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p70S6K is regulated by focal adhesion kinase and is required for Src-selective autophagy

Here we report that focal adhesion kinase (FAK) is required for optimal signalling to the Akt-p70S6K-S6 pathway in squamous cell carcinoma (SCC) cells. Specifically, in SCCs that are genetically deficient for FAK, there is reduced phosphorylation of Akt, p70S6K and S6, and signalling to Akt-p70S6K-S...

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Autores principales: Sandilands, Emma, Schoenherr, Christina, Frame, Margaret C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508348/
https://www.ncbi.nlm.nih.gov/pubmed/26071201
http://dx.doi.org/10.1016/j.cellsig.2015.05.017
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author Sandilands, Emma
Schoenherr, Christina
Frame, Margaret C.
author_facet Sandilands, Emma
Schoenherr, Christina
Frame, Margaret C.
author_sort Sandilands, Emma
collection PubMed
description Here we report that focal adhesion kinase (FAK) is required for optimal signalling to the Akt-p70S6K-S6 pathway in squamous cell carcinoma (SCC) cells. Specifically, in SCCs that are genetically deficient for FAK, there is reduced phosphorylation of Akt, p70S6K and S6, and signalling to Akt-p70S6K-S6 is more sensitive to inhibition by multiple agents that suppress the pathway. By contrast, mTOR is unaffected. Indeed, pharmacological agents that inhibit the Akt-p70S6K-S6 pathway, and PDK1 that lies upstream of Akt, also impair the autophagic targeting of activated c-Src (p-Src) in FAK deficient cells. This is associated with loss of a complex between p-Src and the autophagy protein LC3, a biochemical surrogate of impaired Src-selective autophagy. In keeping with a vital role for p70S6K, inhibition by a selective inhibitor and specific siRNA also impaired Src-selective autophagy. Finally, components of the PDK1-Akt-p70S6K signalling pathway were co-located with p-Src at autophagosomes, and Src and p70S6K co-exist in the same biochemical complex. We therefore deduce that the FAK-regulated signalling module PDK1-Akt-p70S6K that controls Src's intracellular trafficking operates at Src-containing autophagosomes.
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spelling pubmed-45083482015-09-01 p70S6K is regulated by focal adhesion kinase and is required for Src-selective autophagy Sandilands, Emma Schoenherr, Christina Frame, Margaret C. Cell Signal Article Here we report that focal adhesion kinase (FAK) is required for optimal signalling to the Akt-p70S6K-S6 pathway in squamous cell carcinoma (SCC) cells. Specifically, in SCCs that are genetically deficient for FAK, there is reduced phosphorylation of Akt, p70S6K and S6, and signalling to Akt-p70S6K-S6 is more sensitive to inhibition by multiple agents that suppress the pathway. By contrast, mTOR is unaffected. Indeed, pharmacological agents that inhibit the Akt-p70S6K-S6 pathway, and PDK1 that lies upstream of Akt, also impair the autophagic targeting of activated c-Src (p-Src) in FAK deficient cells. This is associated with loss of a complex between p-Src and the autophagy protein LC3, a biochemical surrogate of impaired Src-selective autophagy. In keeping with a vital role for p70S6K, inhibition by a selective inhibitor and specific siRNA also impaired Src-selective autophagy. Finally, components of the PDK1-Akt-p70S6K signalling pathway were co-located with p-Src at autophagosomes, and Src and p70S6K co-exist in the same biochemical complex. We therefore deduce that the FAK-regulated signalling module PDK1-Akt-p70S6K that controls Src's intracellular trafficking operates at Src-containing autophagosomes. Elsevier Science Ltd 2015-09 /pmc/articles/PMC4508348/ /pubmed/26071201 http://dx.doi.org/10.1016/j.cellsig.2015.05.017 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
Sandilands, Emma
Schoenherr, Christina
Frame, Margaret C.
p70S6K is regulated by focal adhesion kinase and is required for Src-selective autophagy
title p70S6K is regulated by focal adhesion kinase and is required for Src-selective autophagy
title_full p70S6K is regulated by focal adhesion kinase and is required for Src-selective autophagy
title_fullStr p70S6K is regulated by focal adhesion kinase and is required for Src-selective autophagy
title_full_unstemmed p70S6K is regulated by focal adhesion kinase and is required for Src-selective autophagy
title_short p70S6K is regulated by focal adhesion kinase and is required for Src-selective autophagy
title_sort p70s6k is regulated by focal adhesion kinase and is required for src-selective autophagy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508348/
https://www.ncbi.nlm.nih.gov/pubmed/26071201
http://dx.doi.org/10.1016/j.cellsig.2015.05.017
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