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#28991210   2017/10/09 Save this To Up

A Central Bioactive Region of LTBP-2 Stimulates the Expression of TGF-β1 in Fibroblasts via Akt and p38 Signalling Pathways.

Latent transforming growth factor-β-1 binding protein-2 (LTBP-2) belongs to the LTBP-fibrillin superfamily of extracellular proteins. Unlike other LTBPs, LTBP-2 does not covalently bind transforming growth factor-β1 (TGF-β1) but appears to be implicated in the regulation of TGF-β1 bioactivity, although the mechanisms are largely unknown. In experiments originally designed to study the displacement of latent TGF-β1 complexes from matrix storage, we found that the addition of exogenous LTBP-2 to cultured human MSU-1.1 fibroblasts caused an increase in TGF-β1 levels in the medium. However, the TGF-β1 increase was due to an upregulation of TGF-β1 expression and secretion rather than a displacement of matrix-stored TGF-β1. The secreted TGF-β1 was mainly in an inactive form, and its concentration peaked around 15 h after addition of LTBP-2. Using a series of recombinant LTBP-2 fragments, the bioactivity was identified to a small region of LTBP-2 consisting of an 8-Cys motif flanked by four epidermal growth factor (EGF)-like repeats. The LTBP-2 stimulation of TGF-β expression involved the phosphorylation of both Akt and p38 mitogen-activated protein kinase (MAPK) signalling proteins, and specific inactivation of each protein individually blocked TGF-β1 increase. The search for the cell surface receptor mediating this LTBP-2 activity proved inconclusive. Inhibitory antibodies to integrins β1 and αVβ5 showed no reduction of LTBP-2 stimulation of TGF-β1. However, TGF-β1 upregulation was partially inhibited by anti-αVβ3 integrin antibodies, suggestive of a direct or indirect role for this integrin. Overall, the study indicates that LTBP-2 can directly upregulate cellular TGF-β1 expression and secretion by interaction with cells via a short central bioactive region. This may be significant in connective tissue disorders involving aberrant TGF-β1 signalling.

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#28845526   2017/08/28 Save this To Up

Serine peptidase inhibitor Kazal type I (SPINK1) promotes BRL-3A cell proliferation via p38, ERK, and JNK pathways.

Serine peptidase inhibitor Kazal type I (SPINK1) has the similar spatial structure as epidermal growth factor (EGF); EGF can interact with epidermal growth factor receptor (EGFR) to promote proliferation in different cell types. However, whether SPINK1 can interact with EGFR and further regulate the proliferation of hepatocytes in liver regeneration remains largely unknown. In this study, we investigated the role of SPINK1 in a rat liver hepatocyte line of BRL-3A in vitro. The results showed the upregulation of endogenous Spink1 (gene addition) significantly increased not only the cell viability, cell numbers in S and G2 /M phase, but also upregulated the genes/proteins expression related to cell proliferation and anti-apoptosis in BRL-3A. In contrast, the cell number in G1 phase and the expression of pro-apoptosis-related genes/proteins were significantly decreased. The similar results were observed when the cells were treated with exogenous rat recombinant SPINK1. Immunoblotting suggested SPINK1 can interact with EGFR. By Ingenuity Pathway Analysis software, the SPINK1 signalling pathway was built; the predicted read outs were validated by qRT-PCR and western blot; and the results showed that p38, ERK, and JNK pathways-related genes/proteins were involved in the cell proliferation upon the treatment of endogenous Spink1 and exogenous SPINK1. Collectively, SPINK1 can associate with EGFR to promote the expression of cell proliferation-related and anti-apoptosis-related genes/proteins; inhibit the expression of pro-apoptosis-related genes/proteins via p38, ERK, and JNK pathways; and consequently promote the proliferation of BRL-3A cells. For the first time, we demonstrated that SPINK1 can associate with EGFR to promote the proliferation of BRL-3A cells via p38, ERK, and JNK pathways. This work has direct implications on the underlying mechanism of SPINK1 in regulating hepatocytes proliferation in vivo and liver regeneration after partial hepatectomy.

