scholarly journals Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival.

1996 ◽  
Vol 134 (2) ◽  
pp. 559-572 ◽  
Author(s):  
J Dowling ◽  
Q C Yu ◽  
E Fuchs
Keyword(s):  
Cell Adhesion ◽  
Cell Survival ◽  
Schwann Cells ◽  
Basal Lamina ◽  
Epidermolysis Bullosa ◽  
Junctional Epidermolysis Bullosa ◽  
Human Disorder ◽  
Stratified Epithelia

The integrin heterodimer alpha 6 beta 4 is expressed in many epithelia and in Schwann cells. In stratified epithelia, alpha 6 beta 4 couple with BPAG1-e and BPAG2 to form hemidesmosomes, attaching externally to laminin and internally to the keratin cytoskeleton. To explore the function of this atypical integrin, and its relation to conventional actin-associated integrins, we targeted the removal of the beta 4 gene in mice. Tissues that express alpha 6 beta 4 are grossly affected. Stratified tissues are devoid of hemidesmosomes, display only a very fragile attachment to the basal lamina, and exhibit signs of degeneration and tissue disorganization. Simple epithelia which express alpha 6 beta 4 are also defective in adherence, even though they do not form hemidesmosomes. In the absence of beta 4, alpha 6 is dramatically downregulated, and other integrins do not appear to compensate for the loss of this heterodimer. These data have important implications for understanding integrin function in cell-substratum adhesion, cell survival and differentiation, and for understanding the role of alpha 6 beta 4 in junctional epidermolysis bullosa, an often lethal human disorder with pathology similar to our mice.

The Regulation of STAT3 and Its Role in the Adhesion and Migration of Chronic Lymphocytic Leukaemia Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4347-4347
Author(s):  
Sarah Brophy ◽  
Fiona M Quinn ◽  
David O'Brien ◽  
Paul Browne ◽  
Elisabeth A. Vandenberghe ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Adhesion ◽  
Cell Survival ◽  
Lymphocytic Leukaemia ◽  
Serine Phosphorylation ◽  
Pre Treatment ◽  
And Migration ◽  
Induced Apoptosis ◽  
Stat3 Inhibition

Abstract The bone marrow and lymph node microenvironments are important in promoting cell proliferation, survival and protection from drug induced apoptosis in chronic lymphocytic leukaemia (CLL). Chemokine networks, such as the CXCR4/CXCL12 axis, in combination with selectins, such as CD62L and integrins allow the migration of CLL cells to these protective niches. The B-cell receptor (BCR) signalling pathway is the most important pathway involved in micro-environmental crosstalk and CLL cell survival. Further, it has been shown to interact with the signal transducer and activator of transcription 3 (STAT3) signalling pathway. The role of the STAT3 in CLL pathogenesis is unclear; however, it is constitutively phosphorylated on serine residue 727 (serine pSTAT3) in CLL cells. Here, we investigate the role of STAT3 in CLL cell survival and migration, using pharmacological inhibition and siRNA knockdown. Phospho-tyrosine and phospho-serine STAT3 were assessed by flow cytometry and western blotting. Apoptosis was assessed by Annexin V/Propidium Iodide staining by flow cytometry. The expression of cell surface markers involved in cell adhesion and homing was determined by multicolour flow cytometry. Stimulation of the BCR using immunoglobulin F(ab´)2 fragments induced tyrosine phosphorylation of STAT3 in CLL cells with unmutated immunoglobulin (IgVH) genes (n=7) but not mutated IgVH genes (n=5). This induced tyrosine phosphorylation was abrogated by pre-treatment with the Janus kinase (JAK) inhibitor Ruxolitinib and the BCR inhibitors Ibrutinib and Idelalisib (p<0.05, n=5). Gene expression studies using Taqman Assays showed BCR stimulation resulted in an upregulation of STAT3 regulated genes in CLL cells with unmutated IgVH genes. Interestingly, stimulation of BCR resulted in a significant increase in CD62L expression, which was inhibited by pre-treatment with Ibrutinib and Ruxolitinib (p<0.05, n=5). STAT3 inhibition was shown to have a divergent effect on CLL cell survival: In patient samples with >70% positive serine pSTAT3 cells, the STAT3 inhibitor cucurbitacin I induced apoptosis with a concurrent downregulation in serine phosphorylation (n=3); while in patient samples with <70% positive serine pSTAT3 cells, treatment with cucurbitacin I resulted in a decrease in apoptosis and a concurrent increase in serine phosphorylation (n=3). The STAT3 inhibitor S3I-201 had a similar effect but the upstream JAK inhibitor Ruxolitinib had no effect on serine phosphorylation and no effect on the apoptosis of CLL cells. In addition, siRNA mediated STAT3 knockdown and treatment with cucurbitacin I and S31-201, resulted in a significant decrease in CD62L positive CLL cells (p<0.0001, n=29). The role of STAT3 in CLL cell adhesion under shear flow conditions was investigated using a microfluidics system including a neMESYS Low Pressure syringe pump system and Human Umbilical Vein Endothelial Cells (HUVEC) coated biochips. Treatment of CLL cells with cucurbitacin I resulted in a significant decrease in adhesion to endothelial cells (p<0.001, n=4). The effect of STAT3 inhibition on the chemotaxis of CLL cells was investigated using Neuroprobe 96-well ChemoTx plates. Treatment with cucurbitacin I resulted in a significant decrease in CLL cells migrated in response to the chemokine CXCL12 compared to control (p=0.0001, n=8). In addition, treatment of CLL cells with CXCL12 resulted in an increase in serine pSTAT3 that was downregulated by pretreatment with cucurbitacin I. This study has shown: 1. Activation of STAT3 by BCR stimulation occurs in poor prognostic unmutated IgVH genes 2. Serine pSTAT3 has a role in cell survival in response to STAT3 inhibition 3. A role for STAT3 in CLL cell adhesion and migration, in particular in the regulation of the expression of CD62L. In conclusion, this study shows a role for the STAT3 pathway in cell survival and CLL cell-microenvironment crosstalk, suggesting therapeutic potential by interfering with the migration and homing of CLL cells to the lymph node and bone marrow microenvironments. Disclosures No relevant conflicts of interest to declare.

