Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation

Oncogene. 2007 Dec 6;26(55):7700-8. doi: 10.1038/sj.onc.1210575. Epub 2007 Jun 11.

Abstract

RASSF1A (RAS-association domain family 1, isoform A) is a newer tumor suppressor that binds to and stabilizes microtubules as well as induces M-phase cell cycle arrest. Several other proteins that interact with and stabilize microtubules also undergo mitotic phase phosphorylation to regulate microtubule dynamics and M-phase cell cycle progression. Currently, however, there is a paucity of information regarding the phosphorylation status of RASSF1A and its regulation during mitosis. In this study, for the first time, we demonstrate that Aurora-A is a RASSF1A kinase and, to the best of our knowledge, this is also the first study reporting the identification of a kinase for RASSF1A. We show that the mitotic kinase Aurora-A directly interacts with and phosphorylates RASSF1 and that RASSF1A is phosphorylated by Aurora-A during mitosis. These findings therefore link an important oncogenic mitotic kinase to regulate RASSF1A tumor suppressor. Aurora-A appears to phosphorylate RASSF1A at Threonine202 and/or Serine203 that reside within the known microtubule-binding domain of RASSF1A. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of RASSF1A, disrupt RASSF1A interactions with microtubules and abolish its ability to induce M-phase cell cycle arrest. Our results further demonstrate that Aurora-A overexpression also interferes with RASSF1A-mediated growth suppression. In view of our results, we propose that Aurora-A-mediated phosphorylation of RASSF1A is a novel mechanism that regulates the ability of this tumor suppressor to interact with microtubules and modulate M-phase cell cycle progression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aurora Kinases
  • Cell Cycle* / genetics
  • Cell Division* / genetics
  • Cell Line
  • Humans
  • Immunoprecipitation
  • Microtubules / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Serine / chemistry
  • Serine / genetics
  • Threonine / chemistry
  • Threonine / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • RASSF1 protein, human
  • Tumor Suppressor Proteins
  • Threonine
  • Serine
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases