Integrin α2 is an early marker for osteoclast differentiation that contributes to key steps in osteoclastogenesis.

Introduction: Osteoclasts determine bone tissue turnover. Their increased activity causes osteoporosis, their dysfunction osteopetrosis.

Methods And Results: Murine monocytic ER-Hoxb8 cells differentiate into OCs upon treatment with M-CSF and RANKL and upregulate the collagen-binding integrin α2β1 distinctly earlier than other OC markers, such as the OC-associated receptor, OSCAR.

Reversible photoregulation of cell-cell adhesions with opto-E-cadherin.

E-cadherin-based cell-cell adhesions are dynamically and locally regulated in many essential processes, including embryogenesis, wound healing and tissue organization, with dysregulation manifesting as tumorigenesis and metastasis. However, the lack of tools that would provide control of the high spatiotemporal precision observed with E-cadherin adhesions hampers investigation of the underlying mechanisms. Here, we present an optogenetic tool, opto-E-cadherin, that allows reversible control of E-cadherin-mediated cell-cell adhesions with blue light.

Multiparametric chemical exchange saturation transfer MRI detects metabolic changes in breast cancer following immunotherapy.

Background: With metabolic alterations of the tumor microenvironment (TME) contributing to cancer progression, metastatic spread and response to targeted therapies, non-invasive and repetitive imaging of tumor metabolism is of major importance. The purpose of this study was to investigate whether multiparametric chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI) allows to detect differences in the metabolic profiles of the TME in murine breast cancer models with divergent degrees of malignancy and to assess their response to immunotherapy.

Methods: Tumor characteristics of highly malignant 4T1 and low malignant 67NR murine breast cancer models were investigated, and their changes during tumor progression and immune checkpoint inhibitor (ICI) treatment were evaluated.

Profiling specific cell populations within the inflammatory tumor microenvironment by oscillating-gradient diffusion-weighted MRI.

Background: The inflammatory tumor microenvironment (TME) is formed by various immune cells, being closely associated with tumorigenesis. Especially, the interaction between tumor-infiltrating T-cells and macrophages has a crucial impact on tumor progression and metastatic spread. The purpose of this study was to investigate whether oscillating-gradient diffusion-weighted MRI (OGSE-DWI) enables a cell size-based discrimination between different cell populations of the TME.

Stimulation of platelet aggregation by affinity captured rhodocytin from the Malayan pit viper Calloselasma rhodostoma.

The receptor protein CLEC-2 on platelet membranes is the target of the endogenous ligand podoplanin found on cancer cells and of rhodocytin, a snake venom component of the Malayan pit viper Calloselasma rhodostoma. Ligand binding results in platelet activation, increased blood coagulation and thrombosis. In an effort to isolate rhodocytin, we have purified CLEC-2 as bait from E.

Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression.

Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell-matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins.

Loss of Endothelial Cell Matrix Metalloproteinase 14 Reduces Melanoma Growth and Metastasis by Increasing Tumor Vessel Stability.

Matrix metalloproteinase (MMP) 14 belongs to a large family of zinc-dependent endopeptidases and plays a critical role in skin physiological and pathological processes. Complete loss of the protease resulted in severe developmental defects leading to early death. However, because of the premature death of the mice, the functional significance for endothelial cell (EC) expression of MMP14 in skin physiology and pathology in vivo after birth is yet unknown.

Hold on or Cut? Integrin- and MMP-Mediated Cell-Matrix Interactions in the Tumor Microenvironment.

The tumor microenvironment (TME) has become the focus of interest in cancer research and treatment. It includes the extracellular matrix (ECM) and ECM-modifying enzymes that are secreted by cancer and neighboring cells. The ECM serves both to anchor the tumor cells embedded in it and as a means of communication between the various cellular and non-cellular components of the TME.

Neuropilin: Handyman and Power Broker in the Tumor Microenvironment.

Neuropilin-1 and neuropilin-2 form a small family of transmembrane receptors, which, due to the lack of a cytosolic protein kinase domain, act primarily as co-receptors for various ligands. Performing at the molecular level both the executive and organizing functions of a handyman as well as of a power broker, they are instrumental in controlling the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. In this setting, the various neuropilin ligands and interaction partners on various cells of the tumor microenvironment, such as cancer cells, endothelial cells, cancer-associated fibroblasts, and immune cells, are surveyed.

The Cognitive Demands of Gait Retraining in Runners: An EEG Study.

High impact forces during running have been associated with tibial stress injuries. Previous research has demonstrated increasing step rate will decrease impact forces during running. However, no research has determined the cognitive demand of gait retraining.

The extracellular matrix in tumor progression and metastasis.

The extracellular matrix (ECM) constitutes the scaffold of tissues and organs. It is a complex network of extracellular proteins, proteoglycans and glycoproteins, which form supramolecular aggregates, such as fibrils and sheet-like networks. In addition to its biochemical composition, including the covalent intermolecular cross-linkages, the ECM is also characterized by its biophysical parameters, such as topography, molecular density, stiffness/rigidity and tension.

Neuropilins in the Context of Tumor Vasculature.

Neuropilin-1 and Neuropilin-2 form a small family of plasma membrane spanning receptors originally identified by the binding of semaphorin and vascular endothelial growth factor. Having no cytosolic protein kinase domain, they function predominantly as co-receptors of other receptors for various ligands. As such, they critically modulate the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes.

Signals of the Neuropilin-1-MET Axis and Cues of Mechanical Force Exertion Converge to Elicit Inflammatory Activation in Coherent Endothelial Cells.

The neuropilin-1 (NRP1)-MET signaling axis regulates the motility of individual endothelial cells (ECs). It is unknown how this signaling pathway affects the endothelial barrier in coherent ECs forming a tight monolayer. We hypothesized that it is involved both in modulation of the endothelial barrier and in EC activation.

