RACK1 regulates Ki-Ras-mediated signaling and morphological transformation of NIH 3T3 cells

✍ Scribed by Bodil Bjørndal; Line M. Myklebust; Ken Roger Rosendal; Frøydis D. Myromslien; James B. Lorens; Garry Nolan; Ove Bruland; Johan R. Lillehaug

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: French
• Weight: 746 KB
• Volume: 120
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.22373

✦ Synopsis

Abstract

Activating Ras mutations are involved in a significant fraction of human tumors. A suppressor screen using a retroviral mouse fibroblast cDNA library was performed to identify novel factors in Ras‐mediated transformation. We identified a novel potent inhibitor of Ras‐mediated morphological transformation encoded by a truncated version of the receptor for activated C‐kinase (RACK1). The truncated protein, designated RACK1ΔWD1, lacked the N‐terminal 49 amino acids encoding the first of the 7 WD40 repeats in RACK1. RACK1ΔWD1 expression restored contact inhibition, stress fiber formation and reduced ERK phosphorylation in Ki‐Ras transformed NIH 3T3 cells. We demonstrate that truncated RACK1 is involved in complexes consisting of wild‐type RACK1 and protein kinase C isoforms α, βI and δ, compromising the transduction of an activated Ras signal to the Raf‐MEK‐ERK pathway. The cellular localization of RACK1ΔWD1 differed from wtRACK1, indicating that signaling complexes containing the truncated version of RACK1 are incorrectly localized. Notably, 12‐O‐tetradecanoyl‐13‐phorbol acetate (TPA) mediated intracellular translocation of RACK1‐interacting PKC α and δ was abrogated in RACK1ΔWD1‐expressing cells. Our data support a model where RACK1 acts as a key factor in Ki‐Ras‐mediated morphological transformation. © 2006 Wiley‐Liss, Inc.