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PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration
It has been reported that p21-activated kinase 4 (PAK4) is amplified in pancreatic cancer tissue. PAK4 is a member of the PAK family of serine/threonine kinases, which act as effectors for several small GTPases, and has been specifically identified to function downstream of HGF-mediated c-Met activa...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312077/ https://www.ncbi.nlm.nih.gov/pubmed/28205613 http://dx.doi.org/10.1038/srep42575 |
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author | King, Helen Thillai, Kiruthikah Whale, Andrew Arumugam, Prabhu Eldaly, Hesham Kocher, Hemant M. Wells, Claire M. |
author_facet | King, Helen Thillai, Kiruthikah Whale, Andrew Arumugam, Prabhu Eldaly, Hesham Kocher, Hemant M. Wells, Claire M. |
author_sort | King, Helen |
collection | PubMed |
description | It has been reported that p21-activated kinase 4 (PAK4) is amplified in pancreatic cancer tissue. PAK4 is a member of the PAK family of serine/threonine kinases, which act as effectors for several small GTPases, and has been specifically identified to function downstream of HGF-mediated c-Met activation in a PI3K dependent manner. However, the functionality of PAK4 in pancreatic cancer and the contribution made by HGF signalling to pancreatic cancer cell motility remain to be elucidated. We now find that elevated PAK4 expression is coincident with increased expression levels of c-Met and the p85α subunit of PI3K. Furthermore, we demonstrate that pancreatic cancer cells have a specific motility response to HGF both in 2D and 3D physiomimetic organotypic assays; which can be suppressed by inhibition of PI3K. Significantly, we report a specific interaction between PAK4 and p85α and find that PAK4 deficient cells exhibit a reduction in Akt phosphorylation downstream of HGF signalling. These results implicate a novel role for PAK4 within the PI3K pathway via interaction with p85α. Thus, PAK4 could be an essential player in PDAC progression representing an interesting therapeutic opportunity. |
format | Online Article Text |
id | pubmed-5312077 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53120772017-02-23 PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration King, Helen Thillai, Kiruthikah Whale, Andrew Arumugam, Prabhu Eldaly, Hesham Kocher, Hemant M. Wells, Claire M. Sci Rep Article It has been reported that p21-activated kinase 4 (PAK4) is amplified in pancreatic cancer tissue. PAK4 is a member of the PAK family of serine/threonine kinases, which act as effectors for several small GTPases, and has been specifically identified to function downstream of HGF-mediated c-Met activation in a PI3K dependent manner. However, the functionality of PAK4 in pancreatic cancer and the contribution made by HGF signalling to pancreatic cancer cell motility remain to be elucidated. We now find that elevated PAK4 expression is coincident with increased expression levels of c-Met and the p85α subunit of PI3K. Furthermore, we demonstrate that pancreatic cancer cells have a specific motility response to HGF both in 2D and 3D physiomimetic organotypic assays; which can be suppressed by inhibition of PI3K. Significantly, we report a specific interaction between PAK4 and p85α and find that PAK4 deficient cells exhibit a reduction in Akt phosphorylation downstream of HGF signalling. These results implicate a novel role for PAK4 within the PI3K pathway via interaction with p85α. Thus, PAK4 could be an essential player in PDAC progression representing an interesting therapeutic opportunity. Nature Publishing Group 2017-02-16 /pmc/articles/PMC5312077/ /pubmed/28205613 http://dx.doi.org/10.1038/srep42575 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article King, Helen Thillai, Kiruthikah Whale, Andrew Arumugam, Prabhu Eldaly, Hesham Kocher, Hemant M. Wells, Claire M. PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration |
title | PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration |
title_full | PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration |
title_fullStr | PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration |
title_full_unstemmed | PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration |
title_short | PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration |
title_sort | pak4 interacts with p85 alpha: implications for pancreatic cancer cell migration |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312077/ https://www.ncbi.nlm.nih.gov/pubmed/28205613 http://dx.doi.org/10.1038/srep42575 |
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