scholarly journals Septin2 mediates podosome maturation and endothelial cell invasion associated with angiogenesis

2019 ◽  
Vol 219 (2) ◽  
Author(s):  
Kerrie B. Collins ◽  
Hojin Kang ◽  
Jacob Matsche ◽  
Jennifer E. Klomp ◽  
Jalees Rehman ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Plasma Membrane ◽  
Endothelial Cell ◽  
Cell Invasion ◽  
Scaffolding Protein ◽  
Matrix Remodeling ◽  
Close Proximity ◽  
Basolateral Plasma Membrane ◽  
Binding Residues ◽  
And Function

Podosomes are compartmentalized actin-rich adhesions, defined by their ability to locally secrete proteases and remodel extracellular matrix. Matrix remodeling by endothelial podosomes facilitates invasion and thereby vessel formation. However, the mechanisms underlying endothelial podosome formation and function remain unclear. Here, we demonstrate that Septin2, Septin6, and Septin7 are required for maturation of nascent endothelial podosomes into matrix-degrading organelles. We show that podosome development occurs through initial mobilization of the scaffolding protein Tks5 and F-actin accumulation, followed by later recruitment of Septin2. Septin2 localizes around the perimeter of podosomes in close proximity to the basolateral plasma membrane, and phosphoinositide-binding residues of Septin2 are required for podosome function. Combined, our results suggest that the septin cytoskeleton forms a diffusive barrier around nascent podosomes to promote their maturation. Finally, we show that Septin2-mediated regulation of podosomes is critical for endothelial cell invasion associated with angiogenesis. Therefore, targeting of Septin2-mediated podosome formation is a potentially attractive anti-angiogenesis strategy.

scholarly journals STIM1- and Orai1-mediated Ca2+ oscillation orchestrates invadopodium formation and melanoma invasion

2014 ◽  
Vol 207 (4) ◽  
pp. 535-548 ◽  
Author(s):  
Jianwei Sun ◽  
Fujian Lu ◽  
Huifang He ◽  
Junling Shen ◽  
Jane Messina ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Plasma Membrane ◽  
Mouse Model ◽  
Matrix Metalloproteinase ◽  
Cell Invasion ◽  
Cancer Cell Invasion ◽  
Invasion And Metastasis ◽  
Melanoma Invasion ◽  
Ecm Degradation ◽  
Underlying Mechanisms

Ca2+ signaling has been increasingly implicated in cancer invasion and metastasis, and yet, the underlying mechanisms remained largely unknown. In this paper, we report that STIM1- and Orai1-mediated Ca2+ oscillations promote melanoma invasion by orchestrating invadopodium assembly and extracellular matrix (ECM) degradation. Ca2+ oscillation signals facilitate invadopodial precursor assembly by activating Src. Disruption of Ca2+ oscillations inhibited invadopodium assembly. Furthermore, STIM1 and Orai1 regulate the proteolysis activity of individual invadopodia. Mechanistically, Orai1 blockade inhibited the recycling of MT1–matrix metalloproteinase (MMP) to the plasma membrane and entrapped MT1-MMP in the endocytic compartment to inhibit ECM degradation. STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft mouse model, implicating the importance of this pathway in metastatic dissemination. Our findings provide a novel mechanism for Ca2+-mediated cancer cell invasion and shed new light on the spatiotemporal organization of store-operated Ca2+ signals during melanoma invasion and metastasis.

scholarly journals ENaC structure and function in the wake of a resolved structure of a family member

2011 ◽  
Vol 301 (4) ◽  
pp. F684-F696 ◽  
Author(s):  
Ossama B. Kashlan ◽  
Thomas R. Kleyman
Keyword(s):  
Plasma Membrane ◽  
Ion Channel ◽  
Functional Data ◽  
Ion Selectivity ◽  
External Environment ◽  
Structure And Function ◽  
Close Proximity ◽  
Channel Assembly ◽  
And Function ◽  
Insight Into

Our understanding of epithelial Na+ channel (ENaC) structure and function has been profoundly impacted by the resolved structure of the homologous acid-sensing ion channel 1 (ASIC1). The structure of the extracellular and pore regions provide insight into channel assembly, processing, and the ability of these channels to sense the external environment. The absence of intracellular structures precludes insight into important interactions with intracellular factors that regulate trafficking and function. The primary sequences of ASIC1 and ENaC subunits are well conserved within the regions that are within or in close proximity to the plasma membrane, but poorly conserved in peripheral domains that may functionally differentiate family members. This review examines functional data, including ion selectivity, gating, and amiloride block, in light of the resolved ASIC1 structure.

scholarly journals N-WASP coordinates the delivery and F-actin–mediated capture of MT1-MMP at invasive pseudopods

