front–rear polarity Dotaz Zobrazit nápovědu
The establishment of cell polarity is an essential step in the process of cell migration. This process requires precise spatiotemporal coordination of signaling pathways that in most cells create the typical asymmetrical profile of a polarized cell with nucleus located at the cell rear and the microtubule organizing center (MTOC) positioned between the nucleus and the leading edge. During cell polarization, nucleus rearward positioning promotes correct microtubule organizing center localization and thus the establishment of front-rear polarity and directional migration. We found that cell polarization and directional migration require also the reorientation of the nucleus. Nuclear reorientation is manifested as temporally restricted nuclear rotation that aligns the nuclear axis with the axis of cell migration. We also found that nuclear reorientation requires physical connection between the nucleus and cytoskeleton mediated by the LINC (linker of nucleoskeleton and cytoskeleton) complex. Nuclear reorientation is controlled by coordinated activity of lysophosphatidic acid (LPA)-mediated activation of GTPase Rho and the activation of integrin, FAK (focal adhesion kinase), Src, and p190RhoGAP signaling pathway. Integrin signaling is spatially induced at the leading edge as FAK and p190RhoGAP are predominantly activated or localized at this location. We suggest that integrin activation within lamellipodia defines cell front, and subsequent FAK, Src, and p190RhoGAP signaling represents the polarity signal that induces reorientation of the nucleus and thus promotes the establishment of front-rear polarity.
- MeSH
- buněčné jádro metabolismus MeSH
- buněčné linie MeSH
- cytoskeletální proteiny metabolismus MeSH
- fibroblasty cytologie fyziologie MeSH
- krysa rodu Rattus MeSH
- pohyb buněk * MeSH
- polarita buněk * MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cytoskeletální proteiny MeSH
Apico-basal polarity is typical of cells present in differentiated epithelium while front-rear polarity develops in motile cells. In cancer development, the transition from epithelial to migratory polarity may be seen as the hallmark of cancer progression to an invasive and metastatic disease. Despite the morphological and functional dissimilarity, both epithelial and migratory polarity are controlled by a common set of polarity complexes Par, Scribble and Crumbs, phosphoinositides, and small Rho GTPases Rac, Rho and Cdc42. In epithelial tissues, their mutual interplay ensures apico-basal and planar cell polarity. Accordingly, altered functions of these polarity determinants lead to disrupted cell-cell adhesions, cytoskeleton rearrangements and overall loss of epithelial homeostasis. Polarity proteins are further engaged in diverse interactions that promote the establishment of front-rear polarity, and they help cancer cells to adopt different invasion modes. Invading cancer cells can employ either the collective, mesenchymal or amoeboid invasion modes or actively switch between them and gain intermediate phenotypes. Elucidation of the role of polarity proteins during these invasion modes and the associated transitions is a necessary step towards understanding the complex problem of metastasis. In this review we summarize the current knowledge of the role of cell polarity signaling in the plasticity of cancer cell invasiveness.
- Klíčová slova
- AMT, EMT, invasion, plasticity, polarity,
- MeSH
- invazivní růst nádoru patologie MeSH
- lidé MeSH
- nádory patologie MeSH
- polarita buněk fyziologie MeSH
- signální transdukce fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Cells attaching to the extracellular matrix spontaneously acquire front-rear polarity. This self-organization process comprises spatial activation of polarity signaling networks and the establishment of a protruding cell front and a non-protruding cell rear. Cell polarization also involves the reorganization of cell mass, notably the nucleus that is positioned at the cell rear. It remains unclear, however, how these processes are regulated. Here, using coherence-controlled holographic microscopy (CCHM) for non-invasive live-cell quantitative phase imaging (QPI), we examined the role of the focal adhesion kinase (FAK) and its interacting partner Rack1 in dry mass distribution in spreading Rat2 fibroblasts. We found that FAK-depleted cells adopt an elongated, bipolar phenotype with a high central body mass that gradually decreases toward the ends of the elongated processes. Further characterization of spreading cells showed that FAK-depleted cells are incapable of forming a stable rear; rather, they form two distally positioned protruding regions. Continuous protrusions at opposite sides results in an elongated cell shape. In contrast, Rack1-depleted cells are round and large with the cell mass sharply dropping from the nuclear area towards the basal side. We propose that FAK and Rack1 act differently yet coordinately to establish front-rear polarity in spreading cells.