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T-cell proliferation grad TCCII T cell proliferatio TCCII T cell proliferatio T-cell proliferation grad TCBII T cell proliferatio TCBII T cell proliferatio T-cell proliferation grad TCPII T cell proliferatio TCPII T cell proliferatio T-cell proliferation grad TCRII T cell proliferatio TCRII T cell proliferatio

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#28827473   2017/08/22 Save this To Up

Restoration of Circulating MFGE8 (Milk Fat Globule-EGF Factor 8) Attenuates Cardiac Hypertrophy Through Inhibition of Akt Pathway.

Cardiac hypertrophy occurs in response to numerous stimuli like neurohumoral stress, pressure overload, infection, and injury, and leads to heart failure. Mfge8 (milk fat globule-EGF factor 8) is a secreted protein involved in various human diseases, but its regulation and function during cardiac hypertrophy remain unexplored. Here, we found that circulating MFGE8 levels declined significantly in failing hearts from patients with dilated cardiomyopathy. Correlation analyses revealed that circulating MFGE8 levels were negatively correlated with the severity of cardiac dysfunction and remodeling in affected patients. Deleting Mfge8 in mice maintained normal heart function at basal level but substantially exacerbated the hypertrophic enlargement of cardiomyocytes, reprogramming of pathological genes, contractile dysfunction, and myocardial fibrosis after aortic banding surgery. In contrast, cardiac-specific Mfge8 overexpression in transgenic mice significantly blunted aortic banding-induced cardiac hypertrophy. Whereas MAPK (mitogen-activated protein kinase) pathways were unaffected in either Mfge8-knockout or Mfge8-overexpressing mice, the activated Akt/PKB (protein kinase B)-Gsk-3β (glycogen synthase kinase-3β)/mTOR (mammalian target of rapamycin) pathway after aortic banding was significantly potentiated by Mfge8 deficiency but suppressed by Mfge8 overexpression. Inhibition of Akt with MK-2206 blocked the prohypertrophic effects of Mfge8 deficiency in angiotensin II-treated neonatal rat cardiomyocytes. Finally, administering a recombinant human MFGE8 in mice in vivo alleviated cardiac hypertrophy induced by aortic banding. Our findings indicate that Mfge8 is an endogenous negative regulator of pathological cardiac hypertrophy and may, thus, have potential both as a novel biomarker and as a therapeutic target for treatment of cardiac hypertrophy.

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Epidermal Growth Factor ( Epidermal Growth Factor ( Epidermal Growth Factor ( Epidermal Growth Factor ( Human Epidermal Growth Fa Mouse Epidermal Growth Fa AKT Phospho-Specific Arra AKT PKB Signaling Phospho IGF-1R Signaling Phospho- Mouse Anti-Human Milk Fat Goat Anti-Human Tissue Fa Human Epidermal Growth Fa

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#28798239   2017/08/11 Save this To Up

Interaction of Munc18c and syntaxin4 facilitates invadopodium formation and extracellular matrix invasion of tumor cells.

Tumor cell invasion involves targeted localization of proteins required for interactions with the extracellular matrix and for proteolysis. The localization of many proteins during these cell-extracellular matrix interactions relies on membrane trafficking mediated in part by SNAREs. The SNARE protein syntaxin4 (Stx4) is involved in the formation of invasive structures called invadopodia; however, it is unclear how Stx4 function is regulated during tumor cell invasion. Munc18c is known to regulate Stx4 activity, and here we show that Munc18c is required for Stx4-mediated invadopodium formation and cell invasion. Biochemical and microscopic analyses revealed a physical association between Munc18c and Stx4, which was enhanced during invadopodium formation, and that a reduction in Munc18c expression decreases invadopodium formation. We also found that an N-terminal Stx4-derived peptide associates with Munc18c and inhibits endogenous interactions of Stx4 with synaptosome-associated protein 23 (SNAP23) and vesicle-associated membrane protein 2 (VAMP2). Furthermore, expression of the Stx4 N-terminal peptide decreased invadopodium formation and cell invasion in vitro Of note, cells expressing the Stx4 N-terminal peptide exhibited impaired trafficking of membrane type 1 matrix metalloproteinase (MT1-MMP) and EGF receptor (EGFR) to the cell surface during invadopodium formation. Our findings implicate Munc18c as a regulator of Stx4-mediated trafficking of MT1-MMP and EGFR, advancing our understanding of the role of SNARE function in the localization of proteins that drive tumor cell invasion.

