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CRL2(LRR-1) targets a CDK inhibitor for cell cycle control in C. elegans and actin-based motility regulation in human

Natalia G Starostina1, Jennifer M Simpliciano, Michael A McGuirk

  • 1Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA. ngs@uga.edu

Developmental Cell
|November 16, 2010
PubMed

Insights

The CRL2(LRR-1) ubiquitin ligase regulates Cip/Kip cyclin-dependent kinase inhibitors (CKIs) like p21. This ligase controls cell proliferation and motility by targeting p21 in different cellular compartments.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The Cip/Kip cyclin-dependent kinase inhibitor (CKI) p21(Cip1/WAF1) has distinct roles in the nucleus and cytoplasm.
  • Nuclear p21 inhibits CDK-cyclin complexes to limit cell proliferation.
  • Cytoplasmic p21 influences cell survival and the actin cytoskeleton.

Purpose of the Study:

  • To identify conserved regulators of Cip/Kip CKIs.
  • To investigate the role of CRL2(LRR-1) in regulating p21 function.
  • To understand how CRL2(LRR-1) controls cell cycle progression and cell motility.

Main Methods:

  • Identification of CRL2(LRR-1) as a regulator of CKI-1 and p21.
  • Analysis of CRL2(LRR-1) function in C. elegans germ cells.
  • Investigation of CRL2(LRR1) in human cells, focusing on the Rho/ROCK/LIMK pathway and actin cytoskeleton.

Main Results:

  • CRL2(LRR-1) ubiquitin ligase promotes the degradation of C. elegans CKI-1 and human p21.
  • In C. elegans, CRL2(LRR-1) negatively regulates nuclear CKI-1 for germ cell cycle progression.
  • In human cells, CRL2(LRR1) targets cytoplasmic p21, inhibiting the Rho/ROCK/LIMK pathway and promoting a nonmotile state.

Conclusions:

  • CRL2(LRR-1) is a conserved regulator of Cip/Kip CKIs with distinct functions in different cellular compartments.
  • CRL2(LRR-1) controls cell cycle progression in nematodes and cell motility in humans.
  • Dysregulation of CRL2(LRR1) in human cells leads to actin cytoskeleton reorganization and increased cell motility.

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