- Klíčová slova
- Rack1, cell adhesion, cell dry mass, cell spreading, coherence-controlled holographic microscopy, extracellular matrix, focal adhesion kinase, front–rear polarity, quantitative phase imaging,
- MeSH
- buněčná adheze genetika fyziologie MeSH
- buněčné linie MeSH
- fibroblasty cytologie metabolismus MeSH
- fokální adhezní tyrosinkinasy genetika metabolismus MeSH
- krysa rodu Rattus MeSH
- mikroskopie fázově kontrastní MeSH
- pohyb buněk genetika fyziologie MeSH
- polarita buněk genetika fyziologie MeSH
- receptory pro aktivovanou kinasu C genetika metabolismus MeSH
- RNA interference MeSH
- tvar buňky genetika fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- fokální adhezní tyrosinkinasy MeSH
- RACK1 protein, rat MeSH Prohlížeč
- receptory pro aktivovanou kinasu C MeSH
In polarized motile cells, stress fibers display specific three-dimensional organization. Ventral stress fibers, attached to focal adhesions at both ends, are restricted to the basal side of the cell and nonprotruding cell sides. Dorsal fibers, transverse actin arcs, and perinuclear actin fibers emanate from protruding cell front toward the nucleus and toward apical side of the cell. Perinuclear cap fibers further extend above the nucleus, associate with nuclear envelope through LINC (linker of nucleoskeleton and cytoskeleton) complex and terminate in focal adhesions at cell rear. How are perinuclear actin fibers formed is poorly understood. We show that the formation of perinuclear actin fibers requires dorsal stress fibers that polymerize from focal adhesions at leading edge, and transverse actin arcs that are interconnected with dorsal fibers in spots rich in α-actinin-1. During cell polarization, the interconnected dorsal fibers and transverse arcs move from leading edge toward dorsal side of the cell. As they move, transverse arcs associate with one end of stress fibers present at nonprotruding cell sides, move them above the nucleus thus forming perinuclear actin fibers. Furthermore, the formation of perinuclear actin fibers induces temporal rotational movement of the nucleus resulting in nuclear reorientation to the direction of migration. These results suggest that the network of dorsal fibers, transverse arcs, and perinuclear fibers transfers mechanical signal between the focal adhesions and nuclear envelope that regulates the nuclear reorientation in polarizing cells.
- Klíčová slova
- actin dorsal fibers, cell polarity, nuclear reorientation, perinuclear actin fibers, transverse arcs, α-actinin-1,
- MeSH
- aktinin fyziologie MeSH
- aktiny fyziologie MeSH
- buněčné jádro fyziologie MeSH
- buněčné linie MeSH
- buněčný převod mechanických signálů fyziologie MeSH
- fibroblasty fyziologie MeSH
- fokální adheze fyziologie MeSH
- kontraktilní svazky fyziologie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- pohyb buněk fyziologie MeSH
- pohyb fyziologie MeSH
- polarita buněk fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- úvodníky MeSH
- Názvy látek
- aktinin MeSH
- aktiny MeSH
The spreading of adhering cells is a morphogenetic process during which cells break spherical or radial symmetry and adopt migratory polarity with spatially segregated protruding cell front and non-protruding cell rear. The organization and regulation of these symmetry-breaking events, which are both complex and stochastic, are not fully understood. Here we show that in radially spreading cells, symmetry breaking commences with the development of discrete non-protruding regions characterized by large but sparse focal adhesions and long peripheral actin bundles. Establishment of this non-protruding static region specifies the distally oriented protruding cell front and thus determines the polarity axis and the direction of cell migration. The development of non-protruding regions requires ERK2 and the ERK pathway scaffold protein RACK1. RACK1 promotes adhesion-mediated activation of ERK2 that in turn inhibits p190A-RhoGAP signaling by reducing the peripheral localization of p190A-RhoGAP. We propose that sustained ERK signaling at the prospective cell rear induces p190A-RhoGAP depletion from the cell periphery resulting in peripheral actin bundles and cell rear formation. Since cell adhesion activates both ERK and p190A-RhoGAP signaling this constitutes a spatially confined incoherent feed-forward signaling circuit.
