scholarly journals Regulation of Rap1 activity by RapGAP1 controls cell adhesion at the front of chemotaxing cells

2007 ◽  
Vol 179 (5) ◽  
pp. 833-843 ◽  
Author(s):  
Taeck J. Jeon ◽  
Dai-Jen Lee ◽  
Susan Lee ◽  
Gerald Weeks ◽  
Richard A. Firtel
Keyword(s):  
Cell Adhesion ◽  
Cell Attachment ◽  
Leading Edge ◽  
Cell Cortex ◽  
Temporal Regulation ◽  
Attachment Sites ◽  
Edge Defects ◽  
Mediate Cell ◽  
Guanosine Triphosphatase ◽  
Rap1 Activation

Spatial and temporal regulation of Rap1 is required for proper myosin assembly and cell adhesion during cell migration in Dictyostelium discoideum. Here, we identify a Rap1 guanosine triphosphatase–activating protein (GAP; RapGAP1) that helps mediate cell adhesion by negatively regulating Rap1 at the leading edge. Defects in spatial regulation of the cell attachment at the leading edge in rapGAP1− (null) cells or cells overexpressing RapGAP1 (RapGAP1OE) lead to defective chemotaxis. rapGAP1− cells have extended chemoattractant-mediated Rap1 activation kinetics and decreased MyoII assembly, whereas RapGAP1OE cells show reciprocal phenotypes. We see that RapGAP1 translocates to the cell cortex in response to chemoattractant stimulation and localizes to the leading edge of chemotaxing cells via an F-actin–dependent pathway. RapGAP1 localization is negatively regulated by Ctx, an F-actin bundling protein that functions during cytokinesis. Loss of Ctx leads to constitutive and uniform RapGAP1 cortical localization. We suggest that RapGAP1 functions in the spatial and temporal regulation of attachment sites through MyoII assembly via regulation of Rap1–guanosine triphosphate.

The mechanics of single cross-links which mediate cell attachment at a hydrogel surface

Nanoscale ◽  
2019 ◽  
Vol 11 (24) ◽  
pp. 11596-11604 ◽  
Author(s):  
Arzu Çolak ◽  
Bin Li ◽  
Johanna Blass ◽  
Kaloian Koynov ◽  
Aranzazu del Campo ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Cell Adhesion ◽  
Cell Attachment ◽  
Force Spectroscopy ◽  
Single Cross ◽  
Mediate Cell Adhesion ◽  
Cross Links ◽  
Hydrogel Surface ◽  
Mediate Cell

The mechanical properties of single cross-links which mediate cell adhesion are explored by force spectroscopy.

scholarly journals CD13 tethers the IQGAP1-ARF6-EFA6 complex to the plasma membrane to promote ARF6 activation, β1 integrin recycling, and cell migration

2019 ◽  
Vol 12 (579) ◽  
pp. eaav5938 ◽  
Author(s):  
Mallika Ghosh ◽  
Robin Lo ◽  
Ivan Ivic ◽  
Brian Aguilera ◽  
Veneta Qendro ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Attachment ◽  
Leading Edge ◽  
Small Gtpase ◽  
Β1 Integrin ◽  
Recycling Endosomes ◽  
Cellular Processes ◽  
Early Endosomes

Cell attachment to the extracellular matrix (ECM) requires a balance between integrin internalization and recycling to the surface that is mediated by numerous proteins, emphasizing the complexity of these processes. Upon ligand binding in various cells, the β1 integrin is internalized, traffics to early endosomes, and is returned to the plasma membrane through recycling endosomes. This trafficking process depends on the cyclical activation and inactivation of small guanosine triphosphatases (GTPases) by their specific guanine exchange factors (GEFs) and their GTPase-activating proteins (GAPs). In this study, we found that the cell surface antigen CD13, a multifunctional transmembrane molecule that regulates cell-cell adhesion and receptor-mediated endocytosis, also promoted cell migration and colocalized with β1 integrin at sites of cell adhesion and at the leading edge. A lack of CD13 resulted in aberrant trafficking of internalized β1 integrin to late endosomes and its ultimate degradation. Our data indicate that CD13 promoted ARF6 GTPase activity by positioning the ARF6-GEF EFA6 at the cell membrane. In migrating cells, a complex containing phosphorylated CD13, IQGAP1, GTP-bound (active) ARF6, and EFA6 at the leading edge promoted the ARF6 GTPase cycling and cell migration. Together, our findings uncover a role for CD13 in the fundamental cellular processes of receptor recycling, regulation of small GTPase activities, cell-ECM interactions, and cell migration.

scholarly journals CYK4 inhibits Rac1-dependent PAK1 and ARHGEF7 effector pathways during cytokinesis

2012 ◽  
Vol 198 (5) ◽  
pp. 865-880 ◽  
Author(s):  
Ricardo Nunes Bastos ◽  
Xenia Penate ◽  
Michelle Bates ◽  
Dean Hammond ◽  
Francis A. Barr
Keyword(s):  
Cell Adhesion ◽  
Mitotic Exit ◽  
Effector Proteins ◽  
Cell Cortex ◽  
Animal Cells ◽  
Rac1 Activity ◽  
Specific Effector ◽  
P21 Activated Kinase ◽  
Guanosine Triphosphatase ◽  
Effector Pathways

In mitosis, animal cells lose their adhesion to the surrounding surfaces and become rounded. During mitotic exit, they reestablish these adhesions and at the same time physically contract and divide. How these competing processes are spatially segregated at the cell cortex remains mysterious. To address this question, we define the specific effector pathways used by RhoA and Rac1 in mitotic cells. We demonstrate that the MKlp1–CYK4 centralspindlin complex is a guanosine triphosphatase–activating protein (GAP) for Rac1 and not RhoA and that CYK4 negatively regulated Rac1 activity at the cell equator in anaphase. Cells expressing a CYK4 GAP mutant had defects in cytokinesis and showed elevated staining for the cell adhesion marker vinculin. These defects could be rescued by depletion of ARHGEF7 and p21-activated kinase, Rac1-specific effector proteins required for cell adhesion. Based on these findings, we propose that CYK4 GAP activity is required during anaphase to inhibit Rac1-dependent effector pathways associated with control of cell spreading and adhesion.

scholarly journals Functionally distinct laminin receptors mediate cell adhesion and spreading: the requirement for surface galactosyltransferase in cell spreading.

1988 ◽  
Vol 107 (5) ◽  
pp. 1863-1871 ◽  
Author(s):  
R B Runyan ◽  
J Versalovic ◽  
B D Shur
Keyword(s):  
Cell Adhesion ◽  
Cell Surface ◽  
Molecular Mechanisms ◽  
Cell Attachment ◽  
Cell Spreading ◽  
Biological Properties ◽  
Initial Cell ◽  
Laminin Receptors ◽  
Mediate Cell ◽  
A Chain

The molecular mechanisms underlying cell attachment and subsequent cell spreading on laminin are shown to be distinct form one another. Cell spreading is dependent upon the binding of cell surface galactosyltransferase (GalTase) to laminin oligosaccharides, while initial cell attachment to laminin occurs independent of GalTase activity. Anti-GalTase IgG, as well as the GalTase modifier protein, alpha-lactalbumin, both block GalTase activity and inhibited B16-F10 melanoma cell spreading on laminin, but not initial attachment. On the other hand, the addition of UDP galactose, which increases the catalytic turnover of GalTase, slightly increased cell spreading. None of these reagents had any effect on cell spreading on fibronectin. When GalTase substrates within laminin were either blocked by affinity-purified GalTase or eliminated by prior galactosylation, cell attachment appeared normal, but subsequent cell spreading was totally inhibited. The laminin substrate for GalTase was identified as N-linked oligosaccharides primarily on the A chain, and to a lesser extent on B chains. That N-linked oligosaccharides are necessary for cell spreading was shown by the inability of cells to spread on laminin surfaces pretreated with N-glycanase, even though cell attachment was normal. Cell surface GalTase was distinguished from other reported laminin binding proteins, most notably the 68-kD receptor, since they were differentially eluted from laminin affinity columns. These data show that surface GalTase does not participate during initial cell adhesion to laminin, but mediates subsequent cell spreading by binding to its appropriate N-linked oligosaccharide substrate. These results also emphasize that some of laminin's biological properties can be attributed to its oligosaccharide residues.

scholarly journals Folliculin Haploinsufficiency Causes Cellular Dysfunction of Pleural Mesothelial Cells

2021 ◽  
Author(s):  
Shouichi Okamoto ◽  
Hiroki Ebana ◽  
Masatoshi Kurihara ◽  
Keiko Mitani ◽  
Etsuko Kobayashi ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Spontaneous Pneumothorax ◽  
Cell Attachment ◽  
Leading Edge ◽  
Cellular Function ◽  
Mesothelial Cells ◽  
Gene Set Enrichment Analysis ◽  
Lung Cysts ◽  
Pleural Mesothelial Cells ◽  
E Cadherin

