Journal
JOURNAL OF CELL BIOLOGY
Volume 170, Issue 3, Pages 455-464Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200503088
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Funding
- NCI NIH HHS [P01 CA089021, CA089021] Funding Source: Medline
- NIDDK NIH HHS [K08 DK065108-01, K08 DK065108] Funding Source: Medline
- NIGMS NIH HHS [R37 GM041890, R01 GM041890, GM41890] Funding Source: Medline
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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.
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