title: CRL2(LRR-1) targets a CDK inhibitor for cell cycle control in C. elegans and actin-based motility regulation in human cells.
abstract: The Cip/Kip CDK inhibitor (CKI) p21(Cip1/WAF1) has a critical role in the nucleus to limit cell proliferation by inhibiting CDK-cyclin complexes. In contrast, cytoplasmic p21 regulates cell survival and the actin cytoskeleton. These divergent functions for p21 in different cellular compartments suggest the necessity for complex regulation. In this study, we identify the CRL2(LRR-1) ubiquitin ligase as a conserved regulator of Cip/Kip CKIs that promotes the degradation of C. elegans CKI-1 and human p21. The nematode CRL2(LRR-1) complex negatively regulates nuclear CKI-1 levels to ensure G1-phase cell cycle progression in germ cells. In contrast, human CRL2(LRR1) targets cytoplasmic p21, acting as a critical regulator of cell motility that promotes a nonmotile stationary cell state by preventing p21 from inhibiting the Rho/ROCK/LIMK pathway. Inactivation of human CRL2(LRR1) leads to the activation of the actin-depolymerizing protein cofilin, dramatic reorganization of the actin cytoskeleton, and increased cell motility.
authors.affiliation: Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA. ngs@uga.edu
authors.forename: Natalia G
authors.initials: NG
authors.lastname: Starostina
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Simpliciano
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuirk
authors.forename: Edward T
authors.initials: ET
authors.lastname: Kipreos
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D005854:Germ Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; C105153:CUL2 protein, human; D029742:Caenorhabditis elegans Proteins; D044842:Cullin Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C464446:LRR1 protein, human; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins