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Control of cell size through phosphorylation of upstream binding factor 1 by nuclear phosphatidylinositol 3-kinase
Xiao Tu, and
Renato Baserga *
Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, 624 Bluemle Life Sciences Building, Philadelphia, PA 19107
Communicated by Hilary Koprowski, Thomas Jefferson University, Philadelphia, PA, May 12, 2004
Received for publication February 2, 2004.
The insulin-like growth factor I/insulin receptor substrate1 axis controls, in a nonredundant way, 50% of cell and bodysize in animals from Drosophila to mice and in cells in culture.Although other factors may also intervene, cell size is stronglydependent on ribosome biogenesis, which is under the controlof RNA polymerase I activity. We have previously shown thatinsulin receptor substrate 1 (IRS-1) translocates to the nucleiand nucleoli, where it binds to the upstream binding factor(UBF) 1, a regulator of RNA polymerase I activity. Activationof UBF1 requires its phosphorylation. However, IRS-1 is nota kinase, and we searched for an intermediate kinase that canphosphorylate UBF1. We demonstrate here that IRS-1 binds alsoto the phosphatidylinositol 3-kinase (PI3-K) subunits in nuclearextracts, and that the p110 subunit of PI3-K directly phosphorylatesand activates UBF1, an exclusively nucleolar protein. The interactionof IRS-1, PI3-K, and UBF1 in the nucleoli provides one of themechanisms for the effects of IRS-1 on cell and body size.