Signal Transduction

Life Beyond Kinase

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Science  12 Sep 2008:
Vol. 321, Issue 5895, pp. 1421
DOI: 10.1126/science.321.5895.1421b

Phosphoinositide 3-kinase (PI3K) enzymes function by transducing the signals from receptor tyrosine kinases and heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. They catalyze the formation of lipid second messengers. Ciraolo et al. explored the biological role of p110β, one of three types of catalytic subunits that make up PI3Ks in mammalian cells. They created mice that express a mutant form of the enzyme that lacks kinase activity. Although complete loss of individual p110 subunits is deadly, the animals expressing the mutant p110β survived, indicating that p110β has functions that are independent of its kinase activity. The mutant animals grew more slowly than normal animals and, as they got older, showed signs of insulin resistance. They also showed impaired signaling from G protein-coupled receptors. In a breast cancer model induced by the ERBB2 oncogene, which signals through PI3K, the mutant animals showed fewer tumors, which grew at a reduced rate. In independent work, Jia et al. explored the effects of tissue-specific depletion of p110β in the liver and provide evidence for kinase-independent roles of p110β and for impaired insulin action in animals lacking p110β. They found that loss of p110β also decreased tumorigenesis in a mouse cancer model caused by loss of the lipid phosphatase PTEN. These studies indicate that tissue-specific actions of p110β may make it a potentially effective target for therapeutic regulation. — LBR

Sci. Signal. 1, ra3 (2008); Nature 454, 776 (2008).

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