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PLK1-dependent activation of LRRK1 regulates spindle orientation by phosphorylating CDK5RAP2

Hiroshi Hanafusa1, Shin Kedashiro1, Motohiro Tezuka1

  • 1Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.

Nature Cell Biology
|July 21, 2015
PubMed

Insights

Leucine-rich repeat kinase 1 (LRRK1) regulates cell division by orienting the mitotic spindle. This process involves LRRK1 acting downstream of Polo-like kinase 1 (PLK1) and influencing microtubule nucleation via CDK5RAP2.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Accurate mitotic spindle orientation is crucial for correct cell division axis formation.
  • Polo-like kinase 1 (PLK1) is essential for centrosome maturation and spindle orientation, but downstream mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms downstream of PLK1 that regulate mitotic spindle orientation.
  • To identify novel substrates and regulators of centrosome maturation involved in cell division.

Main Methods:

  • Phosphorylation site analysis of LRRK1 by PLK1.
  • Investigating the role of LRRK1 in CDK1-mediated activation and centrosome localization.
  • Assessing the impact of LRRK1 on microtubule nucleation and spindle orientation.
  • Examining the interaction between LRRK1, CDK5RAP2, and gamma-tubulin.

Main Results:

  • LRRK1 is phosphorylated by PLK1 at Ser1790, which is necessary for its activation by CDK1 at centrosomes.
  • Activated LRRK1 nucleates astral microtubule growth, thereby regulating mitotic spindle orientation.
  • LRRK1 phosphorylates CDK5RAP2 at Ser140 within its gamma-tubulin-binding motif, enhancing CDK5RAP2 interaction with gamma-tubulin.
  • This LRRK1-mediated phosphorylation is essential for CDK5RAP2-dependent microtubule nucleation.

Conclusions:

  • LRRK1 acts as a key downstream effector of PLK1 in regulating mitotic spindle orientation.
  • The PLK1-LRRK1-CDK5RAP2 pathway is critical for centrosome maturation and proper microtubule nucleation.
  • These findings reveal a novel mechanism controlling cell division axis orientation through LRRK1-mediated regulation of centrosome function.

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