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

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.

• Authors: R Rong, L Y Jiang, M S Sheikh, Y Huang
• Journal: Oncogene (Oncogene) Vol. 26 Issue 55 Pg. 7700-8 (Dec 06 2007) ISSN: 1476-5594 [Electronic] England
• PMID: 17563743 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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