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Full length talin stimulates integrin activation and axon regeneration

Integrin function is regulated by activation involving conformational changes that modulate ligand-binding affinity and downstream signaling. Activation is regulated through inside-out signaling which is controlled by many signaling pathways via a final common pathway through kindlin and talin, whic...

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Autores principales: Tan, Chin Lik, Kwok, Jessica C.F., Heller, Janosch P.D., Zhao, Rongrong, Eva, Richard, Fawcett, James W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Academic Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604251/
https://www.ncbi.nlm.nih.gov/pubmed/25771432
http://dx.doi.org/10.1016/j.mcn.2015.03.011
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author Tan, Chin Lik
Kwok, Jessica C.F.
Heller, Janosch P.D.
Zhao, Rongrong
Eva, Richard
Fawcett, James W.
author_facet Tan, Chin Lik
Kwok, Jessica C.F.
Heller, Janosch P.D.
Zhao, Rongrong
Eva, Richard
Fawcett, James W.
author_sort Tan, Chin Lik
collection PubMed
description Integrin function is regulated by activation involving conformational changes that modulate ligand-binding affinity and downstream signaling. Activation is regulated through inside-out signaling which is controlled by many signaling pathways via a final common pathway through kindlin and talin, which bind to the intracellular tail of beta integrins. Previous studies have shown that the axon growth inhibitory molecules NogoA and chondroitin sulfate proteoglycans (CSPGs) inactivate integrins. Overexpressing kindlin-1 in dorsal root ganglion (DRG) neurons activates integrins, enabling their axons to overcome inhibitory molecules in the environment, and promoting regeneration in vivo following dorsal root crush. Other studies have indicated that expression of the talin head alone or with kindlin can enhance integrin activation. Here, using adult rat DRG neurons, we investigate the effects of overexpressing various forms of talin on axon growth and integrin signaling. We found that overexpression of the talin head activated axonal integrins but inhibited downstream signaling via FAK, and did not promote axon growth. Similarly, co-expression of the talin head and kindlin-1 prevented the growth-promoting effect of kindlin-1, suggesting that the talin head acts as a form of dominant negative for integrin function. Using full-length talin constructs in PC12 cells we observed that neurite growth was enhanced by the expression of wild-type talin and more so by two ‘activated’ forms of talin produced by point mutation (on laminin and aggrecan–laminin substrates). Nevertheless, co-expression of full-length talin with kindlin did not promote neurite growth more than either molecule alone. In vivo, we find that talin is present in PNS axons (sciatic nerve), and also in CNS axons of the corticospinal tract.
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spelling pubmed-46042512015-10-28 Full length talin stimulates integrin activation and axon regeneration Tan, Chin Lik Kwok, Jessica C.F. Heller, Janosch P.D. Zhao, Rongrong Eva, Richard Fawcett, James W. Mol Cell Neurosci Article Integrin function is regulated by activation involving conformational changes that modulate ligand-binding affinity and downstream signaling. Activation is regulated through inside-out signaling which is controlled by many signaling pathways via a final common pathway through kindlin and talin, which bind to the intracellular tail of beta integrins. Previous studies have shown that the axon growth inhibitory molecules NogoA and chondroitin sulfate proteoglycans (CSPGs) inactivate integrins. Overexpressing kindlin-1 in dorsal root ganglion (DRG) neurons activates integrins, enabling their axons to overcome inhibitory molecules in the environment, and promoting regeneration in vivo following dorsal root crush. Other studies have indicated that expression of the talin head alone or with kindlin can enhance integrin activation. Here, using adult rat DRG neurons, we investigate the effects of overexpressing various forms of talin on axon growth and integrin signaling. We found that overexpression of the talin head activated axonal integrins but inhibited downstream signaling via FAK, and did not promote axon growth. Similarly, co-expression of the talin head and kindlin-1 prevented the growth-promoting effect of kindlin-1, suggesting that the talin head acts as a form of dominant negative for integrin function. Using full-length talin constructs in PC12 cells we observed that neurite growth was enhanced by the expression of wild-type talin and more so by two ‘activated’ forms of talin produced by point mutation (on laminin and aggrecan–laminin substrates). Nevertheless, co-expression of full-length talin with kindlin did not promote neurite growth more than either molecule alone. In vivo, we find that talin is present in PNS axons (sciatic nerve), and also in CNS axons of the corticospinal tract. Academic Press 2015-09 /pmc/articles/PMC4604251/ /pubmed/25771432 http://dx.doi.org/10.1016/j.mcn.2015.03.011 Text en © 2015 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tan, Chin Lik
Kwok, Jessica C.F.
Heller, Janosch P.D.
Zhao, Rongrong
Eva, Richard
Fawcett, James W.
Full length talin stimulates integrin activation and axon regeneration
title Full length talin stimulates integrin activation and axon regeneration
title_full Full length talin stimulates integrin activation and axon regeneration
title_fullStr Full length talin stimulates integrin activation and axon regeneration
title_full_unstemmed Full length talin stimulates integrin activation and axon regeneration
title_short Full length talin stimulates integrin activation and axon regeneration
title_sort full length talin stimulates integrin activation and axon regeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604251/
https://www.ncbi.nlm.nih.gov/pubmed/25771432
http://dx.doi.org/10.1016/j.mcn.2015.03.011
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