An Isoform-Selective, Small-Molecule Inhibitor Targets the Autoregulatory Mechanism of p21-Activated Kinase
Open accessAbstract
Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation. We developed a screen for allosteric inhibitors targeting Pak1 activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak.
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Inhibition of Pak with IPA3 decreased the sustained volume change selectively without changing the transient volume change, similarly to inhibition of Cdc42 signalling.
“In contrast, inhibition of Pak with IPA3 (100 μM)28 decreased the sustained volume change selectively without changing the transient volume change (Fig. 4h, i, j) similarly to inhibition of Cdc42 signalling (Fig. 4e, g).”
From Local, persistent activation of Rho GTPases during plasticity of single dendritic spines (2011) · cites this paper as [28]
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Research works printed but not linked: 3
- Peterson, J.R., Lokey, R.S., Mitchison, T.J., and Kirschner, M.W. (2001). A chemical inhibitor of N-WASP reveals a new mechanism for targeting protein interactions. Proc. Natl. Acad. Sci. USA 98, 10624-10629.
- Prowse, C.N., Hagopian, J.C., Cobb, M.H., Ahn, N.G., and Lew, J. (2000). Catalytic reaction pathway for the mitogen-activated protein kinase ERK2. Biochemistry 39, 6258-6266, Erratum: Biochemistry 39(45), 2000.
- Xia, C., Ma, W., Stafford, L.J., Marcus, S., Xiong, W.C., and Liu, M. (2001). Regulation of the p21-activated kinase (PAK) by a human Gb-like WD-repeat protein, hPIP1. Proc. Natl. Acad. Sci. USA 98, 6174-6179.
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Dilna, A., Deepak, K. V., Damodaran, N., Kielkopf, C. S., Kagedal, K., Ollinger, K., & Nath, S. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166246 · Cited by 51 · see citing works
- Authors
- Deacon, S. W., Beeser, A., Fukui, J. A., Rennefahrt, U. E. E., Myers, C., Chernoff, J., & Peterson, J. R.
- Affiliations
- Fox Chase Cancer Center (US)
- Corresponding author
- Peterson, Jeffrey R.
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 15
- Issue
- 4
- Pages
- 322-331
- ISSN
- 1074-5521 (ISSN-L)
- PMC
- PMC4353635
- OpenAlex
- W2155087173
- Cited by
- 366
- References
- 0
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 11 · 2023: 24 · 2022: 6 · 2021: 8 · 2020: 17 · 2019: 21 · 2018: 13 · 2017: 21 · 2016: 26 · 2015: 18 · 2014: 31 · 2013: 31 · 2012: 44
- FWCI
- 9.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense (W81XWH, W81XWH-05-1)
- Pennsylvania Department of Health
- National Institutes of Health (W81XWH, CA006927)
- National Cancer Institute (CA009035, CA 006927, T32CA009035, CA 117884, R01CA117884, P30CA006927)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- p21-activated kinase, PAK1, autoinhibition, allosteric inhibitors, IPA-3, kinase activation, autophosphorylation, kinase isoforms, ERK activation, PDGF signaling, small molecule inhibitors, kinase selectivity
- MeSH terms
- Animals, Disulfides, Drug Evaluation, Preclinical, Enzyme Activation, Fibroblasts, Homeostasis, Isoenzymes, Naphthols, Platelet-Derived Growth Factor, Protein Conformation, Substrate Specificity, Protein Kinase Inhibitors, Mice, p21-Activated Kinases, Small Molecule Libraries
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