacy for IBD has been clinically tested. Nevertheless, how the function of IL-10 is regulated in the...
Background
Perpetuation is the final phase of thrombus formation, however it's mechanisms and regulation are poorly understood.
Objective
To investigate the mechanism of Shp2 in platelet function and thrombosis.
Methods and results
We demonstrate that the platelet‐expressed SH2 domain‐containing protein‐tyrosine phosphatase Shp2 is a negative reg...
Ethnopharmacological relevance
The concept of the prescription in Traditional Chinese Medicine (TCM) is usually characterized by the compatibility principle “monarch, minister, assistant, and guide”, which means herbs play primary, secondary, auxiliary, or harmonic roles, respectively, to achieve the optimally holistic effect. Following this compat...
Vascular endothelial (VE)–cadherin junctional localization is known to play a central role in vascular development, endothelial barrier integrity, and homeostasis. The sarcoma homology domain containing protein tyrosine phosphatase (SHP)2 has been shown to be involved in regulating endothelial barrier function; however, the mechanisms remain largel...
Sonic hedgehog (SHH) is abundantly expressed and critical for morphogenesis in embryonic lungs; however, SHH expression drops to a much lower level in mice from E17.5 and in humans from the 21st gestational week. We find that SHH expression is robustly upregulated in the airway epithelia of children with asthma or mouse models with allergic airway...
Objective:
Class III phosphoinositide 3-kinase, also known as vacuolar protein sorting 34 (VPS34), is a highly conserved enzyme regulating important cellular functions such as NADPH oxidase (NOX) assembly, membrane trafficking, and autophagy. Although VPS34 is expressed in platelets, its involvement in platelet activation remains unclear. Herein,...
Persistent activation of macrophages in lungs plays a critical role in the production of matrix metalloproteinases (MMPs) that contributes to the destruction of alveolar walls, a hallmark for pulmonary emphysema. Dysregulated TGF-β1 signaling has been an essential determinant in the elevation of MMPs during the development of emphysema. Nevertheles...
M2-polarized macrophages, also known as alternatively activated macrophages, have long been associated with pulmonary fibrosis; however, the mechanism has not been fully defined. Gab1 and Gab2 proteins belong to the GAB family of adaptors and are integral components of the signal specificity in response to various extracellular stimuli. In this rep...
Reactive oxygen species (ROS)-induced cysteine S-glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function of extracellular components via S-glutathionylation is unknown. Using a screening approach, we identified...
Shp2 exerts no effect on IL-13-activated stat6; IL-13 alone is insufficient to induce IL-25 in bronchial epithelial cells.
(A) Serum-free Beas-2bs were treated with 20 ng/ml IL-13 for different periods of time (15, 30 and 60 min). Phosphorylation levels of stat6 were measured via immunoblotting. (B) Beas-2bs were treated with 20 ng/ml IL-13 or 100...
OVA activates MAPK p38 and JNK in Beas-2b cells.
Serum-free Beas-2bs were treated with different concentrations (0.2, 2 and 20mg/ml) of OVA for different periods of time (15, 30 and 60 min). Phosphorylation levels of ERK, p38 and JNK were measured via immunoblotting.
(TIF)
Shp2Δ/Δ was undetectable in genomic DNA isolated from other organs.
Genomic DNA was isolated from the brain and liver of CC10-rtTA/(tetO)7-Cre/Shp2f/f mice after 7-day treatment with DOX (through drinking, 2 mg/ml in H2O) and Shp2 allele was detected by PCR.
(TIF)
Shp2 is universally expressed in the lung; it is especially highly expressed in bronchial epithelial cells and was slightly elevated in allergic bronchial epithelial cells.
(A) The cellular distribution of Shp2 (brown staining cells) in the lungs of healthy and allergic mice by immunohistology. (B) Total Shp2 protein expression in the lungs of heal...
Shp2 played an important role in cigarette-smoke-mediated inflammation, surfactant homeostasis and asthmatic airway remodeling. However, whether shp2 plays a key role in epithelium-associated allergic reaction is still unknown. In this study, LPS and OVA were observed to induce the production of IL-25 in bronchial epithelial cells in vitro via the...
