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

R Rong1, L Y Jiang, M S Sheikh

  • 1Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA.

Oncogene
|June 15, 2007
PubMed

Insights

This study identifies Aurora-A as the first kinase to phosphorylate the RASSF1A tumor suppressor. Aurora-A phosphorylation disrupts RASSF1A

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • RAS-association domain family 1, isoform A (RASSF1A) is a tumor suppressor involved in microtubule stabilization and M-phase cell cycle arrest.
  • Mitotic phosphorylation regulates microtubule-associated proteins, but RASSF1A phosphorylation during mitosis remains largely uncharacterized.

Purpose of the Study:

  • To identify the kinase responsible for RASSF1A phosphorylation during mitosis.
  • To investigate the functional consequences of RASSF1A phosphorylation on its interaction with microtubules and cell cycle regulation.

Main Methods:

  • Identification of Aurora-A as a RASSF1A kinase through interaction and phosphorylation assays.
  • Site-directed mutagenesis to mimic constitutive phosphorylation at Threonine202/Serine203.
  • Assessment of RASSF1A-microtubule interactions and cell cycle arrest.
  • Evaluation of Aurora-A overexpression effects on RASSF1A-mediated growth suppression.

Main Results:

  • Aurora-A directly interacts with and phosphorylates RASSF1A at Threonine202 and/or Serine203.
  • Phosphorylation-mimicking mutations disrupt RASSF1A-microtubule binding and abolish M-phase cell cycle arrest.
  • Aurora-A overexpression interferes with RASSF1A's tumor-suppressive functions.

Conclusions:

  • Aurora-A is a novel kinase for RASSF1A, linking an oncogenic mitotic kinase to this tumor suppressor.
  • Aurora-A-mediated phosphorylation regulates RASSF1A's microtubule interactions and M-phase cell cycle control.
  • This phosphorylation mechanism offers a new target for cancer therapy.

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...