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Prenylation is not necessary for endogenous Ras activation in non‐malignant cells
Author(s) -
Khwaja Arif,
Dockrell Mark E.C.,
Hendry Bruce M.,
Sharpe Claire C.
Publication year - 2005
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20641
Subject(s) - prenylation , geranylgeranylation , microbiology and biotechnology , anti apoptotic ras signalling cascade , farnesyltransferase inhibitor , farnesyltransferase , cell growth , biology , cell culture , gtpase , kinase , mapk/erk pathway , biochemistry , enzyme , genetics
Ras monomeric GTPases are pivotal to many core cellular processes such as proliferation and differentiation. The post‐translational prenylation of Ras with a farnesyl or a geranylgeranyl moiety is thought to be critical for its membrane binding and consequent signaling activity. Inhibitors of Ras prenylation have an anti‐proliferative effect in some Ras‐transformed cells. We present a study of the effects of prenylation inhibitors on endogenous, wild‐type Ras in three renal cell types, namely primary adult human renal fibroblasts, primary adult human mesangial cells, and a primate renal fibroblast cell line (Vero cells). We have previously demonstrated that Ras is necessary for normal proliferation in these cells. Here we show that Ras is farnesylated and not geranylgeranylated in all three cell types. Furthermore, inhibiting Ras farnesylation has no effect on cell proliferation or Ras activation. Although inhibiting geranylgeranylation in these cells does inhibit proliferation, this is through an Ras‐independent mechanism. Non‐prenylated Ras is able to localize to the plasma membrane, bind Raf when cells are stimulated by epidermal growth factor or platelet‐derived growth factor, and activate the Ras downstream effectors mitogen‐activated protein kinase and phosphotidylinositol 3‐kinase. We conclude that in wild‐type cells, endogenous Ras does not need to be prenylated to be active. J. Cell. Biochem. © 2005 Wiley‐Liss, Inc.