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Activated Src requires Cadherin-11, Rac, and gp130 for Stat3 activation and survival of mouse Balb/c3T3 fibroblasts

We previously demonstrated that engagement of cadherins, cell to cell adhesion molecules, triggers a dramatic increase in levels and activity of the Rac/Cdc42 small GTPases, which is followed by secretion of IL6 family cytokines and activation of their common receptor, gp130, in an autocrine manner....

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Autores principales: Adan, Hanad, Guy, Stephanie, Arulanandam, Rozanne, Geletu, Mulu, Daniel, Juliet, Raptis, Leda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9576600/
https://www.ncbi.nlm.nih.gov/pubmed/35411090
http://dx.doi.org/10.1038/s41417-022-00462-5
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author Adan, Hanad
Guy, Stephanie
Arulanandam, Rozanne
Geletu, Mulu
Daniel, Juliet
Raptis, Leda
author_facet Adan, Hanad
Guy, Stephanie
Arulanandam, Rozanne
Geletu, Mulu
Daniel, Juliet
Raptis, Leda
author_sort Adan, Hanad
collection PubMed
description We previously demonstrated that engagement of cadherins, cell to cell adhesion molecules, triggers a dramatic increase in levels and activity of the Rac/Cdc42 small GTPases, which is followed by secretion of IL6 family cytokines and activation of their common receptor, gp130, in an autocrine manner. This results in phosphorylation of the Signal Transducer and Activator of Transcription-3 (Stat3) on tyrosine-705, which then dimerizes, migrates to the nucleus, and activates transcription of genes involved in cell division and survival. In the present report we demonstrate that, in mouse Balb/c3T3 fibroblasts, mutationally activated Src(527F) also increases Rac levels, leading to secretion of IL6 family cytokines and gp130 activation, which triggers the Stat3-ptyr705 increase. Interestingly, our results also demonstrate that cadherin-11 is required to preserve gp130 levels for IL6 family signaling. At the same time, however, activated Src(527F) downregulates cadherin-11, in a quantitative manner. As a result, Src(527F) expression to intermediate levels allows sufficient cadherin-11, hence gp130 levels for Stat3 activation, as expected. However, expressed to high levels, Src(527F) eliminates cadherin-11, hence gp130 signaling, thus abolishing Stat3-ptyr705 stimulation. Taken together, these data establish for the first time a loop between Src, cadherin-11, gp130, and Stat3 activation. This fine balance between Src(527F) and cadherin-11 levels which is required for Stat3 activation and cellular survival could have significant therapeutic implications.
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spelling pubmed-95766002022-10-19 Activated Src requires Cadherin-11, Rac, and gp130 for Stat3 activation and survival of mouse Balb/c3T3 fibroblasts Adan, Hanad Guy, Stephanie Arulanandam, Rozanne Geletu, Mulu Daniel, Juliet Raptis, Leda Cancer Gene Ther Article We previously demonstrated that engagement of cadherins, cell to cell adhesion molecules, triggers a dramatic increase in levels and activity of the Rac/Cdc42 small GTPases, which is followed by secretion of IL6 family cytokines and activation of their common receptor, gp130, in an autocrine manner. This results in phosphorylation of the Signal Transducer and Activator of Transcription-3 (Stat3) on tyrosine-705, which then dimerizes, migrates to the nucleus, and activates transcription of genes involved in cell division and survival. In the present report we demonstrate that, in mouse Balb/c3T3 fibroblasts, mutationally activated Src(527F) also increases Rac levels, leading to secretion of IL6 family cytokines and gp130 activation, which triggers the Stat3-ptyr705 increase. Interestingly, our results also demonstrate that cadherin-11 is required to preserve gp130 levels for IL6 family signaling. At the same time, however, activated Src(527F) downregulates cadherin-11, in a quantitative manner. As a result, Src(527F) expression to intermediate levels allows sufficient cadherin-11, hence gp130 levels for Stat3 activation, as expected. However, expressed to high levels, Src(527F) eliminates cadherin-11, hence gp130 signaling, thus abolishing Stat3-ptyr705 stimulation. Taken together, these data establish for the first time a loop between Src, cadherin-11, gp130, and Stat3 activation. This fine balance between Src(527F) and cadherin-11 levels which is required for Stat3 activation and cellular survival could have significant therapeutic implications. Nature Publishing Group US 2022-04-11 2022 /pmc/articles/PMC9576600/ /pubmed/35411090 http://dx.doi.org/10.1038/s41417-022-00462-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Adan, Hanad
Guy, Stephanie
Arulanandam, Rozanne
Geletu, Mulu
Daniel, Juliet
Raptis, Leda
Activated Src requires Cadherin-11, Rac, and gp130 for Stat3 activation and survival of mouse Balb/c3T3 fibroblasts
title Activated Src requires Cadherin-11, Rac, and gp130 for Stat3 activation and survival of mouse Balb/c3T3 fibroblasts
title_full Activated Src requires Cadherin-11, Rac, and gp130 for Stat3 activation and survival of mouse Balb/c3T3 fibroblasts
title_fullStr Activated Src requires Cadherin-11, Rac, and gp130 for Stat3 activation and survival of mouse Balb/c3T3 fibroblasts
title_full_unstemmed Activated Src requires Cadherin-11, Rac, and gp130 for Stat3 activation and survival of mouse Balb/c3T3 fibroblasts
title_short Activated Src requires Cadherin-11, Rac, and gp130 for Stat3 activation and survival of mouse Balb/c3T3 fibroblasts
title_sort activated src requires cadherin-11, rac, and gp130 for stat3 activation and survival of mouse balb/c3t3 fibroblasts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9576600/
https://www.ncbi.nlm.nih.gov/pubmed/35411090
http://dx.doi.org/10.1038/s41417-022-00462-5
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