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The kinase-inhibitory domain of p21-activated kinase 1 (PAK1) inhibits cell cycle progression independent of PAK1 kinase activity

Oncogene volume 26, pages 1820–1828 (2007)Cite this article

Abstract

p21-activated kinase 1 (PAK1) is a mediator of downstream signaling from the small GTPases Rac and Cdc42. In its inactive state, PAK1 forms a homodimer where two kinases inhibit each other in trans. The kinase inhibitory domain (KID) of one molecule of PAK1 binds to the kinase domain of its counterpart and keeps it inactive. Therefore, the isolated KID of PAK1 has been widely used to specifically inhibit and study PAK function. Here, we show that the isolated KID induced a cell cycle arrest with accumulation of cells in the G1 phase of the cell cycle with an inhibition of cyclin D1 and D2 expression. This cell cycle arrest required the intact KID and was also induced by a mutated KID unable to block PAK1 kinase activity. Furthermore, the KID-induced cell cycle arrest could not be rescued by the expression of a constitutively active PAK1-T423E mutant, concluding that this arrest occurs independently of PAK1 kinase activity. Our results suggest that PAK1 through its KID inhibits cyclin D expression and thereby enforces a cell cycle arrest. Our results also call for serious precaution in the use of KID to study PAK function.

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Acknowledgements

We thank Dr Edward Manser for kindly providing the pXJGST-KID and pXJGSTKID-L107F constructs and the Developmental Studies Hybridoma Bank, University of Iowa for providing anti-BrdU mab G3G4 and anti-myc mab 9E10. This work was supported by grants to SS from the Swedish Cancer Society and the Swedish Research Council and to MT from The Swedish Society of Medicine. SS holds a senior scientist position from the Swedish Research Council and MT was supported from The Swedish Cancer Society and The Swedish Society of Medicine. AB and JC were supported by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden

    M Thullberg, A Gad & S Strömblad

  2. Tumor Cell Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    A Beeser & J Chernoff

  3. Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden

    A Gad

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  1. M Thullberg
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Correspondence to M Thullberg.

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Thullberg, M., Gad, A., Beeser, A. et al. The kinase-inhibitory domain of p21-activated kinase 1 (PAK1) inhibits cell cycle progression independent of PAK1 kinase activity. Oncogene 26, 1820–1828 (2007). https://doi.org/10.1038/sj.onc.1209983

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