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Integrin adhesion complexes mediate dynamic cell-matrix interactions to regulate cell adhesion, migration and invasion. While increasing evidence suggests that adhesion components can undergo liquid-liquid phase separation, the functional relevance of adhesion-derived condensates remains elusive. Here, we demonstrate that tensin 1 (TNS1), a multidomain adaptor protein linking active integrins with the actin cytoskeleton, forms condensates in cells to regulate adhesion component availability. We show that endogenous TNS1 condensates are formed upon focal adhesion disassembly or limited integrin-extracellular matrix engagement, acting as reversible reservoirs for unphosphorylated adhesion proteins. We identify the TNS1 intrinsically disordered region as governing TNS1 condensation and condensate biophysical properties. We further demonstrate a negative regulatory role for phosphorylation on condensate assembly upon stress-responsive kinase activation. Finally, we confirm the functional effects of TNS1 condensation on adhesion dynamics and cell migration, identifying a feedback loop acutely regulating kinase-mediated adhesion turnover upon integrin activation. Integrin adhesions allow dynamic cell-matrix interactions to regulate cell behaviour. Here, the authors reveal that tensin 1, a multidomain adaptor protein, forms condensates in cells that act as reversible reservoirs for adhesion proteins.

Tensin1 (TNS1) is a key component of focal and fibrillar adhesions, mediating fibrillogenesis, as well as the transduction of mechanical cues and adhesive signaling. To enable further TNS1 characterization, we have developed a novel transgenic mouse that allows for temporally controlled and lineage specific knockout of TNS1. We found no differentially observed effects of TNS1 knockout on mouse health, breeding capacity, or vital organ histopathology. In contrast, RNA sequencing analysis identified 171 differentially expressed genes with Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrating differential expression in osteoclast differentiation and a number of pathways involved in host immune response. Furthermore, STRING pathway analysis showed differential regulation of genes involved in B-cell and myeloid-related signaling pathways, a number of which were validated by reverse transcription-quantitative polymerase chain reaction (RT qPCR). Loss of TNS1 in THP-1 monocyte/macrophage cell line resulted in impaired migration and phagocytosis. We also observed a trend toward increased detection of lymphocytes in the bronchoalveolar lavage within days following TNS1 knockout. This study provides a novel understanding of the phenotypic and genotypic changes that occur following knockout of TNS1 that may lead to subsequent understanding of its role in disease.

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development 1 , 2 , and increased stiffness is known to promote HCC progression in cirrhotic conditions 3 , 4 . Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1–tensin-1–YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness. Structural changes mediated by advanced glycation end-products enhance extracellular matrix viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

Misregulation of long non-coding RNA (lncRNA) genes has been linked to a wide variety of cancer types. Here we report on Mammary Tumor Associated RNA 25 ( MaTAR25 ), a nuclear enriched and chromatin associated lncRNA that plays a role in mammary tumor cell proliferation, migration, and invasion, both in vitro and in vivo. MaTAR25 functions by interacting with purine rich element binding protein B (PURB), and associating with a major downstream target gene Tensin1 ( Tns1 ) to regulate its expression in trans . The Tns1 protein product is a critical component of focal adhesions linking signaling between the extracellular matrix and the actin cytoskeleton. Knockout of MaTAR25 results in down-regulation of Tns1 leading to a reorganization of the actin cytoskeleton, and a reduction of focal adhesions and microvilli. We identify LINC01271 as the human ortholog of MaTAR25 , and importantly, increased expression of LINC01271 is associated with poor patient prognosis and metastasis. Our findings demonstrate that LINC01271 represents a potential therapeutic target to alter breast cancer progression. A group of long non-coding RNAs (lncRNAs), Mammary Tumor Associated RNA s   1-30 ( MaTARs   1-30 ), are differentially expressed between mammary tumor cells and normal mammary epithelial cells. Here the authors report that MaTAR25 plays a role in breast cancer cell proliferation, migration and invasion by regulating the expression of the Tensin1 gene in trans .

