Campus Units

Zoology, Biochemistry, Biophysics and Molecular Biology

Document Type

Article

Publication Version

Published Version

Publication Date

2000

Journal or Book Title

The Journal of Biological Chemistry

Volume

275

Issue

31

First Page

23559

Last Page

23568

DOI

10.1074/jbc.M001368200

Abstract

In PC12 cells, Ha-Ras modulates multiple effector proteins that induce neuronal differentiation. To regulate these pathways Ha-Ras 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 Ha-Ras that lacks a farnesyl group, induced neurites with more actin cytoskeletal changes and lamellipodia than were induced by farnesylated Ha-Ras61L. Ext61L-triggered neurite outgrowth was prevented easily by co-expressing inhibitory Rho, Cdc42, or p21-activated kinase but required increased amounts of inhibitory Rac. Compared with Ha-Ras61L, Ext61L caused 2-fold greater Rac GTP binding and phosphatidylinositol 3-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 Ha-Ras61L. Thus, accentuated differentiation by Ext61L apparently results from heightened activation of one Ras effector (phosphatidylinositol 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 Ha-Ras-effector utilization and suggest a broader role of the lipidated C terminus in Ha-Ras biological functions.

Comments

This research was originally published in The Journal of Biological Chemistry. Michelle A. Booden, Donald S. Sakaguchi, and Janice E. Buss. Mutation of Ha-Ras C Terminus Changes Effector Pathway Utilization. The Journal of Biological Chemistry. 2000, 275: 23559-23568. © the American Society for Biochemistry and Molecular Biology.

Copyright Owner

The American Society for Biochemistry and Molecular Biology, Inc.

Language

en

File Format

application/pdf

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