Integrins are heterodimeric transmembrane receptors that connect the extracellular matrix environment to the actin cytoskeleton via adaptor molecules through assembly of a range of adhesion ...structures. Recent advances in biochemical, imaging and biophysical methods have enabled a deeper understanding of integrin signalling and their associated regulatory processes. The identification of the consensus integrin-based ‘adhesomes’ within the last 5 years has defined common core components of adhesion complexes and associated partners. These approaches have also uncovered unexpected adhesion protein behaviour and molecules recruited to adhesion sites that have expanded our understanding of the molecular and physical control of integrin signalling.
Contact inhibition of locomotion (CIL) is the process through which cells move away from each other after cell-cell contact, and it contributes to malignant invasion and developmental migration. ...Various cell types exhibit CIL, whereas others remain in contact after collision and may form stable junctions. To investigate what determines this differential behavior, we study neural crest cells, a migratory stem cell population whose invasiveness has been likened to cancer metastasis. By comparing pre-migratory and migratory neural crest cells, we show that the switch from E- to N-cadherin during EMT is essential for acquisition of CIL behavior. Loss of E-cadherin leads to repolarization of protrusions, via p120 and Rac1, resulting in a redistribution of forces from intercellular tension to cell-matrix adhesions, which break down the cadherin junction. These data provide insight into the balance of physical forces that contributes to CIL in cells in vivo.
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•Neural crest cells acquire contact inhibition of locomotion (CIL) during EMT•An E- to N-cadherin switch controls CIL•E-cadherin represses CIL by controlling Rac1-dependent protrusions via p120•During CIL, forces are redistributed from intercellular junctions to cell matrix
Cell-cell adhesions are transiently formed during contact inhibition of locomotion. Scarpa et al. show that an E- to N-cadherin switch controls CIL acquisition upon EMT. E-cadherin loss leads to repolarization of protrusions via p120 and Rac1, resulting in redistribution of forces from intercellular tension to cell-matrix adhesions, triggering junction disassembly.
Integrins are heterodimeric transmembrane receptors that play an essential role in enabling cells to sense and bind to extracellular ligands. Activation and clustering of integrins leads to the ...formation of focal adhesions at the plasma membrane that subsequently initiate signalling pathways to control a broad range of functional endpoints including cell migration, proliferation and survival. The α4 and α9 integrins form a small sub-family of receptors that share some specific ligands and binding partners. Although relatively poorly studied compared with other integrin family members, emerging evidence suggests that despite restricted cell and tissue expression profiles, these integrins play a key role in the regulation of signalling pathways controlling cytoskeletal remodelling and migration in both adherent and non-adherent cell types. This review summarises the known shared and specific roles for α4 and α9 integrins and highlights the importance of these receptors in controlling cell migration within both homeostatic and disease settings.
Directional collective migration is now a widely recognized mode of migration during embryogenesis and cancer. However, how a cluster of cells responds to chemoattractants is not fully understood. ...Neural crest cells are among the most motile cells in the embryo, and their behavior has been likened to malignant invasion. Here, we show that neural crest cells are collectively attracted toward the chemokine Sdf1. While not involved in initially polarizing cells, Sdf1 directionally stabilizes cell protrusions promoted by cell contact. At this cell contact, N-cadherin inhibits protrusion and Rac1 activity and in turn promotes protrusions and activation of Rac1 at the free edge. These results show a role for N-cadherin during contact inhibition of locomotion, and they reveal a mechanism of chemoattraction likely to function during both embryogenesis and cancer metastasis, whereby attractants such as Sdf1 amplify and stabilize contact-dependent cell polarity, resulting in directional collective migration.
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► Neural crest (NC) cells undergo collective chemotaxis toward Sdf1 ► N-cadherin-dependent contacts are required for NC cell chemotaxis toward Sdf1 ► N-cadherin regulates contact inhibition of locomotion by controlling small GTPases ► Sdf1 reinforces cell polarity induced by N-cadherin/contact inhibition
When migrating in vivo, cells are exposed to numerous conflicting signals: chemokines, repellents, extracellular matrix, growth factors. The roles of several of these molecules have been studied ...individually in vitro or in vivo, but we have yet to understand how cells integrate them. To start addressing this question, we used the cephalic neural crest as a model system and looked at the roles of its best examples of positive and negative signals: stromal-cell derived factor 1 (Sdf1/Cxcl12) and class3-Semaphorins. Here we show that Sdf1 and Sema3A antagonistically control cell-matrix adhesion via opposite effects on Rac1 activity at the single cell level. Directional migration at the population level emerges as a result of global Semaphorin-dependent confinement and broad activation of adhesion by Sdf1 in the context of a biased Fibronectin distribution. These results indicate that uneven in vivo topology renders the need for precise distribution of secreted signals mostly dispensable.
