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Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells
The protein kinases PAK4, PAK5 and PAK6 comprise a family of ohnologues. In multiple cancers including melanomas PAK5 most frequently carries non-synonymous mutations; PAK6 and PAK4 have fewer; and PAK4 is often amplified. To help interpret these genomic data, initially we compared the cellular regu...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9444074/ https://www.ncbi.nlm.nih.gov/pubmed/35969127 http://dx.doi.org/10.1042/BCJ20220184 |
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author | Murugesan, Gavuthami Prescott, Alan R. Toth, Rachel Campbell, David G. Wells, Claire M. MacKintosh, Carol |
author_facet | Murugesan, Gavuthami Prescott, Alan R. Toth, Rachel Campbell, David G. Wells, Claire M. MacKintosh, Carol |
author_sort | Murugesan, Gavuthami |
collection | PubMed |
description | The protein kinases PAK4, PAK5 and PAK6 comprise a family of ohnologues. In multiple cancers including melanomas PAK5 most frequently carries non-synonymous mutations; PAK6 and PAK4 have fewer; and PAK4 is often amplified. To help interpret these genomic data, initially we compared the cellular regulation of the sister kinases and their roles in melanoma cells. In common with many ohnologue protein kinases, PAK4, PAK5 and PAK6 each have two 14-3-3-binding phosphosites of which phosphoSer99 is conserved. PAK4 localises to the leading edge of cells in response to phorbol ester-stimulated binding of 14-3-3 to phosphoSer99 and phosphoSer181, which are phosphorylated by two different PKCs or PKDs. These phosphorylations of PAK4 are essential for its phorbol ester-stimulated phosphorylation of downstream substrates. In contrast, 14-3-3 interacts with PAK5 in response to phorbol ester-stimulated phosphorylation of Ser99 and epidermal growth factor-stimulated phosphorylation of Ser288; whereas PAK6 docks onto 14-3-3 and is prevented from localising to cell–cell junctions when Ser133 is phosphorylated in response to cAMP-elevating agents via PKA and insulin-like growth factor 1 via PKB/Akt. Silencing of PAK4 impairs viability, migration and invasive behaviour of melanoma cells carrying BRAF(V600E) or NRAS(Q61K) mutations. These defects are rescued by ectopic expression of PAK4, more so by a 14-3-3-binding deficient PAK4, and barely by PAK5 or PAK6. Together these genomic, biochemical and cellular data suggest that the oncogenic properties of PAK4 are regulated by PKC–PKD signalling in melanoma, while PAK5 and PAK6 are dispensable in this cancer. |
format | Online Article Text |
id | pubmed-9444074 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94440742022-09-07 Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells Murugesan, Gavuthami Prescott, Alan R. Toth, Rachel Campbell, David G. Wells, Claire M. MacKintosh, Carol Biochem J Cancer The protein kinases PAK4, PAK5 and PAK6 comprise a family of ohnologues. In multiple cancers including melanomas PAK5 most frequently carries non-synonymous mutations; PAK6 and PAK4 have fewer; and PAK4 is often amplified. To help interpret these genomic data, initially we compared the cellular regulation of the sister kinases and their roles in melanoma cells. In common with many ohnologue protein kinases, PAK4, PAK5 and PAK6 each have two 14-3-3-binding phosphosites of which phosphoSer99 is conserved. PAK4 localises to the leading edge of cells in response to phorbol ester-stimulated binding of 14-3-3 to phosphoSer99 and phosphoSer181, which are phosphorylated by two different PKCs or PKDs. These phosphorylations of PAK4 are essential for its phorbol ester-stimulated phosphorylation of downstream substrates. In contrast, 14-3-3 interacts with PAK5 in response to phorbol ester-stimulated phosphorylation of Ser99 and epidermal growth factor-stimulated phosphorylation of Ser288; whereas PAK6 docks onto 14-3-3 and is prevented from localising to cell–cell junctions when Ser133 is phosphorylated in response to cAMP-elevating agents via PKA and insulin-like growth factor 1 via PKB/Akt. Silencing of PAK4 impairs viability, migration and invasive behaviour of melanoma cells carrying BRAF(V600E) or NRAS(Q61K) mutations. These defects are rescued by ectopic expression of PAK4, more so by a 14-3-3-binding deficient PAK4, and barely by PAK5 or PAK6. Together these genomic, biochemical and cellular data suggest that the oncogenic properties of PAK4 are regulated by PKC–PKD signalling in melanoma, while PAK5 and PAK6 are dispensable in this cancer. Portland Press Ltd. 2022-08-31 /pmc/articles/PMC9444074/ /pubmed/35969127 http://dx.doi.org/10.1042/BCJ20220184 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . Open access for this article was enabled by the participation of University of Dundee in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with JISC. |
spellingShingle | Cancer Murugesan, Gavuthami Prescott, Alan R. Toth, Rachel Campbell, David G. Wells, Claire M. MacKintosh, Carol Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells |
title | Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells |
title_full | Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells |
title_fullStr | Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells |
title_full_unstemmed | Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells |
title_short | Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells |
title_sort | differential roles and regulation of the protein kinases pak4, pak5 and pak6 in melanoma cells |
topic | Cancer |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9444074/ https://www.ncbi.nlm.nih.gov/pubmed/35969127 http://dx.doi.org/10.1042/BCJ20220184 |
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