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Androgen Receptor (Phosph Androgen Receptor (Phosph Rabbit Anti-Human Androge Rabbit Anti-Human Androge Androgen Receptor (Ab 650 AZD-3514 Mechanisms: Andr 17β-Acetoxy-2α-bromo-5 (5α,16β)-N-Acetyl-16-[2 (5α,16β)-N-Acetyl-16-ac 5α-N-Acetyl-2'H-androst- 5α-N-Acetyl-2'H-androst- 3-O-Acetyl 5,14-Androstad

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#28693996   2017/07/11 Save this To Up

Human epidermal growth factor coupled to different structural classes of cell penetrating peptides: A comparative study.

Human epidermal growth factor (hEGF) plays important roles in wound healing. Due to large molecular weight and hydrophilic nature, cellular uptake and skin permeation of hEGF are very poor, significantly limiting its efficacy. By using recombinant technology, four structural classes of cell penetrating peptides (CPPs) were fused at the C-terminus of hEGF, expressed and purified into homogeneity. Comparative studies were conducted to evaluate their activity, cytotoxicity, cellular uptake and skin permeation. Cell viability assay and in vitro scratch wound-healing assay showed that all four fusion proteins had similar activities with commercial rhEGF. Obvious cytotoxicity was not detected for EGF-TAT, EGF-Pep-1 and EGF-AA3H. However, EGF-MAP was cytotoxic at both moderate and high concentrations. Confocal microscopy indicated that the cellular uptake of the fusion proteins was markedly improved compared with rhEGF, with EGF-TAT and EGF-Pep-1 showing the most abundant presence within cells at incubation concentration of 25μM. Permeation across the excised mouse skin followed the order of EGF-Pep-1>EGF-TAT>EGF-AA3H>rhEGF. These findings demonstrated that there were great gaps between the abilities of different structural types of CPPs to deliver EGF across cell membrane and the skin. EGF coupled with a well-chosen CPP will become a more promising pharmaceutical agent than rhEGF.

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Epidermal Growth Factor ( Epidermal Growth Factor ( Epidermal Growth Factor ( Epidermal Growth Factor ( Growth Differentiation Fa RABBIT ANTI HUMAN SDF-1 A Fibroblast Growth Factor Fibroblast Growth Factor Fibroblast Growth Factor Fibroblast Growth Factor Keratinocyte Growth Facto Keratinocyte Growth Facto

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#28655766   2017/06/28 Save this To Up

A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1.

Bispecific antibodies combine two different antigen-binding sites in a single molecule, enabling more specific targeting, novel mechanisms of action, and higher clinical efficacies. Although they have the potential to outperform conventional monoclonal antibodies, many bispecific antibodies have issues regarding production, stability, and pharmacokinetic properties. Here, we describe a new approach for generating bispecific antibodies using a common light chain format and exploiting the stable architecture of human immunoglobulin G1 We used iterative experimental validation and computational modeling to identify multiple Fc variant pairs that drive efficient heterodimerization of the antibody heavy chains. Accelerated stability studies enabled selection of one Fc variant pair dubbed "DEKK" consisting of substitutions L351D and L368E in one heavy chain combined with L351K and T366K in the other. Solving the crystal structure of the DEKK Fc region at a resolution of 2.3 Å enabled detailed analysis of the interactions inducing CH3 interface heterodimerization. Local shifts in the IgG backbone accommodate the introduction of lysine side chains that form stabilizing salt-bridge interactions with substituted and native residues in the opposite chain. Overall, the CH3 domain adapted to these shifts at the interface, yielding a stable Fc conformation very similar to that in wild-type IgG. Using the DEKK format, we generated the bispecific antibody MCLA-128, targeting human EGF receptors 2 and 3. MCLA-128 could be readily produced and purified at industrial scale with a standard mammalian cell culture platform and a routine purification protocol. Long-term accelerated stability assays confirmed that MCLA-128 is highly stable and has excellent biophysical characteristics.

