POSTTRANSLATIONAL MODIFICATION Regulation of PI3K Signaling by Lysine Oxidation?

Lysyl oxidase (LO) is an enzyme that catalyzes the oxidative deamination of peptidyl lysine and hydrolysine residues, which leads to the spontaneous formation of inter- and intrachain cross-links. LO is decreased in many tumors, and expression of LO is increased upon reversion of the tumorous phenotypes. Jeay et al. showed that overexpression of LO caused reversion of the Ras-transformed phenotype and was associated with inhibition of nuclear factor kappa B (NF-B) signaling. Although Jeay et al. did not determine the target of LO or demonstrate that LO enzymatic activity was required, they did show that overexpression of LO inhibited NF-B reporter gene expression and NF-B DNA binding, stabilized the inhibitor of NF-B (IB), and inhibited the kinase activity of IKK and IKKß (kinase components of the IB complex). Using Ras mutants that could only couple to either the phosphatidylinositol 3-kinase (PI3K) pathway or the mitogen-activated protein kinase (MAPK) pathway, the authors showed that overexpression of LO was most effective at inhibiting Ras activation of the PI3K pathway. LO inhibited the Ras-stimulated recruitment of Akt and phosphoinositide-dependent kinase (PDK) to the plasma membrane, which are early steps downstream of PI3K activation. Forced membrane association of Akt or PKD by myristylation overcame LO-mediated inhibition of NF-B reporter gene expression. Thus, LO appears to inhibit an early step in the PI3K pathway. How LO achieves this inhibition remains an open question, but these results suggest that yet another lysine modification may be added to the posttranslational regulatory mechanisms controlling signaling events.

S. Jeay, S. Pianetti, H. M. Kagan, G. E. Sonenshein, Lysyl oxidase inhibits Ras-mediated transformation by preventing activation of NF-B. Mol. Cell. Biol. 23, 2251-2263 (2003). [Abstract] [Full Text]

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VIRTUAL JOURNAL
Lysyl Oxidase Inhibits Ras-Mediated Transformation by Preventing Activation of NF-B

Sébastien Jeay, Stefania Pianetti, Herbert M. Kagan, and Gail E. Sonenshein (1 April 2003)
Mol. Cell. Biol. 23 (7), 2251. [DOI: 10.1128/MCB.23.7.2251-2263.2003]
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