Rhodocetin-αβ selectively breaks the endothelial barrier of the tumor vasculature in HT1080 fibrosarcoma and A431 epidermoid carcinoma tumor models.

The tumor vasculature differs from normal blood vessels in morphology, composition and stability. Here, we describe a novel tumor vessel-disrupting mechanism. In an HT1080/mouse xenograft tumor model rhodocetin-αβ was highly effective in disrupting the tumor endothelial barrier.

The spatial molecular pattern of integrin recognition sites and their immobilization to colloidal nanobeads determine α2β1 integrin-dependent platelet activation.

Collagen, a strong platelet activator, is recognized by integrin α2β1 and GPVI. It induces aggregation, if added to suspended platelets, or platelet adhesion if immobilized to a surface. The recombinant non-prolylhydroxylated mini-collagen FC3 triple helix containing one α2β1 integrin binding site is a tool to specifically study how α2β1 integrin activates platelet.

Collateral Damage Intended-Cancer-Associated Fibroblasts and Vasculature Are Potential Targets in Cancer Therapy.

After oncogenic transformation, tumor cells rewire their metabolism to obtain sufficient energy and biochemical building blocks for cell proliferation, even under hypoxic conditions. Glucose and glutamine become their major limiting nutritional demands. Instead of being autonomous, tumor cells change their immediate environment not only by their metabolites but also by mediators, such as juxtacrine cell contacts, chemokines and other cytokines.

Correction: Dramatic and concerted conformational changes enable rhodocetin to block α2β1 integrin selectively.

[This corrects the article DOI: 10.1371/journal.pbio.

Ca coordination controls sonic hedgehog structure and its Scube2-regulated release.

Proteolytic processing of cell-surface-bound ligands, called shedding, is a fundamental system to control cell-cell signaling. Yet, our understanding of how shedding is regulated is still incomplete. One way to increase the processing of dual-lipidated membrane-associated Sonic hedgehog (Shh) is to increase the density of substrate and sheddase.

Dramatic and concerted conformational changes enable rhodocetin to block α2β1 integrin selectively.

The collagen binding integrin α2β1 plays a crucial role in hemostasis, fibrosis, and cancer progression amongst others. It is specifically inhibited by rhodocetin (RC), a C-type lectin-related protein (CLRP) found in Malayan pit viper (Calloselasma rhodostoma) venom. The structure of RC alone reveals a heterotetramer arranged as an αβ and γδ subunit in a cruciform shape.

The binding capacity of α1β1-, α2β1- and α10β1-integrins depends on non-collagenous surface macromolecules rather than the collagens in cartilage fibrils.

Interactions of cells with supramolecular aggregates of the extracellular matrix (ECM) are mediated, in part, by cell surface receptors of the integrin family. These are important molecular components of cell surface-suprastructures regulating cellular activities in general. A subfamily of β1-integrins with von Willebrand-factor A-like domains (I-domains) in their α-chains can bind to collagen molecules and, therefore, are considered as important cellular mechano-receptors.

Role of Integrins α1β1 and α2β1 in Wound and Tumor Angiogenesis in Mice.

Integrins are transmembrane receptors composed of one α subunit and one β subunit and are involved in cellular growth, differentiation, and apoptosis. The collagen-binding integrins α1β1 and α2β1 have been shown to regulate wound and tumor vascularization by different mechanisms. In this study, we assessed wound and tumor vascularization in mice with genetic ablation of both integrin subunits α1 and α2, which resulted in loss of integrins α1β1 and α2β1.

Data for a direct fibrinolytic metalloproteinase, barnettlysin-I from Bothrops barnetti (barnett(,)s pitviper) snake venom with anti-thrombotic effect.

Initial association of platelets after vascular injury is mediated by glycoprotein (GP)Ib-IX-V binding to von Willebrand factor (vWf) immobilized on exposed collagens and eventually leads to thrombus formation. This article provides data about a new P-I class snake venom metalloproteinase (SVMP), barnettlysin-I (Bar-I), purified from the venom of Bothrops barnetti. This Data in Brief manuscript complements the main research article by providing additional data of the biochemical characterization of Bar-I 10.

A novel fibrinolytic metalloproteinase, barnettlysin-I from Bothrops barnetti (Barnett´s pitviper) snake venom with anti-platelet properties.

Background: Viperid snake venoms contain active components that interfere with hemostasis. We report a new P-I class snake venom metalloproteinase (SVMP), barnettlysin-I (Bar-I), isolated from the venom of Bothrops barnetti and evaluated its fibrinolytic and antithrombotic potential.

Methods: Bar-I was purified using a combination of molecular exclusion and cation-exchange chromatographies.

Jararhagin disruption of endothelial cell anchorage is enhanced in collagen enriched matrices.

Hemorrhage is one of the most striking effects of bites by viper snakes resulting in fast bleeding and ischemia in affected tissues. Snake venom metalloproteinases (SVMPs) are responsible for hemorrhagic activity, but the mechanisms involved in SVMP-induced hemorrhage are not entirely understood and the study of such mechanisms greatly depends on in vivo experiments. In vivo, hemorrhagic SVMPs accumulate on basement membrane (BM) of venules and capillary vessels allowing the hydrolysis of collagen IV with consequent weakness and rupture of capillary walls.

Rhodocetin-αβ-induced neuropilin-1-cMet association triggers restructuring of matrix contacts in endothelial cells.

Objective: The snake venom component rhodocetin-αβ (RCαβ) stimulates endothelial cell motility in an α2β1 integrin-independent manner. We aimed to elucidate its cellular and molecular mechanisms.

Methods And Results: We identified neuropilin-1 (Nrp1) as a novel target of RCαβ by protein-chemical methods.