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#28587375   2017/06/07 Save this To Up

C-X-C motif chemokine ligand 8 promotes endothelial cell homing via the Akt-signal transducer and activator of transcription pathway to accelerate healing of ischemic and hypoxic skin ulcers.

C-X-C motif chemokine ligand 8 (CXCL-8) promotes cell homing and angiogenesis. However, under hypoxic conditions, the role of CXCL-8 in the homing of human umbilical vein endothelial cells (HUVECs), and its effect on the healing of skin ulcers caused by ischemia and hypoxia remain unknown. In the current study, assays measuring cell proliferation, in vitro angiogenesis and cell migration were performed to evaluate alterations in the proliferation, angiogenic capacity and chemotaxis of HUVECs treated with CXCL-8 protein and/or an Akt inhibitor (AZD5363 group) under hypoxic conditions. Changes in the levels of Akt, signal transducer and activator of transcription 3 (STAT3), vascular endothelial growth factor (VEGF), malondialdehyde (MDA) and total-superoxide dismutase (total-SOD) were also detected by western blotting and ELISA. In addition, in vivo experiments were performed using a skin ulcer model in mice. Ischemic and hypoxic skin ulcers were created on the thighs of C57BL/6J mice, and the effects of CXCL-8 and HUVEC transplantation on the healing capacity of skin ulcers was determined by injecting mice with HUVECs and/or CXCL-8 recombinant protein (CXCL-8, HUVEC and HUVEC + CXCL-8 groups). Vascular endothelial cell homing, changes in vascular density and the expression of VEGF, SOD, EGF and MDA within the ulcer tissue were subsequently measured. In vitro experiments demonstrated that HUVEC proliferation, migration and tube forming capacity were significantly increased by CXCL-8 under hypoxic conditions. Additionally, levels of VEGF, MDA and SOD were significantly higher in the CXCL-8 group, though were significantly decreased by the Akt and STAT3 inhibitors. In vivo experiments demonstrated that the expression of VEGF, total-SOD and EGF proteins were higher in the skin ulcer tissue of mice treated with CXCL-8 + HUVEC, relative to mice treated with HUVECs alone. Furthermore, vascular endothelial cell homing and vascular density were significantly increased in the CXCL-8 + HUVEC group, indicating that combined use of HUVECs and CXCL-8 may promote the healing of ischemic skin ulcers. The present results demonstrate that CXCL-8 may stimulate vascular endothelial cells to secrete VEGF, SOD and other cytokines via the Akt-STAT3 pathway, which in turn serves a key regulatory role in the recruitment of vascular endothelial cells, reduction of hypoxia-related injury and promotion of tissue repair following hypoxic/ischemic injury.

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#28586369   2017/06/06 Save this To Up

Synthesis and biochemical characterization of EGF receptor in a water-soluble membrane model system.

