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Published online 11 December 2000. doi:10.1083/jcb.151.6.1179
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© The Rockefeller University Press, 0021-9525/2000/12/1179/ $5.00
The Journal of Cell Biology, Volume 151, Number 6, December 11, 2000 1179-1192

Original Article

Reversal of the Ras-induced Transformed Phenotype by HR12, a Novel Ras Farnesylation Inhibitor, Is Mediated by the Mek/Erk Pathway

Hadas Reuvenia, Tamar Geigera, Benjamin Geigerb, and Alexander Levitzkia
a Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
b Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel

Correspondence to: Alexander Levitzki, Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Tel:972-2-6585404 Fax:972-2-6512958 E-mail:levitzki{at}vms.huji.ac.il.

We have used the selective farnesylation inhibitor HR12 [cysteine-N(methyl)valine-N(cyclohexyl) glycine-methionine-O-methyl-ester] to study the role of oncogenic Ras in cytoskeletal reorganization in Ha-rasV12-transformed Rat1 cells (Rat1/ras). Application of HR12 resulted in complete restoration of the cytoskeleton and associated cell adhesions disrupted by oncogenic Ras. This included an increase in the number and size of focal adhesions, accompanied by massive stress fiber formation and enhanced tyrosine phosphorylation. Furthermore, HR12 induced assembly of adherens junctions and dramatically elevated the level of the junctional components, cadherin and ß-catenin. HR12 was unable to restore the nontransformed phenotype in cells expressing farnesylation-independent, myristylated Ras. Examination of the main Ras-regulated signaling pathways revealed that HR12 induced a dose- and time-dependent decline in Erk1&2 activation (t1/2 ~ 6 h), which correlated with the accumulation of nonfarnesylated oncogenic-Ras. Inhibition of the Mek/Erk pathway in Rat1/ras cells, using the Mek inhibitor, PD98059, resulted in complete cytoskeletal recovery, indistinguishable from that induced by HR12. Moreover, a constitutively active Mek mimicked the effect of ras transformation in Rat1 cells, and prevented HR12-induced cytoskeletal effects in Rat1/ras cells. No such effects were observed after treatment of Rat1/ras cells with the phosphatidylinositol 3-kinase inhibitor LY294002. These findings establish the Mek/Erk pathway as the dominant pathway involved in conferring the cytoskeletal and junctional manifestations of the Ras-induced transformed phenotype.

Key Words: adherens junctions, farnesyltransferase, Ras, Erk, cytoskeleton


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