Abstract Birt–Hogg–Dubé syndrome (BHDS), an autosomal dominant inheritance disease caused by folliculin (FLCN) mutations, is associated with lung cysts and spontaneous pneumothorax. The possibility of FLCN haploinsufficiency in pleural mesothelial cells (PMCs) contributing to development of pneumothorax has not yet been clarified. Electron microscopy revealed exposed intercellular boundaries between PMCs on visceral pleura and decreased electron density around the adherens junctions in BHDS. To characterize cellular function of PMCs in BHDS patients (BHDS-PMCs), during surgery for pneumothorax, we established the flow cytometry-based methods of isolating high-purity PMCs from pleural lavage fluid. BHDS-PMCs showed impaired cell attachment and a significant decrease in proliferation and migration, but a significant increase in apoptosis compared with PMCs from primary spontaneous pneumothorax (PSP) patients (PSP-PMCs). Microarray analysis using isolated PMCs revealed a significant alteration in the expression of genes belonging to Gene Ontology terms “cell-cell adhesion junction” and “cell adhesion molecule binding”. Gene set enrichment analysis demonstrated that CDH1, encoding E-cadherin, was identified in the down-regulated leading edge of a plot in BHDS-PMCs. AMPK and LKB1 activation were significantly impaired in BHDS-PMCs compared with PSP-PMCs. Our findings indicate that FLCN haploinsufficiency may affect the E-cadherin-LKB1-AMPK axis and lead to abnormal cellular function in BHDS-PMCs.

Role of Rap1 in promoting sickle red blood cell adhesion to laminin via BCAM/LU

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3322-3329 ◽  
Author(s):  
Meghan M. Murphy ◽  
Mohamed A. Zayed ◽  
Allyson Evans ◽  
Carol E. Parker ◽  
Kenneth I. Ataga ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Signaling Pathway ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Guanosine Triphosphatase ◽  
Rap1 Activation ◽  
Cell Adhesion Molecule 1

Abstract Vaso-occlusion is a hallmark of sickle cell disease. Agonist-induced activation of sickle red blood cells (SS RBCs) promotes their adhesion to vascular proteins, potentially contributing to vasoocclusion. Previously, we described a cyclic adenosine monophosphate (cAMP)-dependent increase in SS RBC adhesion to laminin. Here, we investigated whether Rap1, a small guanosine triphosphatase (GTPase) known to promote integrin-mediated adhesion in other cells, was involved in this signaling pathway. We found that agonists known to induce cAMP signaling promoted the GTP-bound, active state of Rap1 in SS RBCs. The cAMP-dependent exchange factor Epac (exchange protein directly activated by cAMP) is a likely upstream activator of Rap1, since Epac is present in these cells and the Epac-specific cAMP analog 8CPT-2-Me (8-(4-cholorophenylthio)-2′-O-methyl-cAMP) activated Rap1 and promoted SS RBC adhesion to laminin. This 8CPT-2-Me-stimulated adhesion was integrin independent, since it was insensitive to RGD peptide or antibodies against the only known integrin on SS RBCs, α4β1. However, this adhesion was completely inhibited by either a soluble version of basal cell adhesion molecule/Lutheran (BCAM/LU) or a BCAM/LU adhesion-blocking anti-body. Surprisingly, 8CPT-2-Me-activated Rap1 did not promote SS RBC adhesion to a known α4β1 ligand, vascular cell adhesion molecule 1 (VCAM-1). These results demonstrate that Epac-induced Rap1 activation in SS RBCs promotes BCAM/LU-mediated adhesion to laminin. Thus, Epac-mediated Rap1 activation may represent an important signaling pathway for promoting SS RBC adhesion. (Blood. 2005;105:3322-3329)

scholarly journals Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shouichi Okamoto ◽  
Hiroki Ebana ◽  
Masatoshi Kurihara ◽  
Keiko Mitani ◽  
Etsuko Kobayashi ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Spontaneous Pneumothorax ◽  
Cell Attachment ◽  
Leading Edge ◽  
Cellular Function ◽  
Mesothelial Cells ◽  
Gene Set Enrichment Analysis ◽  
Lung Cysts ◽  
Pleural Mesothelial Cells ◽  
E Cadherin

AbstractBirt–Hogg–Dubé syndrome (BHDS), an autosomal dominant inheritance disease caused by folliculin (FLCN) mutations, is associated with lung cysts and spontaneous pneumothorax. The possibility of FLCN haploinsufficiency in pleural mesothelial cells (PMCs) contributing to development of pneumothorax has not yet been clarified. Electron microscopy revealed exposed intercellular boundaries between PMCs on visceral pleura and decreased electron density around the adherens junctions in BHDS. To characterize cellular function of PMCs in BHDS patients (BHDS-PMCs), during surgery for pneumothorax, we established the flow cytometry-based methods of isolating high-purity PMCs from pleural lavage fluid. BHDS-PMCs showed impaired cell attachment and a significant decrease in proliferation and migration, but a significant increase in apoptosis compared with PMCs from primary spontaneous pneumothorax (PSP) patients (PSP-PMCs). Microarray analysis using isolated PMCs revealed a significant alteration in the expression of genes belonging to Gene Ontology terms “cell–cell adhesion junction” and “cell adhesion molecule binding”. Gene set enrichment analysis demonstrated that CDH1, encoding E-cadherin, was identified in the down-regulated leading edge of a plot in BHDS-PMCs. AMPK and LKB1 activation were significantly impaired in BHDS-PMCs compared with PSP-PMCs. Our findings indicate that FLCN haploinsufficiency may affect the E-cadherin-LKB1-AMPK axis and lead to abnormal cellular function in BHDS-PMCs.

scholarly journals Differentiation of primitive human multipotent hematopoietic progenitors into single lineage clonogenic progenitors is accompanied by alterations in their interaction with fibronectin.

