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Cited by 141PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingCellular transport and secretion

Quantitative Lipid Imaging Reveals a New Signaling Function of Phosphatidylinositol-3,4-Bisphophate: Isoform- and Site-Specific Activation of Akt

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Liu, Shu-Lin, Wang, Zhi-Gang, Hu, Yusi, Xin, Yao, Singaram, Indira, Gorai, Sukhamoy, Zhou, Xin, Shim, Yoonjung +5 more·2018·Molecular Cell
DOI 10.1016/j.molcel.2018.07.035PMC PMC6214670
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Abstract

Activation of class I phosphatidylinositol 3-kinase (PI3K) leads to formation of phosphatidylinositol-3,4,5-trisphophate (PIP 3) and phosphatidylinositol-3,4-bisphophate (PI34P 2), which spatiotemporally coordinate and regulate a myriad of cellular processes. By simultaneous quantitative imaging of PIP 3 and PI34P 2 in live cells, we here show that they have a distinctively different spatiotemporal distribution and history in response to growth factor stimulation, which allows them to selectively induce the membrane recruitment and activation of Akt isoforms. PI34P 2 selectively activates Akt2 at both the plasma membrane and early endosomes, whereas PIP 3 selectively stimulates Akt1 and Akt3 exclusively at the plasma membrane. These spatiotemporally distinct activation patterns of Akt isoforms provide a mechanism for their differential regulation of downstream signaling molecules. Collectively, our studies show that different spatiotemporal dynamics of PIP 3 and PI34P 2 and their ability to selectively activate key signaling proteins allow them to mediate class I PI3K signaling pathways in a spatiotemporally specific manner.

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  • Certain PZD-domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane.

    “Recent reports suggest that certain PZD-domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane (43, 44, 82–84).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [84]

    The Introduction and Discussion address phosphoinositide signaling and Akt activation, not cholesterol-dependent activation of Dvl2. Searches for Dvl2, PDZ proteins, cholesterol, and the inner leaflet found only a related paper title in the References; our copy does not state the claimed mechanism. (LLM, conf=0.76)

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Authors
Liu, S.-L., Wang, Z.-G., Hu, Y., Xin, Y., Singaram, I., Gorai, S., Zhou, X., Shim, Y., Min, J.-H., Gong, L.-W., Hay, N., Zhang, J., & Cho, W.
Affiliations
  • University of Illinois Chicago (US)
  • University of California San Diego (US)
  • Kyung Hee University (KR)
Corresponding author
Cho, Wonhwa
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2018-09
Volume
71
Issue
6
Pages
1092-1104.e5
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2018.07.035
PMC
PMC6214670
OpenAlex
W2888800216
Cited by
141
References
45
Citations by year
2026: 9 · 2025: 21 · 2024: 16 · 2023: 18 · 2022: 20 · 2021: 21 · 2020: 20 · 2019: 14 · 2018: 2
FWCI
5.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (R35GM122530, R21ES028384, R56MH107387, R01AG016927, R01CA090764, R35CA197622, R01GM111665)
  • National Science Foundation (MCB-1412692)
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-bisphosphate, phosphatidylinositol 3,4,5-trisphosphate, Akt isoforms, AKT2, AKT1, AKT3, lipid signaling, membrane recruitment, early endosomes, growth factor stimulation, spatiotemporal dynamics
MeSH terms
Single Molecule Imaging, Animals, Cell Line, Cell Membrane, Humans, Inositol Phosphates, Phosphatidylinositols, Signal Transduction, Phosphatidylinositol Phosphates, Phosphatidylinositol 3-Kinases, Protein Isoforms, Protein Transport, Proto-Oncogene Proteins c-akt, Mice, Optical Imaging

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