The kinase activity of the PI(3)K subunit p110β is linked to the oncogenic transformation of mouse prostate epithelium, whereas a second, kinase-independent activity regulates cellular proliferation and signaling downstream of tyrosine-kinase receptors.
Class IA phosphatidylinositol-3-OH kinases (PI(3)Ks) are heterodimeric lipid and protein kinases composed of a regulatory subunit (p50α, p55α, p85α, p55γ or p85β) and a catalytic subunit (p110α, p110β or p110δ). PI(3)Ks regulate cell growth and proliferation, and the separable biological activities of the different catalytic subunits are under intense investigation. The ability of p110α to promote angiogenesis and tumor development is well established, but information about the physiological role of p110β is lacking. In Nature, Jean Zhao, Thomas Roberts and colleagues now report that p110β-associated kinase activity is required for the oncogenic transformation of mouse prostate epithelium, whereas a second, kinase-independent activity regulates cell proliferation and signaling downstream of tyrosine–kinase receptors.
p110β has been shown to phosphorylate Akt downstream of the lysophosphatidic acid (LPA) G protein-coupled receptor (GPCR), but not the insulin tyrosine–kinase receptor. In keeping with these observations, p110β-deficient mouse embryonic fibroblasts (MEFs) proliferated slowly and did not activate Akt or its downstream target S6 ribosomal protein (S6RP) in response to LPA. As expected, insulin treatment had no effect on Akt phosphorylation in p110β-deficient MEFs; however, S6RP phosphorylation was moderately depressed. Interestingly, expression of a kinase-deficient p110βK805R mutant was sufficient to restore S6RP phosphorylation in response to insulin, whereas exogenous wild-type p110β was required for Akt/S6RP phosphorylation in response to LPA. In addition, p110βK805R expression permitted normal cell cycle progression in p110β-deficient MEFs, suggesting a kinase-independent role of p110β in cellular proliferation and signaling downstream of the insulin receptor. The nature of the kinase-independent activity is not yet known, nor has a kinase-dependent role for p110β been ruled out in these processes.
Previous studies have indicated that p110β lipid kinase activity is required for prostate cancer progression, and Zhao and colleagues confirmed that loss of p110β blocked tumorigenesis in PTEN-deficient anterior prostatic epithelium. Surprisingly, p110α depletion did not affect either tumor development or Akt phosphorylation. These findings suggest that p110β catalytic activity drives transformation and Akt phosphorylation in the mouse prostate epithelium in the absence of PTEN.
Thus, distinct biological functions for p110α and p110β are beginning to emerge. In a previous report in Nature, Holger Gerhardt, Bart Vanhaesebroeck and colleagues described p110α as a key factor in angiogenesis and endothelial cell migration, whereas Zhao and Roberts' study found a kinase-independent function for p110β in aspects of growth-factor signaling and cell proliferation, and a kinase-dependent role in oncogenic transformation. Even though p110α remains the focus of pharmaceutical efforts to block oncogenic PI(3)K signaling, these findings suggest that p110β may be an equally attractive drug target.
Emily J. Chenette Signaling Gateway
Reference
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Graupera, M., Guillermet-Guibert, J., Foukas, L. C., Phng, L.-K. Cain, R. J., Salpekar, A., Pearce, W., Meek, S., Millan, J., Cutillas, P. R., Smith, A. J. H., Ridley, A. J., Ruhrberg, C., Gerhardt H. & Vanhaesebroeck B. Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migrationNature454, 662-666 (2008) | Article | PubMed |