scholarly journals Tissue culture observations relevant to the study of axon-Schwann cell interactions during peripheral nerve development and repair

1987 ◽  
Vol 132 (1) ◽  
pp. 21-34 ◽  
Author(s):  
R. P. Bunge
Keyword(s):  
Tissue Culture ◽  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Basal Lamina ◽  
Heparan Sulphate ◽  
Cell Contact ◽  
Myelinated Nerve ◽  
Nerve Development

During peripheral nerve development the Schwann cell population is expanded so that adequate numbers are available for ensheathment of both nonmyelinated and myelinated nerve fibres. As ensheathment of these fibres progresses each axon--Schwann cell unit becomes surrounded by a basal lamina, providing a unique microtubular framework within the peripheral nerve trunk. Tissue culture studies of pure populations of neurones and Schwann cells cultured separately and in combination indicate that a surface component on the axon provides a mitogenic signal to Schwann cells requiring cell-cell contact. Biochemical, electron microscopic and immunocytochemical analyses of these cultures indicate that Schwann cells in contact with axons are able to generate a basal lamina (containing type IV collagen, laminin and heparan sulphate proteoglycan) and fibrous collagen, without the aid of other cells, and that axonal contact is required for deposition of the basal lamina. The role of Schwann cells and the extracellular matrix they synthesize and organize, as well as the role of the other known products of the Schwann cells in the process of peripheral nerve regeneration, are discussed. It is suggested that the large numbers and advantageous position of the Schwann cells, as well as their ability to provide their own surfaces, a basal lamina and multiple secretory products, may account for their extraordinary ability to foster nerve fibre regeneration.

scholarly journals Exploring the Role of Cadherins in Epithelial–Mesenchymal Transition and Mesenchymal–Epithelial Transition-Associated Tumorigenesis

2018 ◽  
Vol 6 (02/03) ◽  
pp. 045-052
Author(s):  
Sandhya Kushwaha ◽  
Deepti Jindal ◽  
Sonia Joshi ◽  
Ashwini P. ◽  
Poorva Tiwari
Keyword(s):  
Cell Adhesion ◽  
Cell Survival ◽  
Adhesion Molecule ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Surrounding Tissue ◽  
Mesenchymal Transition ◽  
Mesenchymal Epithelial Transition ◽  
E Cadherin

AbstractThe malignant tumors develop when tumor cells overcome the cell–cell adhesion and invade the surrounding tissue. The epithelium consists of E-cadherin as the main adhesion molecule, which is mainly implicated in the carcinogenesis as it is frequently lost in the human epithelial tumors. Epithelial–mesenchymal transition (EMT) and its reverse mesenchymal–epithelial transition (MET) have been suggested to play crucial roles in metastatic dissemination of carcinomas. E-cadherin loss may promote invasion, and re-expression may facilitate cell survival within metastatic deposits. The mechanisms underlying such plasticity are unclear. Here, we summarize the role of cadherins in EMT- and MET-associated tumorigenesis by accumulating the experimental evidences that directly supports it.

scholarly journals Axonal regulation of Schwann cell integrin expression suggests a role for alpha 6 beta 4 in myelination.

1993 ◽  
Vol 123 (5) ◽  
pp. 1223-1236 ◽  
Author(s):  
S Einheber ◽  
T A Milner ◽  
F Giancotti ◽  
J L Salzer
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Basal Lamina ◽  
Cell Contact ◽  
Myelin Associated Glycoprotein ◽  
Dorsal Root Ganglia Neurons ◽  
Outer Plasma Membrane