T helper type 17 cells (Th17 cells) are major contributors to many autoimmune diseases. In this study, we demonstrate that the germinal center kinase family member MINK1 (misshapen/NIK-related kinase 1) negatively regulates Th17 cell differentiation. The suppressive effect of MINK1 on induction of Th17 cells is mediated by the inhibition of SMAD2 a...
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening diseases that are associated with high mortality rates due to treatment limitations. Neutrophils play key roles in the pathogenesis of ALI/ARDS by promoting the inflammation and injury of the alveolar microenvironment. To date, in vivo...
Asthma is a common allergic disorder involving a complex interplay among multiple genetic and environmental factors. Recent studies identified genetic variants of human GAB1 as a novel asthma susceptibility factor. However, the functions of Gab1 in lung remain largely unexplored. In this study, we first observed an elevation of Gab1 level in periph...
GRB2-associated-binding protein 1 (Gab1) belongs to Gab adaptor family (Gabs), which integrates multiple signals in response to the epithelial growth factors. Recent genetic studies identified genetic variants of human Gab1 gene as potential risk factors of asthmatic inflammation. However, Gab1 functions in lungs remain largely unknown. Alveolar ty...
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening diseases that are associated with high mortality rates due to treatment limitations. Neutrophils play key roles in the pathogenesis of ALI/ARDS by promoting the inflammation and injury of the alveolar microenvironment.
Reciprocal interactions between the metabolic system and immune cells play pivotal roles in diverse inflammatory diseases, but the underlying mechanisms remain elusive. The activation of bile acid-mediated signaling has been linked to improvement in metabolic syndromes and enhanced control of inflammation. Here, we demonstrated that bile acids inhi...
Macrophages are highly plastic cells, which serve as sentinels of the host immune system due to their ability to recognize and respond to microbial products rapidly and dynamically. Appropriate regulation of macrophage activation is essential for pathogen clearance or preventing autoimmune diseases. However, regularly used endpoint assays for analy...
Mast cells play an essential role in initiating allergic diseases. The activation of mast cells are controlled by a complicated signal network of reversible phosphorylation, and finding the key regulators involved in this network has been the focus of the pharmaceutical industry. In this work, we used a method named Time-dependent cell responding p...
Asthma is a phenotypically heterogeneous chronic disease of the airways. Studies have found that neutrophils are crucial to airway inflammation in acute asthma, persistent asthma, particularly in asthma of poor response to glucocorticoid treatment. The role of neutrophils in development of bronchial asthma is complex, as they can release a potent s...
Decreasing the degranulation of RBL-2H3 cells transfected with Gab2 siRNA.
(A) Gab2 mRNA level assay of mast cells transfected with Gab2 siRNA. (B) The β-hexosaminidase release of mast cells transfected with Gab2 siRNA was decreased comparing with the only Lip 2000 treatment. The methods of β-hexosaminidase assay see the Methods.
(TIF)
The effects of adenosine and PMA on mast cell degranulation response.
(A) The β-hexosaminidase release assays of PMA or adenosine on mast cell alone. (B) The enhancing effects of adenosine on β-hexosaminidase release from mast cells sensitized with anti-DNP IgE, when the dose of DNP-BSA fail to induce degranulation. RBL-2H3 cells were sensitized wi...
Chinese herbs have long been used to treat allergic disease, but recently the development was greatly impeded by the lack of good methods to explore the mechanism of action. Here, we showed the effects of Chinese herb Radix Paeoniae alba were identified and characterized by a mast cell activation assay that involves electronic impedance readouts fo...
The HPLC analysis of Radix P. alba.
The 0.5g powered medicinal materials was added 20 mL methanol, soaked for 4h, and ultrasonic treatment for 30 min. The filtrate was 0.45 μm for filtration. Elution condition sees the Methods.
(TIF)
The cytotoxicity examination of Radix P. alba.
(A) The cytotoxicity observation of Radix P. alba with TCRP approach. RBL-2H3 cells were seed on the E-plate allowing to grow for 24 h, and then were added the various concentrations of Radix P. alba monitoring every 15 min for over 20 h. (B) Cytotoxicity assay of Radix P. alba on RBL-2H3 cells. RBL-2H...
The HPLC analyses and activity determination of the five fractions of Radix P. alba.
(A) The HPLC profiles of the five fractions and the control substance Paeoniflorin. (B) The inhibiting effects of the five fracitons on β-hexosaminidase release in RBL-2H3 cells.
(TIF)
Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in their degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. We show that the activation of mast cells is negatively regulated by the newly identified adaptor protein Tespa1. Loss of Tespa1 in mouse mast ce...
The epithelial-mesenchymal transition (EMT) is an essential process for embryogenesis. It also plays a critical role in the initiation of tumor metastasis. Src homology 2 (SH2)-domain containing protein tyrosine phosphatase-2 (SHP2) is a ubiquitously-expressed protein tyrosine phosphatase and is mutated in many tumors. However, its functional role...
The Notch2 is a critical membrane receptor for B-cell functions, and also displays various biological roles in lymphoma pathogenesis. In this article, we reported that 3 of 69 (4.3%) diffuse large B-cell lymphomas (DLBCLs) exhibited a truncate NOTCH2 mutation at the nucleotide 7605 (G/A) in the cDNA sequence, which led to partial deletion of the C-...
The germinal center lymphoma represents a heterogeneous human lymphoma entity. Here we report that constitutive activity of SHP2 (PTPN11) and its downstream kinase ERK are essential for the viability and progression of germinal center lymphoma cells. Mechanistically, SHP2/ERK inhibition impedes c-Myc transcriptional activity, which results in the r...
The alternative activation of M2 macrophages in the lungs has been implicated as a causative agent in pulmonary fibrosis; however, the mechanisms underlying M2 polarization are poorly characterized. In this study, we investigated the role of the ubiquitously expressed Src homology domain-containing tyrosine phosphatase Shp2 in this process. Shp2 in...
Ethnopharmacological relevance:
Danshen (Salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine (TCM), often in combination with other herbs, to treat a diversity of ailments. More recent studies have focused on its possible roles in the treatment of respiratory diseases (pneumonia and pulmonary fibrosis) and found that it has p...
Rationale: Cell-mediated immunity is indispensable for host protection against tuberculosis. Gab2, a scaffolding adaptor protein, negatively regulates signaling pathways critical for T cell-mediated immunity. Objectives: To investigate the clinical significance and immunological role of Gab2 in Mycobacterium tuberculosis infection. Methods: We eval...
PKA signaling is important for the post-translational modification of proteins, especially those in cardiomyocytes involved in cardiac excitation-contraction coupling. PKA activity is spatially and temporally regulated through compartmentalization by protein kinase A anchoring proteins. Cypher/ZASP, a member of PDZ-LIM domain protein family, is a c...
Self‐renewal program enables stem cells to be maintained throughout a lifetime, and to retain the capacity to produce the desired functional cells. However, the molecular mechanisms regulating self‐renewal and differentiation remain unclear. We previously reported that Src‐homology 2 domain‐containing phosphatase 2 (Shp2) is essential for stem cell...
Scaffolding proteins Gab1 and Gab2 are ubiquitously expressed and belong to the GAB family (GABs), which integrates multiple signal events. This protein family has recently attracted interest as genetic variants of human GAB1 are considered a risk factor for asthma; however, GAB functions in lungs remain unclear. Previous studies have suggested tha...
PKA signaling is important in phosphorylation regulation of some key calcium handling proteins and its activity is compartmentalized through A‐kinase anchoring proteins. It has been demonstrated that Cypher/ZASP, a PDZ‐LIM domain protein, plays pivotal structural roles in the integrity of sarcomeres and several of its mutations are identified to as...
Cigarette smoke (CS), the major cause of chronic obstructive pulmonary disease, contains a variety of oxidative components that were implicated in the regulation of Src homology domain 2-containing protein tyrosine phosphatase 2 (Shp2) activity. However, the contribution of Shp2 enzyme to chronic obstructive pulmonary disease pathogenesis remains u...
