PI3K/Akt signaling requires spatial compartmentalization in plasma membrane microdomains

Spatial compartmentalization of signaling pathway components generally defines the specificity and enhances the efficiency of signal transduction. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to be compartmentalized within plasma membrane microdomains; however, the underlying mechan...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 108; no. 35; pp. 14509 - 14514
Main Authors Gao, Xinxin, Lowry, Pamela R, Zhou, Xin, Depry, Charlene, Wei, Zhikui, Wong, G. William, Zhang, Jin
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 30.08.2011
National Acad Sciences
Subjects
3T3-L1 Cells
Adipocytes
Animals
Biological Sciences
Cell membranes
Ceramides
Chromosomes
growth factors
HeLa Cells
Humans
Insulin Resistance
Kinases
Membrane microdomains
Membrane Microdomains - metabolism
Mice
NIH 3T3 cells
P branes
Phosphatases
phosphatidylinositol 3-kinase
Phosphatidylinositol 3-Kinases - physiology
Phosphorylation
Plasma
plasma membrane
Protein-Serine-Threonine Kinases - physiology
Proto-Oncogene Proteins c-akt - physiology
PTEN Phosphohydrolase - physiology
Rafts
Signal transduction
Signal Transduction - physiology
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Summary:Spatial compartmentalization of signaling pathway components generally defines the specificity and enhances the efficiency of signal transduction. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to be compartmentalized within plasma membrane microdomains; however, the underlying mechanisms and functional impact of this compartmentalization are not well understood. Here, we show that phosphoinositide-dependent kinase 1 is activated in membrane rafts in response to growth factors, whereas the negative regulator of the pathway, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), is primarily localized in nonraft regions. Alteration of this compartmentalization, either by genetic targeting or ceramide-induced recruitment of PTEN to rafts, abolishes the activity of the entire pathway. These findings reveal critical steps in raft-mediated PI3K/Akt activation and demonstrate the essential role of membrane microdomain compartmentalization in enabling PI3K/Akt signaling. They further suggest that dysregulation of this compartmentalization may underlie pathological complications such as insulin resistance.
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Edited* by Lewis C. Cantley, Beth Israel Deaconess Medical Center, Boston, MA, and approved July 25, 2011 (received for review December 23, 2010)
Author contributions: X.G., Z.W., G.W.W., and J.Z. designed research; X.G., P.R.L., X.Z., C.D., and Z.W. performed research; X.G., P.R.L., X.Z., C.D., Z.W., and J.Z. analyzed data; and X.G. and J.Z. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1019386108