Oncotarget

Research Papers:

Identification of the PAK4 interactome reveals PAK4 phosphorylation of N-WASP and promotion of Arp2/3-dependent actin polymerization

Miao Zhao, Matthias Spiess, Henrik J. Johansson, Helene Olofsson, Jianjiang Hu, Janne Lehtiö and Staffan Strömblad _

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Oncotarget. 2017; 8:77061-77074. https://doi.org/10.18632/oncotarget.20352

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Abstract

Miao Zhao1, Matthias Spiess1, Henrik J. Johansson2, Helene Olofsson1, Jianjiang Hu1, Janne Lehtiö2 and Staffan Strömblad1

1Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

2Cancer Proteomics Mass Spectrometry, Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden

Correspondence to:

Staffan Strömblad, email: [email protected]

Keywords: p21-activated kinase 4, actin cytoskeleton, protein-protein interaction, mass spectrometry, VCA domain

Received: May 13, 2017    Accepted: July 25, 2017    Published: August 18, 2017

ABSTRACT

p21-activated kinase 4 (PAK4) regulates cell proliferation, apoptosis, cell motility and F-actin remodeling, but the PAK4 interactome has not been systematically analyzed. Here, we comprehensively characterized the human PAK4 interactome by iTRAQ quantitative mass spectrometry of PAK4-immunoprecipitations. Consistent with its multiple reported functions, the PAK4 interactome was enriched in diverse protein networks, including the 14-3-3, proteasome, replication fork, CCT and Arp2/3 complexes. Because PAK4 co-immunoprecipitated most subunits of the Arp2/3 complex, we hypothesized that PAK4 may play a role in Arp2/3 dependent actin regulation. Indeed, we found that PAK4 interacts with and phosphorylates the nucleation promoting factor N-WASP at Ser484/Ser485 and promotes Arp2/3-dependent actin polymerization in vitro. Also, PAK4 ablation in vivo reduced N-WASP Ser484/Ser485 phosphorylation and altered the cellular balance between G- and F-actin as well as the actin organization. By presenting the PAK4 interactome, we here provide a powerful resource for further investigations and as proof of principle, we also indicate a novel mechanism by which PAK4 regulates actin cytoskeleton remodeling.


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