TFEB controls integrin-mediated endothelial cell adhesion by the regulation of cholesterol metabolism

The dynamic integrin-mediated adhesion of endothelial cells (ECs) to the surrounding ECM is fundamental for angiogenesis both in physiological and pathological conditions, such as embryonic development and cancer progression. The dynamics of EC-to-ECM adhesions relies on the regulation of the conformational activation and trafficking of integrins. Here, we reveal that oncogenic transcription factor EB (TFEB), a known regulator of lysosomal biogenesis and metabolism, also controls a transcriptional program that influences the turnover of ECM adhesions in ECs by regulating cholesterol metabolism. We show that TFEB favors ECM adhesion turnover by promoting the transcription of genes that drive the synthesis of cholesterol, which promotes the aggregation of caveolin-1, and the caveolin-dependent endocytosis of integrin β1. These findings suggest that TFEB might represent a novel target for the pharmacological control of pathological angiogenesis and bring new insights in the mechanism sustaining TFEB control of endocytosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10456-022-09840-x

The βI domain promotes active β1 integrin clustering into mature adhesion sites

Modulation of integrin function is required in many physiological and pathological settings, such as angiogenesis and cancer. Integrin allosteric changes, clustering, and trafficking cooperate to regulate cell adhesion and motility on extracellular matrix proteins via mechanisms that are partly defined. By exploiting four monoclonal antibodies recognizing distinct conformational epitopes, we show that in endothelial cells (ECs), the extracellular βI domain, but not the hybrid or I-EGF2 domain of active β1 integrins, promotes their FAK-regulated clustering into tensin 1–containing fibrillar adhesions and impairs their endocytosis. In this regard, the βI domain–dependent clustering of active β1 integrins is necessary to favor fibronectin-elicited directional EC motility, which cannot be effectively promoted by β1 integrin conformational activation alone

Proceedings of the Fifth Italian Conference on Computational Linguistics CLiC-it 2018

On behalf of the Program Committee, a very warm welcome to the Fifth Italian Conference on Computational Linguistics (CLiC-­‐it 2018). This edition of the conference is held in Torino. The conference is locally organised by the University of Torino and hosted into its prestigious main lecture hall “Cavallerizza Reale”. The CLiC-­‐it conference series is an initiative of the Italian Association for Computational Linguistics (AILC) which, after five years of activity, has clearly established itself as the premier national forum for research and development in the fields of Computational Linguistics and Natural Language Processing, where leading researchers and practitioners from academia and industry meet to share their research results, experiences, and challenges

How ICT and non-ICT solutions can facilitate the interactions in migration-related work?

In this poster, we present a preliminary study carried out within the Horizon 2020 PERCEPTIONS project (2019-2023), in which we investigated through quantitative and qualitative methods how ICT and non-ICT solutions can facilitate the interactions among users (practitioners, stakeholders, migrants) in migration-related work

The βI domain promotes active β1 integrin clustering into mature adhesion sites

Modulation of integrin function is required in many physiological and pathological settings, such as angiogenesis and cancer. Integrin allosteric changes, clustering, and trafficking cooperate to regulate cell adhesion and motility on extracellular matrix proteins via mechanisms that are partly defined. By exploiting four monoclonal antibodies recognizing distinct conformational epitopes, we show that in endothelial cells (ECs), the extracellular βI domain, but not the hybrid or I-EGF2 domain of active β1 integrins, promotes their FAK-regulated clustering into tensin 1-containing fibrillar adhesions and impairs their endocytosis. In this regard, the βI domain-dependent clustering of active β1 integrins is necessary to favor fibronectin-elicited directional EC motility, which cannot be effectively promoted by β1 integrin conformational activation alone.</p

LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion

Dynamic modulation of endothelial cell-to-cell and cell-to-extracellular matrix (ECM) adhesion is essential for blood vessel patterning and functioning. Yet the molecular mechanisms involved in this process have not been completely deciphered. We identify the adhesion G protein-coupled receptor (ADGR) Latrophilin 2 (LPHN2) as a novel determinant of endothelial cell (EC) adhesion and barrier function. In cultured ECs, endogenous LPHN2 localizes at ECM contacts, signals through cAMP/Rap1, and inhibits focal adhesion (FA) formation and nuclear localization of YAP/TAZ transcriptional regulators, while promoting tight junction (TJ) assembly. ECs also express an endogenous LPHN2 ligand, fibronectin leucine-rich transmembrane 2 (FLRT2), that prevents ECM-elicited EC behaviors in an LPHN2-dependent manner. Vascular ECs of lphn2a knock-out zebrafish embryos become abnormally stretched, display a hyperactive YAP/TAZ pathway, and lack proper intercellular TJs. Consistently, blood vessels are hyperpermeable, and intravascularly injected cancer cells extravasate more easily in lphn2a null animals. Thus, LPHN2 ligands, such as FLRT2, may be therapeutically exploited to interfere with cancer metastatic dissemination