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Oncogenic signaling of class I PI3K isoforms

Abstract

The catalytic subunits of class I PI3Ks comprise four isoforms: p110α, p110β, p110δ and p110γ. Cancer-specific gain-of-function mutations in p110α have been identified in various malignancies. Cancer-specific mutations in the non-α isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110β, p110γ or p110δ is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-α isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3β and cause degradation of FoxO1. A functional Erk pathway is required for p110γ and p110β transformation but not for transformation by p110δ or the H1047R mutant of p110α. Transformation and signaling by p110γ and p110β are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110δ reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110β and p110γ.

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Abbreviations

4E-BP:

eukaryotic initiation factor 4E binding protein

Akt:

cellular homolog of murine thymoma virus akt8 oncogene

ASV16:

avian sarcoma virus 16

CEF:

chicken embryo fibroblasts

eIF4E:

eukaryotic initiation factor 4E

Erk:

extracellular signal-regulated kinase

FOXO:

forkhead box O transcription factor

GSK3β:

glycogen synthase kinase-3-beta

MAPK:

mitogen-activated protein kinase

MEK:

mitogen-activated protein kinase kinase 1

p70S6K:

ribosomal protein S6 kinase, 70 kDa, polypeptide 1

p90rsk:

ribosomal protein S6 kinase, 90 kDa, polypeptide 1

PI3K:

phosphatidylinositol 3-kinase

Raf:

v-raf-leukemia viral oncogene 1

Ras:

rat sarcoma viral oncogene

RBD:

Ras-binding domain

S6:

S6 ribosomal protein

TOR:

target of rapamycin

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Acknowledgements

We thank Lynn Ueno for expert technical assistance, Kathleen M Alexander for help with the manuscript and Dr Wolf Wrasidlo for BAY-43006. This work is supported by grants from the National Cancer Institute and by the Stein Endowment Foundation. This is manuscript number 18936 of The Scripps Research Institute.

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Denley, A., Kang, S., Karst, U. et al. Oncogenic signaling of class I PI3K isoforms. Oncogene 27, 2561–2574 (2008). https://doi.org/10.1038/sj.onc.1210918

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