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Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):779-84. doi: 10.1073/pnas.1412811112. Epub 2015 Jan 5.

K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif.

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New York University Perlmutter Cancer Institute, New York University School of Medicine, New York, NY 10016;
Departments of Pharmacology and Radiation Oncology, University of North Carolina, Chapel Hill, NC 27599; and.
Department of Medicine, Harvard Medical School, Boston, MA 02215.
New York University Perlmutter Cancer Institute, New York University School of Medicine, New York, NY 10016;


The two products of the KRAS locus, K-Ras4A and K-Ras4B, are encoded by alternative fourth exons and therefore, possess distinct membrane-targeting sequences. The common activating mutations occur in exons 1 or 2 and therefore, render both splice variants oncogenic. K-Ras4A has been understudied, because it has been considered a minor splice variant. By priming off of the splice junction, we developed a quantitative RT-PCR assay for K-Ras4A and K-Ras4B message capable of measuring absolute amounts of the two transcripts. We found that K-Ras4A was widely expressed in 30 of 30 human cancer cell lines and amounts equal to K-Ras4B in 17 human colorectal tumors. Using splice variant-specific antibodies, we detected K-Ras4A protein in several tumor cell lines at a level equal to or greater than that of K-Ras4B. In addition to the CAAX motif, the C terminus of K-Ras4A contains a site of palmitoylation as well as a bipartite polybasic region. Although both were required for maximal efficiency, each of these could independently deliver K-Ras4A to the plasma membrane. Thus, among four Ras proteins, K-Ras4A is unique in possessing a dual membrane-targeting motif. We also found that, unlike K-Ras4B, K-Ras4A does not bind to the cytosolic chaperone δ-subunit of cGMP phosphodiesterase type 6 (PDE6δ). We conclude that efforts to develop anti-K-Ras drugs that interfere with membrane trafficking will have to take into account the distinct modes of targeting of the two K-Ras splice variants.


K-Ras; Ras; alternate splicing; oncogene; palmitoylation

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