2012 ◽  
Vol 199 (3) ◽  
pp. 527-544 ◽  
Author(s):  
Xinzi Yu ◽  
Tobias Zech ◽  
Laura McDonald ◽  
Esther Garcia Gonzalez ◽  
Ang Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Extracellular Matrix ◽  
Plasma Membrane ◽  
Tumor Cells ◽  
Matrix Metalloproteases ◽  
Matrix Remodeling ◽  
Dense Matrix ◽  
Matrix Degradation ◽  
Late Endosomes ◽  
Syndrome Protein

Metastasizing tumor cells use matrix metalloproteases, such as the transmembrane collagenase MT1-MMP, together with actin-based protrusions, to break through extracellular matrix barriers and migrate in dense matrix. Here we show that the actin nucleation–promoting protein N-WASP (Neural Wiskott-Aldrich syndrome protein) is up-regulated in breast cancer, and has a pivotal role in mediating the assembly of elongated pseudopodia that are instrumental in matrix degradation. Although a role for N-WASP in invadopodia was known, we now show how N-WASP regulates invasive protrusion in 3D matrices. In actively invading cells, N-WASP promoted trafficking of MT1-MMP into invasive pseudopodia, primarily from late endosomes, from which it was delivered to the plasma membrane. Upon MT1-MMP’s arrival at the plasma membrane in pseudopodia, N-WASP stabilized MT1-MMP via direct tethering of its cytoplasmic tail to F-actin. Thus, N-WASP is crucial for extension of invasive pseudopods into which MT1-MMP traffics and for providing the correct cytoskeletal framework to couple matrix remodeling with protrusive invasion.

scholarly journals Bovine pericardial extracellular matrix niche modulates human aortic endothelial cell phenotype and function

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jeny Shklover ◽  
James McMasters ◽  
Alba Alfonso-Garcia ◽  
Manuela Lopera Higuita ◽  
Alyssa Panitch ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cell ◽  
Cell Growth ◽  
Basement Membrane ◽  
Inflammatory Marker ◽  
Cell Phenotype ◽  
Human Aortic Endothelial Cell ◽  
Aortic Endothelial Cell ◽  
And Function ◽  
Aortic Endothelial

Abstract Xenogeneic biomaterials contain biologically relevant extracellular matrix (ECM) composition and organization, making them potentially ideal surgical grafts and tissue engineering scaffolds. Defining the effect of ECM niche (e.g., basement membrane vs. non-basement membrane) on repopulating cell phenotype and function has important implications for use of xenogeneic biomaterials, particularly in vascular applications. We aim to understand how serous (i.e., basement membrane) versus fibrous (i.e., non-basement membrane) ECM niche of antigen-removed bovine pericardium (AR-BP) scaffolds influence human aortic endothelial cell (hAEC) adhesion, growth, phenotype, inflammatory response and laminin production. At low and moderate seeding densities hAEC proliferation was significantly increased on the serous side. Similarly, ECM niche modulated cellular morphology, with serous side seeding resulting in a more rounded aspect ratio and intact endothelial layer formation. At moderate seeding densities, hAEC production of human laminin was enhanced following serous seeding. Finally, inflammatory marker and pro-inflammatory cytokine expression decreased following long-term cell growth regardless of seeding side. This work demonstrates that at low and moderate seeding densities AR-BP sidedness significantly impacts endothelial cell growth, morphology, human laminin production, and inflammatory state. These findings suggest that ECM niche has a role in modulating response of repopulating recipient cells toward AR-BP scaffolds for vascular applications.

scholarly journals Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation

2021 ◽  
Vol 11 (11) ◽  
Author(s):  
Nicoline W. E. van den Berg ◽  
Makiri Kawasaki ◽  
Benedetta Fabrizi ◽  
Fransisca A. Nariswari ◽  
Arianne C. Verduijn ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Extracellular Matrix ◽  
Endothelial Cell ◽  
Cell Activation ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Endothelial Cell Activation

Abstract 4952: Differential Expression in the Determinants of Extracellular Matrix Remodeling in Pediatric and Adult Dilated Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Tain-Yen Hsia ◽  
Jeremy M Ringewald ◽  
Robert E Stroud ◽  
Michael C Graves ◽  
Scott M Bradley ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Dilated Cardiomyopathy ◽  
Cell Lineage ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Matrix Remodeling ◽  
Adult Age ◽  
Membrane Type ◽  
And Function ◽  
Aggressive Clinical Course