Tensins belong to the group of adhesion proteins that are involved in cell adhesion and migration, actin cytoskeleton maintenance and intercellular communication. TNS1, TNS2 and TNS3 proteins expression was evaluated in 90 patients with gastric cancer by immunohistochemistry method. TNS1 was more frequently present in non-differentiated tumors compared to poorly and moderately differentiated tumors (p = 0.016). TNS1 was also more often observed in metastatic tumors compared to those without distant metastases (p = 0.001). TNS2 was more common in moderately differentiated tumors than in poorly or non-differentiated ones (p = 0.041). TNS2 expression was also more frequently present in tumors with peritumoral inflammation (p = 0.041) and with concomitant H. pylori infection (p = 0.023). In contrast, TNS3 protein was more prevalent in moderately than in poorly and non-differentiated tumors (p = 0.023). No significant relationship was found between tensins’ expression and the overall survival rate of patients. TNS1 protein expression is associated with a poor-prognosis type of GC. Higher expression of TNS2 is accompanied by peritumoral inflammation and H. pylori infection, which favor the development of GC of a better prognosis, similarly to higher TNS3 protein expression.

Although mesenchymal stem cells (MSCs) transplantation into the IVD (intervertebral disc) may be beneficial in inhibiting apoptosis of nucleus pulposus cells (NPCs) and alleviating IVD degeneration, the underlying mechanism of this therapeutic process has not been fully explained. The purpose of this study was to explore the protective effect of MSC‐derived exosomes (MSC‐exosomes) on NPC apoptosis and IVD degeneration and investigate the regulatory effect of miRNAs in MSC‐exosomes and associated mechanisms for NPC apoptosis. MSC‐exosomes were isolated from MSC medium, and its anti‐apoptotic effect was assessed in a cell and rat model. The down‐regulated miRNAs in apoptotic NPCs were identified, and their contents in MSC‐exosomes were detected. The target genes of eligible miRNAs and possible downstream pathway were investigated. Purified MSC‐exosomes were taken up by NPCs and suppressed NPC apoptosis. The levels of miR‐21 were down‐regulated in apoptotic NPCs while MSC‐exosomes were enriched in miR‐21. The exosomal miR‐21 could be transferred into NPCs and alleviated TNF‐α induced NPC apoptosis by targeting phosphatase and tensin homolog (PTEN) through phosphatidylinositol 3‐kinase (PI3K)‐Akt pathway. Intradiscal injection of MSC‐exosomes alleviated the NPC apoptosis and IVD degeneration in the rat model. In conclusion, MSC‐derived exosomes prevent NPCs from apoptotic process and alleviate IVD degeneration, at least partly, via miR‐21 contained in exosomes. Exosomal miR‐21 restrains PTEN and thus activates PI3K/Akt pathway in apoptotic NPCs. Our work confers a promising therapeutic strategy for IVD degeneration.

Tumor-immune cell interactions shape the immune cell phenotype, with microRNAs (miRs) being crucial components of this crosstalk. How they are transferred and how they affect their target landscape, especially in tumor-associated macrophages (TAMs), is largely unknown. Here we report that breast cancer cells have a high constitutive expression of miR-375, which is released as a non-exosome entity during apoptosis. Deep sequencing of the miRome pointed to enhanced accumulation of miR-375 in TAMs, facilitated by the uptake of tumor-derived miR-375 via CD36. In macrophages, miR-375 directly targets TNS3 and PXN to enhance macrophage migration and infiltration into tumor spheroids and in tumors of a xenograft mouse model. In tumor cells, miR-375 regulates CCL2 expression to increase recruitment of macrophages. Our study provides evidence for miR transfer from tumor cells to TAMs and identifies miR-375 as a crucial regulator of phagocyte infiltration and the subsequent development of a tumor-promoting microenvironment. The mode of miRNA transfer between tumour-immune cells is usually via exosomes. Here, the authors show that an alternative mode of transfer whereby miR-375 from apoptotic tumour cells can be transferred to tumour-associated macrophages via CD36 receptor, which induces macrophage migration and infiltration to the tumours.

