fibronectin receptor
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Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 214
Author(s):  
Elena Ricci ◽  
Mariarosa Fava ◽  
Pietro Rizza ◽  
Michele Pellegrino ◽  
Daniela Bonofiglio ◽  
...  

Resistance to endocrine therapy is still a major clinical challenge in the management of estrogen receptor α-positive (ERα+) breast cancer (BC). Here, the role of the Forkhead box class O (FoxO)3a transcription factor in tumor progression has been evaluated in tamoxifen-resistant BC cells (TamR), expressing lower levels of FoxO3a compared to sensitive ones. FoxO3a re-expression reduces TamR motility (wound-healing and transmigration assays) and invasiveness (matrigel transwell invasion assays) through the mRNA (qRT-PCR) and protein (Western blot) induction of the integrin α5 subunit of the α5β1 fibronectin receptor, a well-known membrane heterodimer controlling cell adhesion and signaling. The induction occurs through FoxO3a binding to a specific Forkhead responsive core sequence located on the integrin α5 promoter (cloning, luciferase, and ChIP assays). Moreover, FoxO3a failed to inhibit migration and invasion in integrin α5 silenced (siRNA) cells, demonstrating integrin α5 involvement in both processes. Finally, using large-scale gene expression data sets, a strong positive correlation between FoxO3a and integrin α5 in ERα+, but not in ER-negative (ERα−), BC patients emerged. Altogether, our data show how the oncosuppressor FoxO3a, by increasing the expression of its novel transcriptional target integrin α5, reverts the phenotype of endocrine-resistant BC toward a lower aggressiveness.


Morphologia ◽  
2021 ◽  
Vol 15 (1) ◽  
pp. 79-87
Author(s):  
N.V. Stanishevska

Background Stellate pancreatocytes, being cells - producers of stromal components, actively interact with cancer cells, determine the formation of a stromal barrier between the latter and thereby provide tumor chemoresistance. Objective The review is devoted to the analysis of recent data on the role of stellate pancreatocytes in the formation of the stromal microenvironment of pancreatic tumors, molecular mechanisms through which the regulation and realization of stellate cell functions is carried out. Methods Data processing was carried out by the method of complex material analysis. Results. Stellate pancreatocytes (PSC) exhibit phenotypically and functionally two states: inactive and active. PSC activation is carried out by cells of the developing tumor through a variety of molecular mediators. Activation triggers for PSC are Yes-associated protein, TGF-β1, miRNA let-7d, IL-8, MCP1, TGF-β2, IGFBP2, and others. 10 actively expressed genes were identified: TP53, SRC, IL6, JUN, ISG15, CAD, STAT1, OAS3, OAS1, VIM during co-cultivation of a cancer cell line (PCC) with PSC. PSC deactivation is associated with speckle-type mediator POZ (SPOP) acting through nuclear factor-kappaB, transretinoic acid (ATRA). Exhibiting their activity, PSCs express several stem cell markers, α-SMA (α-actin of smooth muscle cells), vimentin, α ITGA 11 (collagen type I receptor), α5 integrin receptor ITGA5 (fibronectin receptor), hyaluronic acid, hyaluronan synthase 2 (HAS2), hyaluronidase 1 (HYAL1), BAG3 , matrix metallopeptidase 2 (MMP2), Nodal protein, miR-1246 and miR-1290, miR-210, CCN2 (connective tissue growth factor), TRPV1, SP and CGRP (Calcitonin gene-related peptide) and many other factors. Сonclusion. Stellate pancreatocytes, being producers of the interacinar stroma, are activated by various factors (TNF-α, IL-6, MCP-1, ATP, and HMGB1, etc.), including factors produced by tumor cells of the pancreas, and act as regulators of proliferation, migration, and suppression apoptosis of the latter. An increase in the expression of α ITGA 11 (type I collagen receptor), α5 integrin receptor ITGA5 (fibronectin receptor), metallopeptidases, Nodal protein, miR-1246, miR-1290, and miR-210 is observed in tumor tissue, that indicates the activation of these cells. The maintenance of the active state of PSC is provided by tumor cells, for which stellate pancreatocytes are partners in the progression of the neoplastic process. Further study of the mechanisms of interaction in the PSC-tumor cell system creates the prospect of revealing levers of influence on the pathogenesis of pancreatic tumors.


Author(s):  
Luiz Ricardo Berbert ◽  
Florencia Belén González ◽  
Silvina Raquel Villar ◽  
Carlos Vigliano ◽  
Susana Lioi ◽  
...  

