Functional Proteomic Analysis of Lipid Raft Kinase Complexes

Authors: Wei Yang; CHILDREN'S HOSPITAL CORP BOSTON MA

Abstract:

A series of studies from our laboratories suggested that survival signaling in prostate cancer cells is mediated, in part, through lipid raftresident Akt. I have hypothesized that the lipid raft-resident Akt in prostate tumor cells is a privileged Akt population that mediates cell survival by interacting with discrete subsets of regulatory proteins and by transmitting signals that are unique to the lipid raft environment. Many components in lipid raft-resident Akt complexes and Akt pathways are likely to be palmitoylated, given that a number of key signaling molecules are palmitoylated and that palmitoyl proteins have been proposed to be enriched in lipid rafts. As an approach into the analysis of Akt signaling through lipid rafts, in year 1 of this project I developed a novel, proteomic method of palmitoyl protein analysis, which resulted in many interesting and unanticipated biological findings. In addition, our group has very recently reported that EGF stimulation or accumulation of Akt1 in lipid rafts resulted in the rapid formation of secreted microvesicles, which are capable of activating phosphotyrosine and Akt pathway signaling as well as stimulating proliferation and migration in recipient cells. Functional palmitoylproteomics analysis suggested that certain palmitoyl proteins actively participate in transmitting EGFR-Akt signaling. The protein acyltransferases and acylprotein thioesterases regulating the palmitoylation levels of these key palmitoyl proteins may be novel targets for the inhibition of EGFR-Akt signaling, which can be exploited for the treatment of advanced prostate cancer.

Limitations:

APPROVED FOR PUBLIC RELEASE