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Papers In Press, published online ahead of print May 8, 2000
Dept. of Biochemistry, Biophysics, Iowa State University, Ames, IA 50011
Corresponding Author: jbuss{at}iastate.edu
In PC12 cells, HRas modulates multiple effector proteins that induce neuronal differentiation. To regulate these pathways HRas must be located at the plasma membrane, a process normally requiring attachment of farnesyl and palmitate lipids to the C-terminus. Ext61L, a constitutively activated and palmitoylated HRas that lacks a farnesyl group, induced neurites with more actin cytoskeletal changes and lamellipodia than were induced by farnesylated HRas61L. Ext61L-triggered neurite outgrowth was prevented easily by co-expressing inhibitory Rho, Cdc42, and PAK, but required increased amounts of inhibitory Rac. Compared to HRas61L, Ext61L caused 2-fold greater Rac GTP-binding and phosphatidylinositol 3-kinase (PI3-kinase) activity in membranes, a hyperactivation that explained the numerous lamellipodia and ineffectiveness of Rac(N17). In contrast, Ext61L activated B-Raf kinase and ERK phosphorylation more poorly than HRas61L. Thus, accentuated differentiation by Ext61L apparently results from heightened activation of one Ras effector (PI-3 kinase) and suboptimal activation of another (B-Raf). This surprising unbalanced effector activation, without changes in the designated Ras effector domain, indicates the Ext61L C-terminal alternations are a new way to influence HRas:effector utilization and suggest a broader role of the lipidated C-terminus in HRas biological functions.
J. Biol. Chem, 10.1074/jbc.M001368200
Submitted on February 18, 2000
Revised on May 2, 2000
Accepted on May 8, 2000
Mutation of HRas C-terminus changes effector pathway utilization
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