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Oncogene Aug 2018E-cadherin is a key component of the adherens junctions that are integral in cell adhesion and maintaining epithelial phenotype of cells. Homophilic E-cadherin binding... (Review)
Review
E-cadherin is a key component of the adherens junctions that are integral in cell adhesion and maintaining epithelial phenotype of cells. Homophilic E-cadherin binding between cells is important in mediating contact inhibition of proliferation when cells reach confluence. Loss of E-cadherin expression results in loss of contact inhibition and is associated with increased cell motility and advanced stages of cancer. In this review we discuss the role of E-cadherin and its downstream signaling in regulation of contact inhibition and the development and progression of cancer.
Topics: Animals; Cadherins; Cell Adhesion; Cell Movement; Contact Inhibition; Disease Progression; Epithelial Cells; Humans; Neoplasms; Signal Transduction
PubMed: 29780167
DOI: 10.1038/s41388-018-0304-2 -
The Journal of Clinical Investigation Oct 2023The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a...
The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and MST2 (MST1/2). WW45 interaction with MST1/2 was thereby enhanced, resulting in the activation of Hippo signaling to block YAP activity for cell contact inhibition. Importantly, low cell density led to SPTAN1 dephosphorylation and NUMB cytoplasmic location, along with MST1/2 inhibition and, consequently, YAP activation. Moreover, double KO of NUMB and WW45 in the liver led to appreciable organ enlargement and rapid tumorigenesis. Interestingly, NUMB isoforms 3 and 4, which have a truncated phosphotyrosine-binding (PTB) domain and are thus unable to interact with phosphorylated SPTAN1 and activate MST1/2, were selectively upregulated in liver cancer, which correlated with YAP activation. We have thus revealed a SPTAN1/NUMB1/2 axis that acts as a cell density sensor to restrain cell growth and oncogenesis by coupling external cell-cell contact signals to intracellular Hippo signaling.
Topics: Humans; Hippo Signaling Pathway; Protein Serine-Threonine Kinases; Spectrin; Adaptor Proteins, Signal Transducing; YAP-Signaling Proteins; Transcription Factors; Carcinogenesis
PubMed: 37843276
DOI: 10.1172/JCI168888 -
Genes & Development Nov 2007The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that...
The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.
Topics: 14-3-3 Proteins; Amino Acid Motifs; Amino Acid Sequence; Animals; Cell Communication; Cell Count; Cell Proliferation; Cells, Cultured; Contact Inhibition; Drosophila; Drosophila Proteins; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins; Mice; Models, Biological; NIH 3T3 Cells; Nuclear Proteins; Phosphorylation; Protein Binding; Protein Kinases; Protein Serine-Threonine Kinases; Protein Transport; Signal Transduction; Trans-Activators; YAP-Signaling Proteins
PubMed: 17974916
DOI: 10.1101/gad.1602907 -
The International Journal of... 2018Michael Abercrombie is regarded as one of the principal pioneers of cell biology. Although Abercrombie began his career as an experimental embryologist, working on the... (Review)
Review
Michael Abercrombie is regarded as one of the principal pioneers of cell biology. Although Abercrombie began his career as an experimental embryologist, working on the avian organizer with C. H. Waddington, questions on how cells in culture migrate and interact dominated his career. Whilst studying the social behaviour of chick heart embryonic fibroblasts, Abercrombie identified a phenomenon whereby colliding cells collapse their protrusions towards the cell-cell contact upon a collision, preventing their continued migration. The cells then form protrusions away from the contact and, space permitting, migrate away from each other. This behaviour is now referred to as 'contact inhibition of locomotion' and has been identified within embryology as the driving force behind the directional migration of the neural crest and the dispersion patterning of haemocytes and Cajal-Retzius neurons. Furthermore, its loss between collisions of cancer cells and healthy cells is associated with metastasis. In this review we begin with an overview of Abercrombie's life and highlight some of his key publications. We then discuss Abercrombie's discovery of contact inhibition of locomotion, the roles which cell-cell adhesions, cell-matrix adhesions and the cytoskeleton play in facilitating this phenomenon, and the importance of contact inhibition of locomotion within the living organism.
