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

  1. Bodil Bjørndal1,†,*,
  2. Line M. Myklebust1,†,
  3. Ken Roger Rosendal1,
  4. Frøydis D. Myromslien1,
  5. James B. Lorens2,
  6. Garry Nolan3,
  7. Ove Bruland4,
  8. Johan R. Lillehaug1

Article first published online: 5 DEC 2006

DOI: 10.1002/ijc.22373

Issue

International Journal of Cancer

International Journal of Cancer

Volume 120, Issue 5, pages 961–969, 1 March 2007

Additional Information

How to Cite

Bjørndal, B., Myklebust, L. M., Rosendal, K. R., Myromslien, F. D., Lorens, J. B., Nolan, G., Bruland, O. and Lillehaug, J. R. (2007), RACK1 regulates Ki-Ras-mediated signaling and morphological transformation of NIH 3T3 cells. Int. J. Cancer, 120: 961–969. doi: 10.1002/ijc.22373

Author Information

  1. 1

    Department of Molecular Biology, University of Bergen, Bergen, Norway

  2. 2

    Department of Biomedicine, University of Bergen, Bergen, Norway

  3. 3

    Department of Immunology and Microbiology, Stanford University School of Medicine, Stanford, CA

  4. 4

    Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway

  1. †

    The first 2 authors contributed equally to this work.

*Department of Molecular Biology, University of Bergen, Bergen, Norway

Publication History

  1. Issue published online: 19 JAN 2007
  2. Article first published online: 5 DEC 2006
  3. Manuscript Accepted: 31 AUG 2006
  4. Manuscript Received: 3 JUL 2006

Funded by

  • Norwegian Cancer Society
  • Norwegian Research Council
  • The Locus on Cancer Research, Faculty of Medicine, University of Bergen

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Keywords:

  • ERK;
  • PKC;
  • RACK1;
  • Ras;
  • transformation

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.

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