The signal transduction mechanisms underlying progression to androgen-independent prostate cancer (PCa) are still poorly understood. In addition to the well-known role for androgen in development and progression of the disease, the phosphoinositide-3-kinase (PI3K) -Akt/protein kinase B (PKB) -> mTOR (mammalian target of rapamycin) pathway has recently been identified as an important regulator of prostate tumor cell growth and survival. The mechanisms of intersection of androgenic signaling with other signaling pathways, and in particular the PI3K/Akt/mTOR pathway, have not been clearly delineated, and in a number of respects are in dispute. We present evidence in this proposal that a major point of intersection between the androgen receptor (AR) and PI3K/Akt signaling is in the cholesterol-rich lipid raft component of the plasma membrane. We present several lines of evidence for this conclusion, including multiple independent observations that lipid raft membranes are sites of direct regulation of the Akt serine-threonine kinase, evidence that the AR can transit through this membrane compartment, and that AR and Akt form a ligand-dependent protein complex preferentially within lipid raft membranes. An important hypothesis obtained directly from our preliminary data is that androgen regulates Akt by direct interaction between AR and one or more phosphorylated forms of Akt, suggesting that the raft membrane is an important point of bifurcation for androgenic signals. In this proposal we will test this hypothesis by pursuing the following specific aims:
Aim 1. Determine how androgen regulates lipid raft-resident Akt.
Aim 2. Identify signaling pathways transmitted through lipid rafts, and signaling components present within rafts, that lie downstream of androgen and other AR activators. We believe these experiments will provide substantial new insight into the role of the AR, soluble factors other than androgen present in the tumor milieu, and cholesterol-rich membranes in PCa progression. They are also designed to identify new signaling proteins of potential relevance to PCa, thereby widening possibilities for therapeutic intervention.
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