title: A novel mutation in β integrin reveals an integrin-mediated interaction between the extracellular matrix and cki-1/p27KIP1.
abstract: The cell-extracellular matrix (ECM) interaction plays an essential role in maintaining tissue shapes and regulates cell behaviors such as cell adhesion, differentiation and proliferation. The mechanism by which the ECM influences the cell cycle in vivo is poorly understood. Here we demonstrate that the β integrin PAT-3 regulates the localization and expression of CKI-1, a C. elegans homologue of the cyclin dependent kinase inhibitor p27(KIP1). In nematodes expressing wild type PAT-3, CKI-1::GFP localizes primarily to nucleoli in hypodermal cells, whereas in animals expressing mutant pat-3 with a defective splice junction, CKI-1::GFP appears clumped and disorganized in nucleoplasm. RNAi analysis links cell adhesion genes to the regulation of CKI-1. RNAi of unc-52/perlecan, ina-1/α integrin, pat-4/ILK, and unc-97/PINCH resulted in abnormal CKI-1::GFP localization. Additional RNAi experiments revealed that the SCF E3 ubiquitin-ligase complex genes, skpt-1/SKP2, cul-1/CUL1 and lin-23/F-box, are required for the proper localization and expression of CKI-1, suggesting that integrin signaling and SCF E3 ligase work together to regulate the cellular distribution of CKI-1. These data also suggest that integrin plays a major role in maintaining proper CKI-1/p27(KIP1) levels in the cell. Perturbed integrin signaling may lead to the inhibition of SCF ligase activity, mislocalization and elevation of CKI-1/p27(KIP1). These results suggest that adhesion signaling is crucial for cell cycle regulation in vivo.
authors.affiliation: Department of Biology, Baylor University, Waco, Texas, United States of America.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kihira
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Yu
authors.forename: Jessica
authors.initials: J
authors.lastname: Cunningham
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Cram
authors.forename: Myeongwoo
authors.initials: M
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015151:Immunoblotting; D039641:Integrin beta Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D039641:Integrin beta Chains; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; C115024:cki-1 protein, C elegans; C093515:pat-3 protein, C elegans; D049452:Green Fluorescent Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27