ErbB (Erythroblastic Leukemia Viral Oncogene Homolog) receptor tyrosine kinases are critical for tissue development and maintenance, and frequently become oncogenic when mutated or overexpressed. In vitro analysis of ErbB receptor kinases can be difficult because of their large size and poor water solubility. Here we report improved production and assembly of the correctly folded full-length EGF receptor (EGFR) into nanolipoprotein particles (NLPs). NLPs are ~10 nm in diameter discoidal cell membrane mimics composed of apolipoproteins surrounding a lipid bilayer. NLPs containing EGFR were synthesized via incubation of baculovirus-produced recombinant EGFR with apolipoprotein and phosphoplipids under conditions that favor self-assembly. The resulting EGFR-NLPs were the correct size, formed dimers and multimers, had intrinsic autophosphorylation activity, and retained the ability to interact with EGFR-targeted ligands and inhibitors consistent with previously-published in vitro binding affinities. We anticipate rapid adoption of EGFR-NLPs for structural studies of full-length receptors and drug screening, as well as for the in vitro characterization of ErbB heterodimers and disease-relevant mutants.

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Nuclear Membrane Receptor Androgen Receptor (Phosph Androgen Receptor (Phosph Interferon-a Receptor Typ Mouse Anti-Human Interleu Rabbit Anti-Human Androge Rabbit Anti-Human Androge RANK Ligand Soluble, Huma Androgen Receptor (Ab 650 interleukin 17 receptor C interferon-alpha receptor Human integrin aVb3, affi

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#28489325   2017/05/10 Save this To Up

Reducing Macro- and Microheterogeneity of N-Glycans Enables the Crystal Structure of the Lectin and EGF-Like Domains of Human L-Selectin To Be Solved at 1.9 Å Resolution.

L-Selectin, a cell-adhesion receptor on the surface of most leukocytes, contains seven N-glycosylation sites. In order to obtain the crystal structure of human L-selectin, we expressed a shortened version of L-selectin comprising the C-type lectin and EGF-like domains (termed LE) and systematically analysed mutations of the three glycosylation sites (Asn22, Asn66 and Asn139) in order to reduce macroheterogeneity. After we further removed microheterogeneity, we obtained crystals that diffracted X-rays up to 1.9 Å from a variant (LE010) with exchanges N22Q and N139Q and one GlcNAc2 Man5 N-glycan chain attached to Asn66. Crystal-structure analysis showed that the terminal mannose of GlcNAc2 Man5 of one LE010 molecule was coordinated to Ca(2+) in the binding site of a symmetry-related LE010. The orientation of the lectin and EGF-like domain was similar to the described "bent" conformation of E- and P-selectins. The Ca(2+) -binding site reflects the binding mode seen in E- and P-selectin structures co-crystallised with ligands.

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#28487468   2017/05/10 Save this To Up

Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains.

Epigallocatechin gallate (EGCG) is the principal bioactive ingredient in green tea and has been reported to have many health benefits. EGCG influences multiple signal transduction pathways related to human diseases, including redox, inflammation, cell cycle, and cell adhesion pathways. However, the molecular mechanisms of these varying effects are unclear, limiting further development and utilization of EGCG as a pharmaceutical compound. Here, we examined the effect of EGCG on two representative transmembrane signaling receptors, integrinαIIbβ3 and epidermal growth factor receptor (EGFR). We report that EGCG inhibits talin-induced integrin αIIbβ3 activation, but it activates αIIbβ3 in the absence of talin both in a purified system and in cells. This apparent paradox was explained by the fact that the activation state of αIIbβ3 is tightly regulated by the topology of β3 transmembrane domain (TMD); increases or decreases in TMD embedding can activate integrins. Talin increases the embedding of integrin β3 TMD, resulting in integrin activation, whereas we observed here that EGCG decreases the embedding, thus opposing talin-induced integrin activation. In the absence of talin, EGCG decreases the TMD embedding, which can also disrupt the integrin α-β TMD interaction, leading to integrin activation. EGCG exhibited similar paradoxical behavior in EGFR signaling. EGCG alters the topology of EGFR TMD and activates the receptor in the absence of EGF, but inhibits EGF-induced EGFR activation. Thus, this widely ingested polyphenol exhibits pleiotropic effects on transmembrane signaling by modifying the topology of TMDs.

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