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RACK1 regulates Ki‐Ras‐mediated signaling and morphological transformation of NIH 3T3 cells
Author(s) -
Bjørndal Bodil,
Myklebust Line M.,
Rosendal Ken Roger,
Myromslien Frøydis D.,
Lorens James B.,
Nolan Garry,
Bruland Ove,
Lillehaug Johan R.
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22373
Subject(s) - 3t3 cells , mapk/erk pathway , signal transduction , microbiology and biotechnology , biology , kinase , protein kinase c , gene isoform , transformation (genetics) , phosphorylation , cell culture , biochemistry , transfection , genetics , gene
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.