Goblet cell hyperplasia (GCH) and mucous hypersecretion are common pathological features of chronic pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Despite numerous studies, the molecular basis for this condition remains elusive. Gab2 is a member of the Dos/Gab subfamily scaffold...
Interleukin-22 (IL-22) is one of the key mediators of keratinocyte alterations in psoriasis. IL-22 inhibits keratinocyte differentiation and induces the migration of human keratinocytes. Grb2-associated binder 1 (Gab1) has been shown to mediate epidermal growth factor-induced epidermal growth and differentiation via interaction with the Src homolog...
The intestinal epithelium functions as a physical barrier against the harmful environment of the lumen, which usually becomes impaired in the presence of intestinal diseases. In this work, we introduce an electronic impedance-based analysis using a real-time xCELLigence system to record the dynamic processes of ethanol-induced intestinal barrier dy...
Type II alveolar epithelial (AT-II) cells produce pulmonary surfactant proteins that are essential for alveolar function. AT-II is a major target in lung injury, and ineffective repair of damaged alveolar epithelia has been postulated to cause pulmonary fibrosis. Previous studies have shown that tyrosine phosphatase Shp2 is expressed highly in the...
Different cell lines show different TCRPs of Salmonella infection. (A) TCRPs of HCT116 cells in response to S. typhimurium infection. (B) TCRPs of SW480 cells in response to S. typhimurium infection. Arrows, bacterial addition. Representative curves are an average of four replicate wells.
(TIF)
MICs of eight antibiotics for
Salmonella
strain SL1344.
(DOC)
Sequential morphological changes of cells infected with Salmonella visualized by scanning electron microscopy (SEM). HT-29 cells were seeded into 24-well plates with cover slides and infected with SL1344 (MOI = 200). Cells were fixed at 0 (a), 0.75 (b), 1.5 (c), 3 (d), 5 (e), and 7 (f) h post infection and observed by SEM. Scale bar, 20 µm. Arrows,...
Dynamic monitoring of intestinal epithelial cell response to S. entertidis infection. (A) HT-29 cells (10,000 cells per well) were seeded into E-plates. After approximately 46 h, the cells were infected with MOIs 0.1, 1, 10, 50, 100, or 200 of S. entertidis. (B) Inoculums of 5,000, 10,000, or 20,000 cells per well of HT-29 cells were seeded into E-...
Pathways in response of HT29 epithelia to
S. typhimurium
.
(DOC)
Gene ontology terms most highly represented in genes with significantly different expression.
(DOC)
The interaction between mammalian host cells and bacteria is a dynamic process, and the underlying pathologic mechanisms are poorly characterized. Limited information describing the host-bacterial interaction is based mainly on studies using label-based endpoint assays that detect changes in cell behavior at a given time point, yielding incomplete...
Microarray analysis of HT-29 cellular responses to Salmonella infection. (A) Scatter plot of infected samples (45 min, 3 h, and 7 h post-infection) vs. uninfected sample (0 h). Each dot represents a normalized intensity of a probe sets. (B) CV curve for identifying significantly differently expressed genes. Each probe set is presented as a circle....
Genes with significantly different expression during infection (272 total).
(DOC)
Natural products have always been a major source of therapeutic agents; however, the development of traditional herbal products has been currently hampered by the lack of analytic methods suitable for both high-throughput screening and evaluating the mechanism of action. Cellular processes such as proliferation, apoptosis, and toxicity are well-orc...
Src activation involves the coordinated regulation of positive and negative tyrosine phosphorylation sites. The mechanism whereby receptor tyrosine kinases, cytokine receptors, and integrins activate Src is not known. Here, we demonstrate that granulocyte colony-stimulating factor (G-CSF) activates Lyn, the predominant Src kinase in myeloid cells,...
Interleukin-22 (IL-22) is a member of the IL-10 family of cytokines produced by activated T cells and is involved in several
tissue responses. IL-22 signals through a heterodimeric receptor composed of IL-22 receptor 1 (IL-22R1) and IL-10R2, and the
intracellular signaling pathways mediated by IL-22 receptor are not completely known. Here we invest...