The coxsackievirus and adenovirus receptor (CAR) is a transmembrane receptor that plays a key role in cell-cell adhesion. CAR is found in normal epithelial cells and is increased in abundance in ...various human tumors, including lung carcinomas. We investigated the potential mechanisms by which CAR contributes to cancer cell growth and found that depletion of CAR in human lung cancer cells reduced anchorage-independent growth, epidermal growth factor (EGF)-dependent proliferation, and tumor growth in vivo. EGF induced the phosphorylation of CAR and its subsequent relocalization to cell junctions through the activation of the kinase PKCδ. EGF promoted the binding of CAR to the chromokinesin KIF22. KIF22-dependent regulation of microtubule dynamics led to delayed EGFR internalization, enhanced EGFR signaling, and coordination of CAR dynamics at cell-cell junctions. These data suggest a role for KIF22 in the coordination of membrane receptors and provide potential new therapeutic strategies to combat lung tumor growth.
Abstract
Assessing the quality of localisation microscopy images is highly challenging due to the difficulty in reliably detecting errors in experimental data. The most common failure modes are the ...biases and errors produced by the localisation algorithm when there is emitter overlap. Also known as the high density or crowded field condition, significant emitter overlap is normally unavoidable in live cell imaging. Here we use Haar wavelet kernel analysis (HAWK), a localisation microscopy data analysis method which is known to produce results without bias, to generate a reference image. This enables mapping and quantification of reconstruction bias and artefacts common in all but low emitter density data. By avoiding comparisons involving intensity information, we can map structural artefacts in a way that is not adversely influenced by nonlinearity in the localisation algorithm. The HAWK Method for the Assessment of Nanoscopy (HAWKMAN) is a general approach which allows for the reliability of localisation information to be assessed.
Mechanical forces are central to developmental, physiological and pathological processes. However, limited understanding of force transmission within sub-cellular structures is a major obstacle to ...unravelling molecular mechanisms. Here we describe the development of a calibrated biosensor that measures forces across specific proteins in cells with piconewton (pN) sensitivity, as demonstrated by single molecule fluorescence force spectroscopy. The method is applied to vinculin, a protein that connects integrins to actin filaments and whose recruitment to focal adhesions (FAs) is force-dependent. We show that tension across vinculin in stable FAs is ∼2.5 pN and that vinculin recruitment to FAs and force transmission across vinculin are regulated separately. Highest tension across vinculin is associated with adhesion assembly and enlargement. Conversely, vinculin is under low force in disassembling or sliding FAs at the trailing edge of migrating cells. Furthermore, vinculin is required for stabilizing adhesions under force. Together, these data reveal that FA stabilization under force requires both vinculin recruitment and force transmission, and that, surprisingly, these processes can be controlled independently.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metabolic perturbations in fibrosis disease Ung, Chuin Ying; Onoufriadis, Alexandros; Parsons, Maddy ...
The international journal of biochemistry & cell biology,
October 2021, 2021-10-00, 20211001, Letnik:
139
Journal Article
Recenzirano
Odprti dostop
Metabolic changes occur in all forms of disease but their impact on fibrosis is a relatively recent area of interest. This review provides an overview of the major metabolic pathways, glycolysis, ...amino acid metabolism and lipid metabolism, and highlights how they influence fibrosis at a cellular and tissue level, drawing on key discoveries in dermal, renal, pulmonary and hepatic fibrosis. The emerging influence of adipose tissue-derived cytokines is discussed and brings a link between fibrosis and systemic metabolism. To close, the concept of targeting metabolism for fibrotic therapy is reviewed, drawing on lessons from the more established field of cancer metabolism, with an emphasis on important considerations for clinical translation.
The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates ...tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK.
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