Nercc1, a mammalian NIMA-family kinase, binds the Ran GTPase and regulates mitotic progression

  1. Joan Roig,
  2. Alexei Mikhailov,
  3. Christopher Belham, and
  4. Joseph Avruch1
  1. Department of Molecular Biology and the Diabetes Unit and Medical Services, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA

Abstract

The protein kinase NIMA is an indispensable pleiotropic regulator of mitotic progression in Aspergillus. Although several mammalian NIMA-like kinases (Neks) are known, none appears to have the broad importance for mitotic regulation attributed to NIMA. Nercc1 is a new NIMA-like kinase that regulates chromosome alignment and segregation in mitosis. Its NIMA-like catalytic domain is followed by a noncatalytic tail containing seven repeats homologous to those of the Ran GEF, RCC1, a Ser/Thr/Pro-rich segment, and a coiled-coil domain. Nercc1 binds to another NIMA-like kinase, Nek6, and also binds specifically to the Ran GTPase through both its catalytic and its RCC1-like domains, preferring RanGDP in vivo. Nercc1 exists as a homooligomer and can autoactivate in vitro by autophosphorylation. Nercc1 is a cytoplasmic protein that is activated during mitosis and is avidly phosphorylated by active p34Cdc2. Microinjection of anti-Nercc1 antibodies in prophase results in spindle abnormalities and/or chromosomal misalignment. In Ptk2 cells the outcome is prometaphase arrest or aberrant chromosome segregation and aneuploidy, whereas in CFPAC-1 cells prolonged arrest in prometaphase is the usual response. Nercc1 and its partner Nek6 represent a new signaling pathway that regulates mitotic progression.

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Footnotes

  • 1 Corresponding author.

  • E-MAIL avruch{at}helix.mgh.harvard.edu; FAX (617) 726-5649.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.972202.

    • Received December 20, 2001.
    • Accepted May 16, 2002.
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