Trypanosoma cruzi infection in humans leads to progression to chronic chagasic myocarditis (CCM) in 30% of infected individuals, paralleling T cell inflammatory infiltrates in the heart tissue. T-cell trafficking into the hearts of CCM patients may be modulated by in situ expression of chemotactic or haptotactic molecules, as the chemokine CXCL12, the cytokine tumor necrosis factor-alpha (TNF-α), and extracellular matrix proteins (ECM), such as fibronectin. Herein we evaluated the expression of fibronectin, CXCL12, and TNF-α in the myocardial tissue of T. cruzi seropositive (asymptomatic or with CCM), as well as seronegative individuals as healthy controls. Hearts from CCM patients exhibited enhanced expression of these three molecules. CXCL12 and TNF-α serum levels were also increased in CCM individuals. We then evaluated T lymphocytes from chronic chagasic patients by cytofluorometry, in terms of membrane expression levels of molecules involved in cell activation and cell migration, respectively, HLA-DR and the VLA-4 (very late antigen-4, being one integrin-type fibronectin receptor). Indeed, the expression of HLA-DR and VLA-4 was enhanced on T lymphocytes from chagasic patients, especially in the CCM group. To further approach the dynamics of T cell migratory events, we performed fibronectin-, TNF-α-, and CXCL12-driven migration. Peripheral blood mononuclear cells (PBMCs) and T cells from CCM patients presented an ex vivo enhanced migratory capacity driven by fibronectin alone when this ECM protein was placed in the membrane of transwell migration chambers. When TNF-α was previously placed upon fibronectin, we observed a further and significant increase in the migratory response of both PBMCs and T lymphocytes. Overall, these data suggest the existence in patients with chronic Chagas disease of a cardiac inflammatory infiltrate vector that promotes the recruitment and accumulation of activated T cells, driven in part by enhanced tissue expression of fibronectin and TNF-α, as well as the respective corresponding VLA-4 and TNF receptors.


eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jacopo Di Russo ◽  
Jennifer L Young ◽  
Julian WR Wegner ◽  
Timmy Steins ◽  
Horst Kessler ◽  
...  

Nanometer-scale properties of the extracellular matrix influence many biological processes, including cell motility. While much information is available for single-cell migration, to date, no knowledge exists on how the nanoscale presentation of extracellular matrix receptors influences collective cell migration. In wound healing, basal keratinocytes collectively migrate on a fibronectin-rich provisional basement membrane to re-epithelialize the injured skin. Among other receptors, the fibronectin receptor integrin α5β1 plays a pivotal role in this process. Using a highly specific integrin α5β1 peptidomimetic combined with nanopatterned hydrogels, we show that keratinocyte sheets regulate their migration ability at an optimal integrin α5β1 nanospacing. This efficiency relies on the effective propagation of stresses within the cell monolayer independent of substrate stiffness. For the first time, this work highlights the importance of extracellular matrix receptor nanoscale organization required for efficient tissue regeneration.


2021 ◽  
Vol 7 (19) ◽  
pp. eabe9716
Author(s):  
Stephanie Schumacher ◽  
Dirk Dedden ◽  
Roberto Vazquez Nunez ◽  
Kyoko Matoba ◽  
Junichi Takagi ◽  
...  

Integrin α5β1 is a major fibronectin receptor critical for cell migration. Upon complex formation, fibronectin and α5β1 undergo conformational changes. While this is key for cell-tissue connections, its mechanism is unknown. Here, we report cryo–electron microscopy structures of native human α5β1 with fibronectin to 3.1-angstrom resolution, and in its resting state to 4.6-angstrom resolution. The α5β1-fibronectin complex revealed simultaneous interactions at the arginine-glycine-aspartate loop, the synergy site, and a newly identified binding site proximal to adjacent to metal ion–dependent adhesion site, inducing the translocation of helix α1 to secure integrin opening. Resting α5β1 adopts an incompletely bent conformation, challenging the model of integrin sharp bending inhibiting ligand binding. Our biochemical and structural analyses showed that affinity of α5β1 for fibronectin is increased with manganese ions (Mn2+) while adopting the half-bent conformation, indicating that ligand-binding affinity does not depend on conformation, and α5β1 opening is induced by ligand-binding.


2021 ◽  
Author(s):  
Jacopo Di Russo ◽  
Jennifer L. Young ◽  
Julian W. R. Wegner ◽  
Timmy Steins ◽  
Horst Kessler ◽  
...  

AbstractNanometer-scale properties of the extracellular matrix influence many biological processes, including cell motility. While much information is available for single cell migration, to date, no knowledge exists on how the nanoscale presentation of extracellular matrix receptors influences collective cell migration. In wound healing, basal keratinocytes collectively migrate on a fibronectin-rich provisional basement membrane to re-epithelialize the injured skin. Among other receptors, the fibronectin receptor integrin α5β1 plays a pivotal role in this process. Using a highly specific integrin α5β1 peptidomimetic combined with nanopatterned hydrogels, we show that keratinocyte sheets regulate their migration ability at an optimal integrin α5β1 nanospacing. This efficiency relies on the effective propagation of stresses within the cell monolayer independent of substrate stiffness. For the first time, this work highlights the importance of extracellular matrix receptor nanoscale organization required for efficient tissue regeneration.


2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Joaquin Alvaro Victoria-Hernández ◽  
Anayansi Ventura-Saucedo ◽  
Aurelio López-Morones ◽  
Sandra Luz Martínez-Hernández ◽  
Marina Nayeli Medina-Rosales ◽  
...  