Ventricular phenotype of idiopathic dilated cardiomyopathy (DCM) can appear similar in pediatric and adult patients, but a more aggressive clinical course often occurs with pediatric DCM. A structural underpinning of DCM is extracellular matrix changes, which are determined by a balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). This study tests the hypothesis that different MMP/TIMP profiles occur in pediatric and adult DCM patients. Left ventricular samples were taken from pediatric (age 12±4 yr; n=5) and adult (age 63±3 yr; n=11) patients during heart transplantation for DCM. Myocardial levels were quantified for all MMP classes: gelatinases (MMP-2, -9), collagenases (MMP-8, -13), lysins (MMP-7), membrane-type (MT1-MMP), and for all 4 known TIMPs. Patients with structural or ischemic etiologies of DCM were excluded. Compared to adults, MMP-8 levels increased by over 350% (Figure ), and MMP-7 and MT1-MMP levels (75±9% and 76±9%, respectively; p<0.05) were lower in pediatric patients. In contrast, pediatric TIMP-1 levels were reduced by over 50% (Figure). Pediatric DCM patients manifest a robust increase in MMP-8, which degrades all components of the extracellular matrix, and a decrease in TIMP-1, which inhibits MMP-8. This heightened MMP-8/TIMP-1 ratio would favor aggressive matrix remodeling in pediatric DCM. Since MMP-8 is primarily expressed by macrophage cell lineage, a unique proteolytic program may exist in pediatric DCM. These distinct differences in determinants of myocardial matrix structure and function likely contribute to the more progressive nature of DCM in children.

scholarly journals Characterization of a von Hippel Lindau Pathway Involved in Extracellular Matrix Remodeling, Cell Invasion, and Angiogenesis

2006 ◽  
Vol 66 (3) ◽  
pp. 1313-1319 ◽  
Author(s):  
Ghada Kurban ◽  
Valérie Hudon ◽  
Eric Duplan ◽  
Michael Ohh ◽  
Arnim Pause
Keyword(s):  
Extracellular Matrix ◽  
Cell Invasion ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Von Hippel Lindau

scholarly journals Interaction With the Extracellular Matrix Triggers Calcium Signaling in Trypanosoma cruzi Prior to Cell Invasion

2021 ◽  
Vol 11 ◽  
Author(s):  
Nubia Carolina Manchola Varón ◽  
Guilherme Rodrigo R. M. dos Santos ◽  
Walter Colli ◽  
Maria Julia M. Alves
Keyword(s):  
Extracellular Matrix ◽  
Tissue Culture ◽  
Plasma Membrane ◽  
Trypanosoma Cruzi ◽  
Calcium Signaling ◽  
Host Cell ◽  
Cell Invasion ◽  
Early Phase ◽  
Host Cell Invasion ◽  
Dependent Manner

Trypanosoma cruzi, the etiological agent of Chagas disease in humans, infects a wide variety of vertebrates. Trypomastigotes, the parasite infective forms, invade mammalian cells by a still poorly understood mechanism. Adhesion of tissue culture- derived trypomastigotes to the extracellular matrix (ECM) prior to cell invasion has been shown to be a relevant part of the process. Changes in phosphorylation, S-nitrosylation, and nitration levels of proteins, in the late phase of the interaction (2 h), leading to the reprogramming of both trypomastigotes metabolism and the DNA binding profile of modified histones, were described by our group. Here, the involvement of calcium signaling at a very early phase of parasite interaction with ECM is described. Increments in the intracellular calcium concentrations during trypomastigotes-ECM interaction depends on the Ca2+ uptake from the extracellular medium, since it is inhibited by EGTA or Nifedipine, an inhibitor of the L-type voltage gated Ca2+ channels and sphingosine-dependent plasma membrane Ca2+ channel, but not by Vanadate, an inhibitor of the plasma membrane Ca2+-ATPase. Furthermore, Nifedipine inhibits the invasion of host cells by tissue culture- derived trypomastigotes in a dose-dependent manner, reaching 95% inhibition at 100 µM Nifedipine. These data indicate the importance of both Ca2+ uptake from the medium and parasite-ECM interaction for host-cell invasion. Previous treatment of ECM with protease abolishes the Ca2+ uptake, further reinforcing the possibility that these events may be connected. The mitochondrion plays a relevant role in Ca2+ homeostasis in trypomastigotes during their interaction with ECM, as shown by the increment of the intracellular Ca2+ concentration in the presence of Antimycin A, in contrast to other calcium homeostasis disruptors, such as Cyclopiazonic acid for endoplasmic reticulum and Bafilomycin A for acidocalcisome. Total phosphatase activity in the parasite decreases in the presence of Nifedipine, EGTA, and Okadaic acid, implying a role of calcium in the phosphorylation level of proteins that are interacting with the ECM in tissue culture- derived trypomastigotes. In summary, we describe here the increment of Ca2+ at an early phase of the trypomastigotes interaction with ECM, implicating both nifedipine-sensitive Ca2+ channels in the influx of Ca2+ and the mitochondrion as the relevant organelle in Ca2+ homeostasis. The data unravel a complex sequence of events prior to host cell invasion itself.

Sign in / Sign up

Export Citation Format

Share Document