Cited by 172PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingCellular transport and secretion

Comprehensive Identification of PIP3-Regulated PH Domains from C. elegans to H. sapiens by Model Prediction and Live Imaging

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Park, Wei Sun, Do Heo, Won, Whalen, James H., O'Rourke, Nancy A., Bryan, Heather M., Meyer, Tobias, Teruel, Mary N.·2008·Molecular Cell

Abstract

Phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol(3,4,5)-trisphosphate (PIP3) control cell growth, migration, and other processes by recruiting proteins with pleckstrin homology (PH) domains and possibly other domains to the plasma membrane (PM). However, previous experimental and structural work with PH domains left conflicting evidence about which ones are PIP3 regulated. Here we used live-cell confocal imaging of 130 YFP-conjugated mouse PH domains and found that 20% translocated to the PM in response to receptor-generated PIP3 production. We developed a recursive-learning algorithm to predict PIP3 regulation of 1200 PH domains from different eukaryotes and validated that it accurately predicts PIP3 regulation. Strikingly, this algorithm showed that PIP3 regulation is specified by amino acids across the PH domain, not just the PIP3-binding pocket, and must have evolved several times independently from PIP3-insensitive ancestral PH domains. Finally, our algorithm and live-cell experiments provide a functional survey of PH domains in different species, showing that PI3K regulation increased from approximately two C. elegans and four Drosophila to 40 vertebrate proteins.

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Crossref · 10.1016/j.molcel.2008.04.008

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  • PI(3,4,5)P3 and its derivative PI(3,4)P2 interact with the lipid-binding PH domain in a range of protein effectors, resulting in their recruitment to membrane-signalling complexes and/or modulation of their activity.

    “PI(3,4,5)P3 and PI(3,4)P2 interact with the lipid-binding PH-domain in a range of protein effectors, resulting in their recruitment to membrane-signalling complexes and/or modulation of their activity [78–81].”

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Authors
Park, W. S., Do Heo, W., Whalen, J. H., O'Rourke, N. A., Bryan, H. M., Meyer, T., & Teruel, M. N.
Affiliations
Stanford University (US)
Corresponding author
Teruel, Mary N.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2008-05
Volume
30
Issue
3
Pages
381-392
ISSN
1097-2765 (ISSN-L)
OpenAlex
W2038641650
Cited by
167
References
41
Citations by year
2026: 3 · 2025: 7 · 2024: 3 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 9 · 2019: 13 · 2018: 6 · 2017: 6 · 2016: 4 · 2015: 14 · 2014: 15 · 2013: 11 · 2012: 15
FWCI
5.62
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (GM0653702, MH064801)
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
phosphatidylinositol 3,4,5-trisphosphate, pleckstrin homology domain, phosphatidylinositol 3-kinase, plasma membrane translocation, live-cell imaging, Caenorhabditis elegans, Drosophila, vertebrates
MeSH terms
Algorithms, Amino Acid Sequence, Animals, Humans, Models, Molecular, Models, Theoretical, Molecular Sequence Data, Phylogeny, Protein Binding, Protein Conformation, Recombinant Fusion Proteins, Sequence Alignment, Caenorhabditis elegans, Phosphatidylinositol Phosphates, Microscopy, Confocal, Phosphatidylinositol 4,5-Diphosphate, Phosphatidylinositol 3-Kinases, Proteome, Caenorhabditis elegans Proteins, NIH 3T3 Cells, Mice

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