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Killer K-Ras

K-Ras (green) moves to mitochondria (red) when phosphorylated (right). PHILIPS/ELSEVIER

K-Ras resides at the plasma membrane (PM) where it promotes cell survival and proliferation. Now, Trever Bivona, Mark Philips (New York University, New York, NY), and colleagues find that fluorescent K-Ras moves to internal cell membranes within a few minutes after activating protein kinase C (PKC), with deadly consequences.

Philips' group happened to stimulate GFP-labeled T cells for an unrelated experiment. "Before our eyes, K-Ras shot off the membrane and into the cell interior," says Philips. K-Ras is attached peripherally to the PM by a farnesyl lipid group and an adjacent polybasic sequence. The team hypothesized that phosphorylation by PKC within the polybasic region acted like a switch, neutralizing the positive charge and releasing K-Ras from the PM. Indeed, blocking this serine-181 phosphorylation by PKC prevented K-Ras internalization.

A phosphate-mimicking Glu-181 mutant gave another shocking result. Cells expressing this K-Ras construct died off rapidly by apoptosis, as internalized K-Ras inhabited ER, Golgi, and—more importantly—mitochondrial membranes.

The outer mitochondrial membrane hosts apoptosis regulators such as the Bcl-2 family members. Philips' group found that the PKC-phosphorylated K-Ras interacted with Bcl-XL at mitochondrial membranes to promote apoptosis. Human T cells lacking K-Ras were resistant to activation-induced apoptosis.

Although Bcl-XL is normally antiapoptotic, the group proposes that K-Ras either sequesters Bcl-XL or converts it to a proapoptotic molecule.

Mutated Ras proteins are known to drive uncontrolled cell proliferation in 30 percent of human cancers. PKC agonists may be a possible strategy for treating such cancers, as the group found that oncogenic K-Ras also moved to the mitochondria when phosphorylated by PKC. Furthermore, K-Ras–driven tumors treated with the PKC agonist bryostatin-1 underwent apoptosis. PKC agonists such as bryostatin "cause K-Ras to fall off the plasma membrane," says Philips, "and it goes from being a molecule that drives cell growth to one that kills the cell instead."

Reference:

Bivona, T.G., et al. 2006. Mol. Cell. 21:481–493.[CrossRef][Medline]

Kendall Powell

kendall2{at}nasw.org

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This Article Full Text (PDF, 892K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Powell, K. Search for Related Content PubMed Articles by Powell, K. Social Bookmarking                            What's this?