Membrane Heterogeneity in Akt Activation in Prostate Cancer
Final rept. 15 Feb 207-14 Jun 2009
CHILDREN'S HOSPITAL MEDICAL CENTER BOSTON MA
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This project focuses on the novel finding from our group that the serine-threonine kinase Akt1 partitions into specialized membrane microdomains, termed lipid rafts, and that this localization event strongly influences the nature of Akt1 signaling. Lipid rafts are cholesterol-enriched membrane microdomains that serve as signal transduction platforms by sequestering and excluding signaling proteins and by harboring multi-protein complexes. Evidence was presented in the original proposal that in prostate cancer cells critical cell survival cues are processed via lipid rafts, which are dependent on cholesterol for signal transduction. This is a significant finding because the Akt1 kinase is a central signaling protein that is frequently activated in prostate cancer. I have hypothesized in this project that cholesterol accumulation in prostate cancer cells may promote oncogenesis by altering the nature of Akt1 signals that flow through lipid raft microdomains. The purpose of this project is to identify the mechanism of Akt1 recruitment to cholesterol-rich microdomains and to explore the biological consequences for regulation of this important kinase. Several new lines of evidence consistent with my hypothesis have been produced in the second year and are described and summarized in this report.
- Medicine and Medical Research