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Published online 25 July 2005. doi:10.1083/jcb.200503088
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 3, 455-464
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Article

The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex



Ji Luo1,2, Seth J. Field1,2,3, Jennifer Y. Lee1,2, Jeffrey A. Engelman1,2,4, and Lewis C. Cantley1,2

1 Department of Systems Biology, Harvard Medical School
2 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115
3 Division of Endocrinology, Massachusetts General Hospital, Boston, MA 02114
4 Department of Hematology/Oncology, Massachusetts General Hospital, Boston, MA 02114

Correspondence to Lewis C. Cantley: lewis_cantley{at}hms.harvard.edu

Phosphoinositide (PI) 3-kinase is required for most insulin and insulin-like growth factor (IGF) 1–dependent cellular responses. The p85 regulatory subunit of PI 3-kinase is required to mediate the insulin-dependent recruitment of PI 3-kinase to the plasma membrane, yet mice with reduced p85 expression have increased insulin sensitivity. To further understand the role of p85, we examined IGF-1–dependent translocation of p85{alpha} by using a green fluorescence protein (GFP)–tagged p85{alpha} (EGFP–p85{alpha}). In response to IGF-1, but not to PDGF signaling, EGFP–p85{alpha} translocates to discrete foci in the cell. These foci contain the insulin receptor substrate (IRS) 1 adaptor molecule, and their formation requires the binding of p85 to IRS-1. Surprisingly, monomeric p85 is preferentially localized to these foci compared with the p85–p110 dimer, and these foci are not sites of phosphatidylinositol-3,4,5-trisphosphate production. Ultrastructural analysis reveals that p85–IRS-1 foci are cytosolic protein complexes devoid of membrane. These results suggest a mechanism of signal down-regulation of IRS-1 that is mediated by monomeric p85 through the formation of a sequestration complex between p85 and IRS-1.

S.J. Field's present address is Division of Endocrinology, Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.

Abbreviations used in this paper: IGF, insulin-like growth factor; IRS, insulin receptor substrate; MEF, mouse embryonic fibroblasts; PH, pleckstrin homology; PI, phosphoinositide; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PI-3,4-P2, phosphatidylinositol-3,4-bisphosphate; SH, Src homology; TIRFM, total internal reflection fluorescence microscopy.


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