The pseudophosphatases, atypical members of the protein tyrosine phosphatase family, have emerged as bona fide signaling regulators within the past two decades. Their roles as regulators have led to a renaissance of the pseudophosphatase and pseudoenyme fields, catapulting interest from a mere curiosity to intriguing and relevant proteins to investigate. Pseudophosphatases make up approximately fourteen percent of the phosphatase family, and are conserved throughout evolution. Pseudophosphatases, along with pseudokinases, are important players in physiology and pathophysiology. These atypical members of the protein tyrosine phosphatase and protein tyrosine kinase superfamily, respectively, are rendered catalytically inactive through mutations within their catalytic active signature motif and/or other important domains required for catalysis. This new interest in the pursuit of the relevant functions of these proteins has resulted in an elucidation of their roles in signaling cascades and diseases. There is a rapid accumulation of knowledge of diseases linked to their dysregulation, such as neuropathies and various cancers. This review analyzes the involvement of pseudophosphatases in diseases, highlighting the function of various role(s) of pseudophosphatases involvement in pathologies, and thus providing a platform to strongly consider them as key therapeutic drug targets.

Myofibroblasts, the primary effector cells that mediate matrix remodeling during pulmonary fibrosis, rapidly assemble an extracellular fibronectin matrix. Tensin (TNS) 1 is a key component of specialized cellular adhesions (fibrillar adhesions) that bind to extracellular fibronectin fibrils. We hypothesized that TNS1 may play a role in modulating myofibroblast-mediated matrix formation. We found that TNS1 expression is increased in fibroblastic foci from lungs with idiopathic pulmonary fibrosis. Transforming growth factor (TGF)-β profoundly up-regulates TNS1 expression with kinetics that parallel the expression of the myofibroblast marker, smooth muscle α-actin. TGF-β–induced TNS1 expression is dependent on signaling through the TGF-β receptor 1 and is Rho coiled-coiled kinase/actin/megakaryoblastic leukemia-1/serum response factor dependent. Small interfering RNA–mediated knockdown of TNS1 disrupted TGF-β–induced myofibroblast differentiation, without affecting TGF-β/Smad signaling. In contrast, loss of TNS1 resulted in disruption of focal adhesion kinase phosphorylation, focal adhesion formation, and actin stress fiber development. Finally, TNS1 was essential for the formation of fibrillar adhesions and the assembly of nascent fibronectin and collagen matrix in myofibroblasts. In summary, our data show that TNS1 is a novel megakaryoblastic leukemia-1–dependent gene that is induced during pulmonary fibrosis. TNS1 plays an essential role in TGF-β–induced myofibroblast differentiation and myofibroblast-mediated formation of extracellular fibronectin and collagen matrix. Targeted disruption of TNS1 and associated signaling may provide an avenue to inhibit tissue fibrosis.

Biomolecular condensates are nonmembranous structures that are mainly formed through liquid—liquid phase separation. Tensins are focal adhesion (FA) proteins linking the actin cytoskeleton to integrin receptors. Here, we report that GFP-tagged tensin-1 (TNS1) proteins phase-separate to form biomolecular condensates in cells. Live-cell imaging showed that new TNS1 condensates are budding from the disassembling ends of FAs, and the presence of these condensates is cell cycle dependent. TNS1 condensates dissolve immediately prior to mitosis and rapidly reappear while postmitotic daughter cells establish new FAs. TNS1 condensates contain selected FA proteins and signaling molecules such as pT308Akt but not pS473Akt, suggesting previously unknown roles of TNS1 condensates in disassembling FAs, as the storage of core FA components and the signaling intermediates.