1991 ◽  
Vol 174 (3) ◽  
pp. 693-703 ◽  
Author(s):  
C M Verfaillie ◽  
J B McCarthy ◽  
P B McGlave
Keyword(s):  
Bone Marrow ◽  
Cell Adhesion ◽  
Cell Attachment ◽  
Bone Marrow Stroma ◽  
Heparin Binding ◽  
Hematopoietic Progenitors ◽  
Adhesive Interaction ◽  
Attachment Sites ◽  
Dependent Cell ◽  
Marrow Stroma

We have previously demonstrated that primitive progenitors from human bone marrow termed long term bone marrow culture initiating cells (LTBMC-IC) adhere avidly to irradiated bone marrow stroma, while more mature clonogenic progenitors fail to do so. In this study we examine the interaction between these progenitors and components of the bone marrow stroma. (a) We demonstrate that both primitive LTBMC-IC and more mature clonogenic progenitors adhere to intact fibronectin. (b) Primitive LTBMC-IC and multi-lineage CFU-MIX progenitors adhere to the 33/66 kD COOH-terminal heparin-binding cell-adhesion promoting fragment of fibronectin, but adhere significantly less to its 75 kD RGDS-dependent cell-binding fragment. In contrast, more differentiated single-lineage progenitors adhere equally well to the 33/66 kD RGDS independent and the 75 kD RGDS-dependent cell-adhesion fragments of fibronectin. (c) Both primitive LTBMC-IC and clonogenic progenitors adhere to the three known cell-attachment sites in the 33/66 kD cell-adhesion promoting fragment, FN-C/H I, FN-C/H II and CS1. However, LTBMC-IC and CFU-MIX progenitors adhere significantly better to FN-C/H II than to the flanking FN-C/H I and CS1 cell-attachment sites. In contrast, single-lineage progenitors adhere equally well to all three cell attachment sites in the 33/66 kD cell-adhesion promoting fragment. (d) Finally, adhesion of primitive LTBMC-IC to intact irradiated stroma can be inhibited partially by peptide FN-C/H II and almost completely by a combination of FN-C/H II and peptide FN-C/H I and CS1. This study demonstrates that adhesive interactions between primitive hematopoietic progenitors and the extracellular matrix component fibronectin can occur. Specific changes in adhesion to the 33/66 kD cell-adhesion promoting fragment and the 75 kD RGDS-dependent cell-adhesion fragment of fibronectin are associated with differentiation of primitive multi-lineage progenitors into committed single-lineage progenitors. Such differences in adhesive interaction with fibronectin may allow hematopoietic progenitors at various stages of differentiation to interact with specific supportive loci of the bone marrow microenvironment. Finally, the ability to block adhesion of LTBMC-IC to intact irradiated stroma with peptides FN-C/H II, FN-C/H I and CS1 suggests that receptors responsible for this interaction may be important in the homing of primitive progenitors to the bone marrow.

scholarly journals Integrins: An Important Link between Angiogenesis, Inflammation and Eye Diseases

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1703
Author(s):  
Małgorzata Mrugacz ◽  
Anna Bryl ◽  
Mariusz Falkowski ◽  
Katarzyna Zorena
Keyword(s):  
Cell Adhesion ◽  
Tissue Repair ◽  
Normal Development ◽  
Cell Attachment ◽  
Biological Activities ◽  
Integrin Receptors ◽  
Cytokine Activation ◽  
Eye Disorders ◽  
Membrane Bound ◽  
Cell To Cell Adhesion

Integrins belong to a group of cell adhesion molecules (CAMs) which is a large group of membrane-bound proteins. They are responsible for cell attachment to the extracellular matrix (ECM) and signal transduction from the ECM to the cells. Integrins take part in many other biological activities, such as extravasation, cell-to-cell adhesion, migration, cytokine activation and release, and act as receptors for some viruses, including severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). They play a pivotal role in cell proliferation, migration, apoptosis, tissue repair and are involved in the processes that are crucial to infection, inflammation and angiogenesis. Integrins have an important part in normal development and tissue homeostasis, and also in the development of pathological processes in the eye. This review presents the available evidence from human and animal research into integrin structure, classification, function and their role in inflammation, infection and angiogenesis in ocular diseases. Integrin receptors and ligands are clinically interesting and may be promising as new therapeutic targets in the treatment of some eye disorders.

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