Computerized model for DCA interaction with Shp2. (A) A computerized mode of DCA binding to the active site of Shp2. (B) A: zoomed in view of DCA in the active site of Shp2 shows the carboxylic acid group which is placed close to small binding pockets (indicated by a white arrow). B: the 2-hydroxyl group is situated near a groove, indicated by a wh...
DNA sequences of primers used for qRT-PCR.
(0.06 MB DOC)
Isolation of Shp2 inhibitors. (A) Screening procedure of chemical library. (B) The chemical structure of DCA. (C) IC50 values of DCA against various PTPs. (D) DCA inhibits Erk phosphorylation and activity in MEFs. Overnight-starved MEFs were treated with increasing dosages of DCA: 5, 20, 100 µM for 1 hr followed by stimulation with PDGFbb (50 ng/ml...
Biological activity of Shp2 inhibitor (DCA). (A) Specificity of DCA in mESCs. Overnight-starved mESCs were treated with 50 µM DCA for 1 hr followed by stimulation with IGF-1 (100 ng/ml) for 10 min. Total cell lysates were immunoblotted with the indicated antibodies. (B) CytoQuant fluorescence assay for proliferation of mESCs treated with DMSO or DC...
Growth, survival and differentiation of Shp2−/− mES cells. (A) Proliferation rate. mESCs were seeded on gelatin-coated plates at 50,000 cells/ml in the absence of feeder cells and cell numbers were determined by CytoQuant fluorescence assay at 12, 24, 36, 48, 72 hrs after seeding. The cell numbers were normalized against the value at 12 hrs (Mean±S...
Gene expression profiles during mESC differentiation. (A) Total RNAs were extracted from three seperate mESC lines for both WT and Shp2−/− during differentiation at various time points as indicated. The microarray data collected from the triplacate samples were grouped and analysed by GeneSpring GX Software (Agilent Technologies). (B) Total RNA sam...
Recent studies have suggested distinctive biological properties and signaling mechanisms between human and mouse embryonic stem cells (hESCs and mESCs). Herein we report that Shp2, a protein tyrosine phosphatase with two SH2 domains, has a conserved role in orchestration of intracellular signaling cascades resulting in initiation of differentiation...
The PTEN tumour suppressor gene is induced by the early growth response 1 (EGR1) transcription factor, which also transactivates p53, p73, and p300/CBP as well as other proapoptotic and anti-cancer genes. Here, we describe a novel Akt-EGR1-alternate reading frame (ARF)-PTEN axis, in which PTEN activation in vivo requires p14ARF-mediated sumoylation...
Citations
... It upregulates the expression of the iron transporter protein in macrophages. This regulation occurs through the reduction of histone deacetylase enrichment, which in turn promotes iron e ux [50]. Research has shown that supplementing with butyrate can effectively restore iron metabolism in IDA models. ...
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... In addition, extruded apoptotic cells release ABs that, upon engulfment, stimulate cytokine production by the phagocyting cell [228]. Necroptosis has also been involved in intestinal inflammation and tumorigenesis [229,230]. Pyroptosis is also an important part of the host defense arsenal in epithelial tissues [231]. Activation of the inflammasome has been involved in IEC extrusion, along with a loss of plasma membrane integrity and death by pyroptosis. ...
Reference: Cell Death, by Any Other Name…
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... In addition, a recent study suggests that SHP2 interacts with the scaffold protein kinase suppressor of RAS1 (KSR1). This interaction results in the detachment of KSR1 from activated SHP2, followed by anchoring to the plasma membrane through the dephosphorylation of Tyr25, facilitating ERK signal transduction (30). ...
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... The expression pattern of SLC5A1 in LPS-PKCOS was consistent with previous findings, in which stevia leaf extracts promoted the activity and expression of SGLT1 and enhanced the intestinal capacity to absorb glucose in rabbits [69]. After entering into cells, mannose can be catalysed by hexokinase (HK) to produce 6-phospho-mannose (M6P), which is then catalysed by phosphomannose isomerase (MPI) into the glycolytic pathway or catalysed by phosphomannose mutase (PMM2) into the glycosylation pathway [70,71]. Interestingly, the transcriptional expression of gene HK/MPI was increased by PKCOS treatment with and without added LPS, while the mRNA expression of PMM2 did not show a difference across the five groups, suggesting that PKCOS promoted the glycolytic pathway in IPEC-J2 cells, which may be associated with cell proliferation and alleviation of inflammation-induced apoptosis [72]. ...