Topics: Animals; Cell Adhesion; Cell Biology; Cell Communication; Cell Movement; Chick Embryo; Cytoskeleton; Embryology; England; History, 20th Century; Humans; Neoplasm Metastasis; Neoplasms; Neurons
PubMed: 29616739
DOI: 10.1387/ijdb.170277rm -
Oncotarget Sep 2014
Topics: Animals; Cellular Senescence; Contact Inhibition; Humans
PubMed: 25277173
DOI: 10.18632/oncotarget.2446 -
International Journal of Molecular... Dec 2016Integrins are heterodimeric cell surface receptors that bind to different extracellular ligands depending on their composition and regulate all processes which enable... (Review)
Review
Integrins are heterodimeric cell surface receptors that bind to different extracellular ligands depending on their composition and regulate all processes which enable multicellular life. In cancer, integrins trigger and play key roles in all the features that were once described as the . In this review, we will discuss the contribution of integrins to these hallmarks, including uncontrolled and limitless proliferation, invasion of tumor cells, promotion of tumor angiogenesis and evasion of apoptosis and resistance to growth suppressors, by highlighting the latest findings. Further on, given the paramount role of integrins in cancer, we will present novel strategies for integrin inhibition that are starting to emerge, promising a hopeful future regarding cancer treatment.
Topics: Animals; Apoptosis; Humans; Integrins; Neoplasms; Neovascularization, Pathologic; Signal Transduction
PubMed: 27929432
DOI: 10.3390/ijms17122037 -
International Journal of Molecular... Oct 2020Over millions of years of evolution, bacteria have developed complex strategies for intra-and interspecies interactions and competition for ecological niches and... (Review)
Review
Over millions of years of evolution, bacteria have developed complex strategies for intra-and interspecies interactions and competition for ecological niches and resources. Contact-dependent growth inhibition systems (CDI) are designed to realize a direct physical contact of one bacterial cell with other cells in proximity via receptor-mediated toxin delivery. These systems are found in many microorganisms including clinically important human pathogens. The main purpose of these systems is to provide competitive advantages for the growth of the population. In addition, non-competitive roles for CDI toxin delivery systems including interbacterial signal transduction and mediators of bacterial collaboration have been suggested. In this review, our goal was to systematize the recent findings on the structure, mechanisms, and purpose of CDI systems in bacterial populations and discuss the potential biological and evolutionary impact of CDI-mediated interbacterial competition and/or cooperation.
Topics: Bacteria; Bacterial Proteins; Biofilms; Contact Inhibition; Microbial Interactions
PubMed: 33121148
DOI: 10.3390/ijms21217990 -
Trends in Microbiology May 2013Bacteria cooperate to form multicellular communities and compete against one another for environmental resources. Here, we review recent advances in the understanding of... (Review)
Review
Bacteria cooperate to form multicellular communities and compete against one another for environmental resources. Here, we review recent advances in the understanding of bacterial competition mediated by contact-dependent growth inhibition (CDI) systems. Different CDI+ bacteria deploy a variety of toxins to inhibit neighboring cells and protect themselves from autoinhibition by producing specific immunity proteins. The genes encoding CDI toxin-immunity protein pairs appear to be exchanged between cdi loci and are often associated with other toxin-delivery systems in diverse bacterial species. CDI also appears to facilitate cooperative behavior between kin, suggesting that these systems may have other roles beyond competition.
Topics: Bacteria; Bacterial Proteins; Contact Inhibition
PubMed: 23473845
DOI: 10.1016/j.tim.2013.02.003 -
Cellular and Molecular Life Sciences :... Mar 2016Contact inhibition of locomotion (CIL) is a complex process, whereby cells undergoing a collision with another cell cease their migration towards the colliding cell. CIL... (Review)
Review
Contact inhibition of locomotion (CIL) is a complex process, whereby cells undergoing a collision with another cell cease their migration towards the colliding cell. CIL has been identified in numerous cells during development including embryonic fibroblasts, neural crest cells and haemocytes and is the driving force behind a range of phenomenon including collective cell migration and dispersion. The loss of normal CIL behaviour towards healthy tissue has long been implicated in the invasion of cancer cells. CIL is a multi-step process that is driven by the tight coordination of molecular machinery. In this review, we shall breakdown CIL into distinct steps and highlight the key molecular mechanisms and components that are involved in driving each step of this process.
Topics: Animals; Cadherins; Cell Adhesion; Cell Movement; Cell Polarity; Contact Inhibition; Humans; rho GTP-Binding Proteins
PubMed: 26585026
DOI: 10.1007/s00018-015-2090-0 -
Nature Jul 2013The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years. This is the longest reported lifespan for a...
The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years. This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years. In addition to their longevity, naked mole rats show an unusual resistance to cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of cancer. Here we identify a mechanism responsible for the naked mole rat's cancer resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species.
Topics: Amino Acid Sequence; Animals; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Contact Inhibition; Disease Resistance; Fibroblasts; Glucuronosyltransferase; Guinea Pigs; Humans; Hyaluronan Synthases; Hyaluronic Acid; Mice; Mole Rats; Molecular Sequence Data
PubMed: 23783513
DOI: 10.1038/nature12234