Abstract Background The parasite Entamoeba histolytica is the causal agent of amoebiasis, a worldwide emerging disease. Amebic brain abscess is a form of invasive amebiasis that is both rare and frequently lethal. This condition always begins with the infection of the colon by E. histolytica trophozoites, which subsequently travel through the bloodstream to extraintestinal tissues. Case presentation We report a case of a 71-year-old female who reported an altered state of consciousness, disorientation, sleepiness and memory loss. She had no history of hepatic or intestinal amoebiasis. A preliminary diagnosis of colloidal vesicular phase neurocysticercosis was made based on nuclear magnetic resonance imaging (NMRI). A postsurgery immunofluorescence study was positive for the 140 kDa fibronectin receptor of E. histolytica, although a serum analysis by ELISA was negative for IgG antibodies against this parasite. A specific E. histolytica 128 bp rRNA gene was identified by PCR in biopsy tissue. The final diagnosis was cerebral amoebiasis. The patient underwent neurosurgery to eliminate amoebic abscesses and was then given a regimen of metronidazole, ceftriaxone and dexamethasone for 4 weeks after the neurosurgery. However, a rapid decline in her condition led to death. Conclusions The present case of an individual with a rare form of cerebral amoebiasis highlights the importance of performing immunofluorescence, NMRI and PCR if a patient has brain abscess and a poorly defined diagnosis. Moreover, the administration of corticosteroids to such patients can often lead to a rapid decline in their condition.


2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Anja Jäckle ◽  
Focke Ziemssen ◽  
Eva-Maria Kuhn ◽  
Jürgen Kampmeier ◽  
Gerhard K. Lang ◽  
...  

Inhibitors of dipeptidyl peptidase-4 (DPP-4) are widely used to treat diabetes mellitus, but data concerning their effects on the barrier stability of retinal endothelial cells (REC) in vivo and in vitro are inconsistent. Therefore, we studied whether the barrier properties of immortalized endothelial cells of the bovine retina (iBREC) were affected by the inhibitors of DPP-4 sitagliptin (10-1000 nM) and diprotin A (1-25 μM). Their effects were also investigated in the presence of VEGF-A165 because diabetic patients often develop macular edema caused by VEGF-A-induced permeability of REC. To detect even transient or subtle changes of paracellular and transcellular flow as well as adhesion of the cells to the extracellular matrix, we continuously monitored the cell index (CI) of confluent iBREC grown on gold electrodes. Initially, the CI remained stable but started to decline significantly and persistently at 40 h or 55 h after addition of sitagliptin or diprotin A, respectively. Both inhibitors did not modulate, prevent, or revert the persistent VEGF-A165-induced reduction of the CI. Interestingly, sitagliptin and diprotin A increased the expression of the tight-junction protein claudin-1 which is an important component of a functional barrier formed by iBREC. In contrast, expressions of CD29—a subunit of the fibronectin receptor—or of the tetraspanin CD9 were lower after extended treatment with the DPP-4 inhibitors; less of the CD9 was seen at the plasma membrane after prolonged exposure to sitagliptin. Because both associated proteins are important for adhesion of iBREC to the extracellular matrix, the observed low CI might be caused by weakened attachment of the cells. From our results, we conclude that extended inhibition of DPP-4 destabilizes the barrier formed by microvascular REC and that DPP-4 inhibitors like sitagliptin do not counteract or enhance a VEGF-A165-induced barrier dysfunction as frequently observed in DME.


Talanta ◽  
2020 ◽  
Vol 212 ◽  
pp. 120718 ◽  
Author(s):  
Fan Liu ◽  
Jia-Rui Yan ◽  
Si Chen ◽  
Guo-Ping Yan ◽  
Bo-Qun Pan ◽  
...  

2019 ◽  
Author(s):  
Sanguk Yun ◽  
Rui Hu ◽  
Melanie E. Schwaemmle ◽  
Alexander N. Scherer ◽  
Zhenwu Zhuang ◽  
...  

AbstractFibronectin in the vascular wall promotes inflammatory activation of the endothelium during vascular remodeling and atherosclerosis. These effects are mediated in part by fibronectin binding to integrin α5, which recruits and activates phosphodiesterase 4D5 (PDE4D5) by inducing its dephosphorylation on an inhibitory site Ser651. Active PDE then hydrolyzes anti-inflammatory cAMP to facilitate inflammatory signaling. To test this model in vivo, we mutated the integrin binding site in PDE4D5 in mice. This mutation reduced endothelial inflammatory activation in athero-prone regions of arteries, and, in a hyperlipidemia model, reduced atherosclerotic plaque size while increasing markers of plaque stability. We then investigated the mechanism of PDE4D5 activation. Proteomics identified the PP2A regulatory subunit B55α as the factor recruiting PP2A to PDE4D5. The B55α-PP2A complex localized to adhesions and directly dephosphorylated PDE4D5. This interaction also unexpectedly stabilized the PP2A-B55α complex. The integrin-regulated, pro-atherosclerotic transcription factor Yap is also dephosphorylated and activated through this pathway. PDE4D5 therefore mediates matrix-specific regulation of EC phenotype via an unconventional adapter role, assembling and anchoring a multifunctional PP2A complex with other targets. These results are likely to have widespread consequences for control of cell function by integrins.


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