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PAK Kinases Target Sortilin and Modulate Its Sorting
The multifunctional type 1 receptor sortilin is involved in endocytosis and intracellular transport of ligands. The short intracellular domain of sortilin binds several cytoplasmic adaptor proteins (e.g., the AP-1 complex and GGA1 to -3), most of which target two well-defined motifs: a C-terminal ac...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965034/ https://www.ncbi.nlm.nih.gov/pubmed/31767632 http://dx.doi.org/10.1128/MCB.00411-19 |
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author | Pallesen, Lone Tjener Gustafsen, Camilla Cramer, Jacob Flyvholm Petersen, Steen Vang Thirup, Søren Skou Madsen, Peder Petersen, Claus Munck |
author_facet | Pallesen, Lone Tjener Gustafsen, Camilla Cramer, Jacob Flyvholm Petersen, Steen Vang Thirup, Søren Skou Madsen, Peder Petersen, Claus Munck |
author_sort | Pallesen, Lone Tjener |
collection | PubMed |
description | The multifunctional type 1 receptor sortilin is involved in endocytosis and intracellular transport of ligands. The short intracellular domain of sortilin binds several cytoplasmic adaptor proteins (e.g., the AP-1 complex and GGA1 to -3), most of which target two well-defined motifs: a C-terminal acidic cluster dileucine motif and a YXXΦ motif in the proximal third of the domain. Both motifs contribute to endocytosis as well as Golgi-endosome trafficking of sortilin. The C-terminal acidic cluster harbors a serine residue, which is subject to phosphorylation by casein kinase. Phosphorylation of this serine residue is known to modulate adaptor binding to sortilin. Here, we show that the cytoplasmic domain of sortilin also engages Rac-p21-activated kinases 1 to 3 (PAK1-3) via a binding segment that includes a tyrosine-based motif, also encompassing a serine residue. We further demonstrate that PAK1-3 specifically phosphorylate this serine residue and that this phosphorylation alters the affinity for AP-1 binding and consequently changes the intracellular localization of sortilin as a result of modulated trafficking. Our findings suggest that trafficking of ligands bound to sortilin is in part regulated by group A PAK kinases, which are downstream effectors of Rho GTPases and are known to affect a variety of processes by remodeling the cytoskeleton and by promoting gene transcription and cell survival. |
format | Online Article Text |
id | pubmed-6965034 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-69650342020-02-03 PAK Kinases Target Sortilin and Modulate Its Sorting Pallesen, Lone Tjener Gustafsen, Camilla Cramer, Jacob Flyvholm Petersen, Steen Vang Thirup, Søren Skou Madsen, Peder Petersen, Claus Munck Mol Cell Biol Research Article The multifunctional type 1 receptor sortilin is involved in endocytosis and intracellular transport of ligands. The short intracellular domain of sortilin binds several cytoplasmic adaptor proteins (e.g., the AP-1 complex and GGA1 to -3), most of which target two well-defined motifs: a C-terminal acidic cluster dileucine motif and a YXXΦ motif in the proximal third of the domain. Both motifs contribute to endocytosis as well as Golgi-endosome trafficking of sortilin. The C-terminal acidic cluster harbors a serine residue, which is subject to phosphorylation by casein kinase. Phosphorylation of this serine residue is known to modulate adaptor binding to sortilin. Here, we show that the cytoplasmic domain of sortilin also engages Rac-p21-activated kinases 1 to 3 (PAK1-3) via a binding segment that includes a tyrosine-based motif, also encompassing a serine residue. We further demonstrate that PAK1-3 specifically phosphorylate this serine residue and that this phosphorylation alters the affinity for AP-1 binding and consequently changes the intracellular localization of sortilin as a result of modulated trafficking. Our findings suggest that trafficking of ligands bound to sortilin is in part regulated by group A PAK kinases, which are downstream effectors of Rho GTPases and are known to affect a variety of processes by remodeling the cytoskeleton and by promoting gene transcription and cell survival. American Society for Microbiology 2020-01-16 /pmc/articles/PMC6965034/ /pubmed/31767632 http://dx.doi.org/10.1128/MCB.00411-19 Text en Copyright © 2020 Pallesen et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Pallesen, Lone Tjener Gustafsen, Camilla Cramer, Jacob Flyvholm Petersen, Steen Vang Thirup, Søren Skou Madsen, Peder Petersen, Claus Munck PAK Kinases Target Sortilin and Modulate Its Sorting |
title | PAK Kinases Target Sortilin and Modulate Its Sorting |
title_full | PAK Kinases Target Sortilin and Modulate Its Sorting |
title_fullStr | PAK Kinases Target Sortilin and Modulate Its Sorting |
title_full_unstemmed | PAK Kinases Target Sortilin and Modulate Its Sorting |
title_short | PAK Kinases Target Sortilin and Modulate Its Sorting |
title_sort | pak kinases target sortilin and modulate its sorting |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965034/ https://www.ncbi.nlm.nih.gov/pubmed/31767632 http://dx.doi.org/10.1128/MCB.00411-19 |
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