Abstract: Series 100, Lecture 4

The Harvey Lectures Series 100 (2004—2005)

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Lecture #4: Thursday, February 17, 2005 — Time and Location

The Role of Phosphoinositide 3-kinase in Development and Disease

Lewis C Cantley, PhD


Professor of Systems Biology
Chief, Division of Signal Transduction Department of Medicine

Beth Israel Deaconess Medical Center, Harvard Medical School

Boston, Massachusetts

We discovered phosphoinositide 3-kinases (PI3K) more than 15 years ago because of its co-purification with the oncoproteins pp60v-src and polyoma middle t. These early studies indicated a role for this enzyme in transformation of cells in vitro and in retrovirus induced tumor formation in mice and chickens. The relevance of PI3K to human cancers was supported by the discovery from Jack Dixon’s laboratory that the tumor suppressor gene, PTEN encodes a phosphatase that degrades the lipid products of PI3K, phosphatidylinositol-3,4-bisphosphate and phosphatidylinositol-3,4,5-trisphosphate. Very recent studies have shown a surprisingly high rate of activating mutations in the p110alpha subunit of PI3K in colon cancer, brain cancers and breast cancer (25% to 35%). These studies indicate that activation of the PI3K pathway may contribute to a larger fraction of human cancers than activation of ras. We have used a variety of biochemical approaches and genetic manipulation in mice to elucidate the role of PI3K in normal growth and development and to identify pathways downstream of PI3K that contribute to cell transformation. Many responses downstream of PI3K are mediated by the protein kinase, AKT. We recently showed that AKT phosphorylates the tuberous sclerosis-2 gene product, tuberin and thereby eliminates the ability of tuberin to act as a GAP for the ras-like G-protein, RHEB. This allows RHEB to turn on the mTOR pathway that regulates protein synthesis, cell growth and cell survival. Interestingly, we have also found that the Peutz-Jeghers Syndrome tumor suppressor gene product, LKB1 regulates this same pathway by phosphorylating and activating AMP activated protein kinase, a sensor for the energy state of the cell. Loss of LKB1, like loss of PTEN or tuberin, results in activation of mTOR. Our progress in elucidating the biochemical basis for regulation of these pathways will be discussed.