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Cited by 102PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingMass Spectrometry Techniques and Applications

Dynamic steps in receptor tyrosine kinase mediated activation of class IA phosphoinositide 3-kinases (PI3K) captured by H/D exchange (HDX-MS)

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Burke, John E., Williams, Roger L.·2013·Advances in Biological Regulation
DOI 10.1016/j.jbior.2012.09.005PMC PMC3613897
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Abstract

The catalytic subunits of all class IA phosphoinositide 3-kinases (PI3Ks) associate with identical p85-related subunits and phosphorylate PIP2 yielding PIP3, but they can vary greatly in the signaling pathways in which they participate. The binding of the p85 subunit to the p110 catalytic subunits is constitutive, and this inhibits activity, but some of the inhibitory contacts are reversible and subject to regulation. Interaction with phosphotyrosine-containing peptides (RTK-pY) releases a subset of these inhibitory contacts. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) provides a map of the dynamic interactions unique to each of the isotypes. RTK-pY binding exposes the p110 helical domains for all class IA enzymes (due to release of the nSH2 contact) and exposes the C-lobe of the kinase domains of p110β and p110δ (resulting from release of the cSH2 contact). Consistent with this, our in vitro assays show that all class IA isoforms are inhibited by the nSH2, but only p110β and p110δ are inhibited by the cSH2. While a C2/iSH2 inhibitory contact exists in all isoforms, HDX indicates that p110β releases this contact most readily. The unique dynamic relationships of the different p110 isozymes to the p85 subunit may facilitate new strategies for specific inhibitors of the PI3Ks.

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  • PI3K activity in the p110α-p85 heterodimer is inhibited by intra- and inter-subunit contacts that become disrupted following engagement of p85 SH2 domains with phosphorylated tyrosine residues in RTK/adapter proteins, and activation favours interaction with the plasma membrane.

    “In this case, the PI3K activity is inhibited by a combination of intra- and inter-subunit contacts that become disrupted following the engagement of the SH2 domains, present in p85, with the phosphorylated tyrosine residues in RTK/adapter proteins in stimulated cells; the activation also favours the interaction with the plasma membrane [74–76].”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [75]

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Authors
Burke, J. E., & Williams, R. L.
Affiliations
MRC Laboratory of Molecular Biology (GB)
Corresponding author
  • Burke, John E.
  • Williams, Roger L.
ORCID
Burke, John E.
Venue
Advances in Biological Regulation
Publisher
Elsevier BV
Published
2013-01
Volume
53
Issue
1
Pages
97-110
ISSN
2212-4926 (ISSN-L)
DOI
10.1016/j.jbior.2012.09.005
PMC
PMC3613897
OpenAlex
W2095812294
Cited by
102
References
2
Citations by year
2026: 7 · 2025: 8 · 2024: 1 · 2023: 15 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 7 · 2017: 10 · 2016: 8 · 2015: 9 · 2014: 5 · 2013: 6
FWCI
2.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Advances in Biological Regulation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Medical Research Council (U105184308)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
Keywords
p85 regulatory subunit, receptor tyrosine kinase signaling, phosphotyrosine binding, p110β, p110δ, p110α, PI3K activation, PI3K inhibitors, protein-protein interaction
MeSH terms
Animals, Deuterium, Enzyme Activation, Hydrogen, Isoenzymes, Models, Molecular, Phosphorylation, Recombinant Proteins, Mass Spectrometry, Signal Transduction, Protein Structure, Secondary, src Homology Domains, Phosphotyrosine, Phosphatidylinositol 3-Kinases, Protein Subunits, Deuterium Exchange Measurement, Mice

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