Journal
JOURNAL OF CELL SCIENCE
Volume 119, Issue 24, Pages 5160-5168Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.000133
Keywords
phosphoinositide 3-kinase; phosphatidylinositol trisphosphate; nucleus; phosphatase; PTEN; electron microscopy
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Funding
- MRC [G9403619] Funding Source: UKRI
- Medical Research Council [G9403619] Funding Source: researchfish
- Medical Research Council [G9403619] Funding Source: Medline
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Phosphatidylinositol (3,4,5) trisphosphate [PtdIns(3,4,5)P-3] is a lipid second messenger, produced by Type I phosphoinositide 3-kinases (PI 3-kinases), which mediates intracellular responses to many growth factors. Although PI 3-kinases are implicated in events at both the plasma membrane and intracellular sites, including the nucleus, direct evidence for the occurrence of PtdIns( 3,4,5) P-3 at non-plasma membrane locations is limited. We made use of the pleckstrin homology (PH) domain of general receptor for phosphoinositides (Grp1) to detect PtdIns(3,4,5) P-3 in an on-section labeling approach by quantitative immunogold electron microscopy. Swiss 3T3 cells contained low levels of PtdIns(3,4,5) P-3 that increased up to 15-fold upon stimulation with platelet-derived growth factor (PDGF). The signal was sensitive to PI 3-kinase inhibitors and present mainly at plasma membranes, including lamellipodia, and in a surprisingly large pool within the nuclear matrix. Comparatively little labeling was observed in endomembranes. A similar distribution of PtdIns(3,4,5) P-3 was observed in U87MG cells, which lack the PtdIns( 3,4,5) P-3 phosphatase, PTEN. Re-expression of PTEN into U87MG cells ablated plasma membrane PtdIns(3,4,5) P-3, but not the nuclear pool of this lipid even when PTEN was targeted to nuclei. These data have important implications for the versatility of PI 3-kinase signaling and for the proposed functions of PTEN in the nucleus.
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