CANCER Mobilizing K-Ras to Fight Cancer

K-Ras, a small guanosine triphosphatase whose constitutive activation through mutation is associated with cancer, is targeted to the plasma membrane through a farnesylated C-terminal and a nearby polybasic region (see Feig). Noting that the polybasic region is phosphorylated by protein kinase C (PKC), a modification that could neutralize its charge and destabilize electrostatic interactions with membrane phospholipids, Bivona et al. investigated the effects of K-Ras phosphorylation on its localization. Pharmacological activation of PKC promoted the reversible translocation of green fluorescent protein (GFP)-labeled K-Ras from the plasma membrane to the endoplasmic reticulum, Golgi apparatus, and mitochondrial outer membranes. Translocation was also promoted by a construct containing the PKC catalytic domain fused with a Ras binding domain. Substitution of alanine for serine at position 181 in the K-Ras C-terminal region, which reduced K-Ras phosphorylation in response to PKC, blocked K-Ras translocation, whereas substitution with glutamic acid (creating a phosphomimetic residue) led to constitutive internalization. Stimulating PKC in cells expressing a constitutively active oncogenic K-Ras mutant (K-Ras12V), or expressing K-Ras12V with glutamic acid at position 181 (K-Ras12V181E), promoted apoptosis. K-Ras associated with Bcl-XL; this association was promoted by K-Ras activation, PKC activation, or glutamic acid substitution of S181 and took place on mitochondria. Moreover, the ability of K-Ras12V181E to stimulate apoptosis depended on Bcl-XL. Intriguingly, pharmacological stimulation of PKC inhibited K-Ras12V-dependent tumorigenesis in a manner that depended on S181. Thus, the authors conclude that PKC regulates K-Ras localization and function and that manipulation of K-Ras phosphorylation could represent a novel approach to antineoplastic therapy.

T. G. Bivona, S. E. Quatela, B. O. Bodemann, I. M. Ahearn, M. J. Soskis, A. Mor, J. Miura, H. H. Wiener, L. Wright, S. G. Saba, D. Yim, A. Fein, I. Pérez de Castro, C. Li, C. B. Thompson, A. D. Cox, M. R. Philips, PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol. Cell 21, 481-493 (2006). [PubMed]

L. A. Feig, The odyssey of K-Ras. Mol. Cell 21, 447-449 (2006). [PubMed]

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