- Klíčová slova
- ERK, FAK, Feed-forward loop, Polarity, RACK1, p190A-RhoGAP,
- MeSH
- aktiny metabolismus MeSH
- biologické modely MeSH
- buněčná adheze MeSH
- fenotyp MeSH
- fibroblasty cytologie enzymologie metabolismus MeSH
- fokální adhezní tyrosinkinasy metabolismus MeSH
- genový knockdown MeSH
- krysa rodu Rattus MeSH
- MAP kinasový signální systém * MeSH
- mitogenem aktivovaná proteinkinasa 1 metabolismus MeSH
- pohyb buněk MeSH
- proteiny vázající GTP nedostatek metabolismus MeSH
- receptory pro aktivovanou kinasu C MeSH
- represorové proteiny metabolismus MeSH
- tvar buňky MeSH
- umlčování genů MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- aktiny MeSH
- Arhgap35 protein, rat MeSH Prohlížeč
- fokální adhezní tyrosinkinasy MeSH
- mitogenem aktivovaná proteinkinasa 1 MeSH
- proteiny vázající GTP MeSH
- RACK1 protein, rat MeSH Prohlížeč
- receptory pro aktivovanou kinasu C MeSH
- represorové proteiny MeSH
Stress fibers are actin bundles encompassing actin filaments, actin-crosslinking, and actin-associated proteins that represent the major contractile system in the cell. Different types of stress fibers assemble in adherent cells, and they are central to diverse cellular processes including establishment of the cell shape, morphogenesis, cell polarization, and migration. Stress fibers display specific cellular organization and localization, with ventral fibers present at the basal side, and dorsal fibers and transverse actin arcs rising at the cell front from the ventral to the dorsal side and toward the nucleus. Perinuclear actin cap fibers are a specific subtype of stress fibers that rise from the leading edge above the nucleus and terminate at the cell rear forming a dome-like structure. Perinuclear actin cap fibers are fixed at three points: both ends are anchored in focal adhesions, while the central part is physically attached to the nucleus and nuclear lamina through the linker of nucleoskeleton and cytoskeleton (LINC) complex. Here, we discuss recent work that provides new insights into the mechanism of assembly and the function of these actin stress fibers that directly link extracellular matrix and focal adhesions with the nuclear envelope.
- Klíčová slova
- Dorsal fibers, Focal adhesions, LINC, Perinuclear actin cap, Stress fibers, α-Actinin,
- MeSH
- aktin zastřešující proteiny metabolismus MeSH
- buněčné jádro metabolismus MeSH
- buněčný převod mechanických signálů fyziologie MeSH
- fokální adheze fyziologie MeSH
- jaderný obal metabolismus MeSH
- kontraktilní svazky fyziologie MeSH
- lidé MeSH
- pohyb buněk fyziologie MeSH
- polarita buněk fyziologie MeSH
- tvar buňky fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- aktin zastřešující proteiny MeSH
During pancreas development endocrine cells leave the ductal epithelium to form the islets of Langerhans, but the morphogenetic mechanisms are incompletely understood. Here, we identify the Ca2+-independent atypical Synaptotagmin-13 (Syt13) as a key regulator of endocrine cell egression and islet formation. We detect specific upregulation of the Syt13 gene and encoded protein in endocrine precursors and the respective lineage during islet formation. The Syt13 protein is localized to the apical membrane of endocrine precursors and to the front domain of egressing endocrine cells, marking a previously unidentified apical-basal to front-rear repolarization during endocrine precursor cell egression. Knockout of Syt13 impairs endocrine cell egression and skews the α-to-β-cell ratio. Mechanistically, Syt13 is a vesicle trafficking protein, transported via the microtubule cytoskeleton, and interacts with phosphatidylinositol phospholipids for polarized localization. By internalizing a subset of plasma membrane proteins at the front domain, including α6β4 integrins, Syt13 modulates cell-matrix adhesion and allows efficient endocrine cell egression. Altogether, these findings uncover an unexpected role for Syt13 as a morphogenetic driver of endocrinogenesis and islet formation.
- MeSH
- endokrinní buňky * MeSH
- integriny MeSH
- Langerhansovy ostrůvky * MeSH
- morfogeneze MeSH
- pankreas MeSH
- synaptotagminy genetika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- integriny MeSH
- synaptotagminy MeSH