Pellinen Teijo, Tuomi Saara, Arjonen Antti, Wolf Maija, Edgren Henrik, Meyer Hannelore, Grosse Robert, Kitzing Thomas, Rantala Juha K, Kallioniemi Olli, Fässler Reinhard, Kallio Marko, Ivaska Johanna
Medical Biotechnology, VTT Technical Research Centre of Finland and University of Turku, Turku FIN-20520, Finland.
Medical Biotechnology, VTT Technical Research Centre of Finland and University of Turku, Turku FIN-20520, Finland; FIMM, Institute of Molecular Medicine and the Genome-Scale Biology Research Program, Biomedicum, 00014 University of Helsinki, Helsinki, Finland.
Dev Cell. 2008 Sep;15(3):371-385. doi: 10.1016/j.devcel.2008.08.001.
Adherent cells undergo remarkable changes in shape during cell division. However, the functional interplay between cell adhesion turnover and the mitotic machinery is poorly understood. The endo/exocytic trafficking of integrins is regulated by the small GTPase Rab21, which associates with several integrin alpha subunits. Here, we show that targeted trafficking of integrins to and from the cleavage furrow is required for successful cytokinesis, and that this is regulated by Rab21. Rab21 activity, integrin-Rab21 association, and integrin endocytosis are all necessary for normal cytokinesis, which becomes impaired when integrin-mediated adhesion at the cleavage furrow fails. We also describe a chromosomal deletion and loss of Rab21 gene expression in human cancer, which leads to the accumulation of multinucleate cells. Importantly, reintroduction of Rab21 rescued this phenotype. In conclusion, Rab21-regulated integrin trafficking is essential for normal cell division, and its defects may contribute to multinucleation and genomic instability, which are hallmarks of cancer.
贴壁细胞在细胞分裂过程中会发生显著的形态变化。然而，细胞黏附周转与有丝分裂机制之间的功能相互作用却鲜为人知。整合素的内吞/外排运输由小GTP酶Rab21调控，Rab21与几种整合素α亚基相关联。在此，我们表明，整合素往返于分裂沟的靶向运输是成功进行胞质分裂所必需的，且这一过程受Rab21调控。Rab21活性、整合素与Rab21的关联以及整合素内吞作用对于正常的胞质分裂均必不可少，当整合素介导的分裂沟黏附失败时，胞质分裂就会受损。我们还描述了人类癌症中Rab21基因的染色体缺失和表达缺失，这会导致多核细胞的积累。重要的是，重新引入Rab21可挽救这一表型。总之，Rab21调控的整合素运输对于正常细胞分裂至关重要，其缺陷可能导致多核化和基因组不稳定，而这正是癌症的特征。