Ensheathment and myelination of axons by Schwann cells in the peripheral nervous system requires contact with a basal lamina. The molecular mechanism(s) by which the basal lamina promotes myelination is not known but is likely to reflect the activity of integrins expressed by Schwann cells. To initiate studies on the role of integrins during myelination, we characterized the expression of two integrin subunits, beta 1 and beta 4, in an in vitro myelination system and compared their expression to that of the glial adhesion molecule, the myelin-associated glycoprotein (MAG). In the absence of neurons, Schwann cells express significant levels of beta 1 but virtually no beta 4 or MAG. When Schwann cells are cocultured with dorsal root ganglia neurons under conditions promoting myelination, expression of beta 4 and MAG increased dramatically in myelinating cells, whereas beta 1 levels remained essentially unchanged. (In general agreement with these findings, during peripheral nerve development in vivo, beta 4 levels also increase during the period of myelination in sharp contrast to beta 1 levels which show a striking decrease.) In cocultures of neurons and Schwann cells, beta 4 and MAG appear to colocalize in nascent myelin sheaths but have distinct distributions in mature sheaths, with beta 4 concentrated in the outer plasma membrane of the Schwann cell and MAG localized to the inner (periaxonal) membrane. Surprisingly, beta 4 is also present at high levels with MAG in Schmidt-Lanterman incisures. Immunoprecipitation studies demonstrated that primary Schwann cells express beta 1 in association with the alpha 1 and alpha 6 subunits, while myelinating Schwann cells express alpha 6 beta 4 and possibly alpha 1 beta 1. beta 4 is also downregulated during Wallerian degeneration in vitro, indicating that its expression requires continuous Schwann cell contact with the axon. These results indicate that axonal contact induces the expression of beta 4 during Schwann cell myelination and suggest that alpha 6 beta 4 is an important mediator of the interactions of myelinating Schwann cells with the basal lamina.

N-cadherin expression in developing, adult and denervated chicken neuromuscular system: accumulations at both the neuromuscular junction and the node of Ranvier

Development ◽  
1994 ◽  
Vol 120 (1) ◽  
pp. 1-11 ◽  
Author(s):  
C. Cifuentes-Diaz ◽  
M. Nicolet ◽  
D. Goudou ◽  
F. Rieger ◽  
R.M. Mege
Keyword(s):  
Neuromuscular Junction ◽  
Schwann Cells ◽  
Basal Lamina ◽  
Cellular Localization ◽  
Node Of Ranvier ◽  
Muscle Fibres ◽  
Neuromuscular System ◽  
Distal Stump ◽  
Denervated Muscle

N-cadherin, a member of the Ca(2+)-dependent cell adhesion molecule family plays essential roles in morphogenesis and histogenesis. N-cadherin has been shown in vitro to promote myoblast fusion and neurite outgrowth. We report here the cellular localization of N-cadherin during development and regeneration of the chick neuromuscular system. N-cadherin was uniformly expressed along the surface of myoblasts and myotubes of E6 limb muscles. Later, as synaptogenesis and secondary myogenesis proceeded, N-cadherin expression was down-regulated and restricted to some large-diameter fibres, then to the areas of contact between few myofibres and subsequently disappeared by embryonic day 17, suggesting that this cadherin may be implicated predominantly in fusion of primary myoblasts and, at lower degree, of secondary myoblasts. The presence of N-cadherin in muscle during the period of nerve trunk ingrowth and its down-regulation after synaptogenesis suggests that this molecule might be implicated in both processes. N-cadherin became accumulated at the neuromuscular junction only a few days after the first synaptic contacts were established and remained at the adult neuromuscular junction, suggesting a role of this molecule in the stabilization of the mature neuromuscular junction. In sciatic nerve, the level of N-cadherin expression remained unchanged from hatching to adult life. N-cadherin was widely distributed on the surface of myelinated fibres and on myelinating Schwann cells: in addition, it was concentrated at the node of Ranvier. At the ultrastructural level, the molecule was detected inside, at the surface and in the basal lamina of Schwann cells and also associated with endoneurial collagen. These observations suggest a role of N-cadherin in the structuring and stabilization of the myelin sheaths. After nerve injury, N-cadherin continued to be expressed by proliferating Schwann cells in the distal stump providing a substratum for regenerating axons. N-cadherin reappeared at the surface of denervated muscle fibres without disappearing from the former synaptic sites. It was detected not only in the sarcoplasm and on sarcolemma of denervated muscle fibres, but also in the basal lamina and in the extracellular matrix. The reexpression of N-cadherin at the surface of denervated muscle fibres suggests a role for this molecule in muscle reinnervation. The presence of N-cadherin in basal lamina and its association with collagen fibres raise questions about the release of N-cadherin in the extracellular space and the existence of a putative heterophilic ligand for N-cadherin.

Role of the Bullous Pemphigoid Antigen 180 (BP180) in the Assembly of Hemidesmosomes and Cell Adhesion—Reexpression of BP180 in Generalized Atrophic Benign Epidermolysis Bullosa Keratinocytes

1998 ◽  
Vol 239 (2) ◽  
pp. 463-476 ◽  
Author(s):  
Luca Borradori ◽  
Stéphane Chavanas ◽  
Roel Q.J. Schaapveld ◽  
Laurent Gagnoux-Palacios ◽  
Jero Calafat ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Bullous Pemphigoid ◽  
Epidermolysis Bullosa ◽  
Bullous Pemphigoid Antigen
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