... In intrahepatic cholangiocarcinoma, GAB1 regulates migration through the PI3K/AKT signaling pathway [116]. Furthermore, GAB1 has been described to be upregulated to promote migration in anaplastic thyroid carcinoma cells through modulation of the AKT-Multidrug Resistance Protein 1 (MDR1) axis [117]. GAB1 overexpression increases migratory and invasive activity in cervical cancer cell lines [96]. ...
Reference: The Role of GAB1 in Cancer
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... Accumulated evidence indicates that endothelial cells (ECs) lining the pulmonary vasculature regulate lung function not only through oxygen and nutrient delivery but also participate in alveolar regeneration, immune responses, and fibrotic remodeling through the production and release of paracrine signals, also known as angiocrine factors [17][18][19][20][21] . Prior work has identified EC-derived signals that alter macrophage activation state to protect the lungs from injury 22,23 . Secreted protein acidic and rich in cysteine-like protein 1 (SPARCL1) is a matricellular protein reported to inhibit angiogenesis in colorectal carcinoma but also contribute to nonalcoholic steatohepatitis progression in mice 24,25 . ...
... M1 macrophages release a variety of potent proinflammatory cytokines, including TNF-α, IL-6 and IL-1β. Lung macrophages are the main coordinating cells involved in the termination and regression of lung inflammation, and modulation of AMs has been found to attenuate lung injury by attenuating neutrophil accumulation and reducing proinflammatory cytokines; however, much work still needs to be done to continue investigating the specific signaling pathways and cellular mechanisms involved in inflammation [106,107]. N. Ding [108] developed a pH-responsive nanodelivery system consisting of β-cyclodextrin-poly(2-(diisopropylamino) ethylmethacrylate)/distearoylphosphatidylethanolaminepolyethyleneglycol (β-CD-PDPA/DSPE-PEG) for targeting M1 macrophages and encapsulating miR-223 in NPs for ALI therapy (Fig. 7). D. Sun [109] constructed two anti-inflammatory N-acetylcysteine (NAC)-loaded macrophage-targeting apoptotic cell-inspired phosphatidylserine (PS)-containing nanoliposomes (PSLipos). ...
... SHP-2 also plays an important role in angiogenesis and endothelial permeability by controlling endocytosis-mediated VE-cadherin cycling [281]. ANXA2, a scaffolding protein, contributes to SHP-2-mediated dephosphorylation of VE-cadherin in angiogenesis [284]. Growth factor receptor bound protein 2 (GRB2) associated binding protein 1 (GAB1), another wellknown scaffolding protein for SHP-2, promotes postnatal angiogenesis. ...
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... Accumulation of myofibroblasts and excessive secretion of α-SMA and collagen type I were associated with the secretion of fibrotic mediator TGF-β1 (figure 3(C)) from BEAS-2B cells [43]. TGF-β1 is reported to activate the feedback mechanism of TGF-β/SMAD pathway, which leads to aberrant formation of collagen in the fibroblasts and myofibroblasts causing a scar and subsequent fibrosis [44,45], resulting in upregulation of SMAD1 and downregulation of SMAD4 in BLM-induced fibrotic model [46][47][48]. Moreover, TGF-β/SMAD pathway is shown to regulate the α-SMA and collagen type I transcriptions [48,49], which is in agreement with our ELISA results of collagen type I and immunofluorescence staining results of both α-SMA and collagen type I representing their increased levels in fibrotic MCS model. ...
... Overexpressed LIN28B initiated growth of breast cancerinducing cells, but knock-down of SHP2 depreciated the breast cancer cell growth and metastasis. Unlike in breast cancer, SHP2 has shown a contradictory role in the case of hepatocellular carcinoma (HCC) [35]. The tumor suppressor role of PTPN11/SHP2 in hepatocytes is unexpected because SHP2 has predominantly been denoted as a proto-oncogene and its role is defined as a tumor proliferator [36]. ...
