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Differential regulation of cortactin and N-WASP-mediated actin polymerization by missing in metastasis (MIM) protein

Oncogene volume 24, pages 2059–2066 (2005)Cite this article

Abstract

Missing in metastasis (MIM) gene encodes an actin binding protein that is expressed at low levels in a subset of malignant cell lines. MIM protein tagged by green fluorescent protein (GFP) colocalizes with cortactin, an Arp2/3 complex activator, and interacts directly with the SH3 domain of cortactin. Recombinant full-length MIM promotes markedly cortactin and Arp2/3 complex-mediated actin polymerization in an SH3 dependent manner. In contrast, MIM-CT, a short splicing variant of MIM, binds poorly to cortactin in vitro and is unable to enhance actin polymerization. Full-length MIM binds to G-actin with a similar affinity as N-WASP-VCA, a constitutively active form of N-WASP, and inhibits N-WASP-VCA-mediated actin polymerization as analysed in vitro. The significance of the association of MIM with cortactin and G-actin was evaluated in NIH3T3 cells expressing several MIM constructs. Overexpression of full-length wild-type MIM-GFP inhibited markedly the motility of NIH3T3 cells induced by PDGF and that of human vein umbilical endothelial cells induced by sphingosine 1 phosphate. However, an MIM mutant with deletion of the WH2 domain, which is responsible for G-actin binding, enhanced cell motility. The motility inhibition imposed by MIM was compromised in the cells overexpressing N-WASP. In contrast, deletion of an MIM proline-rich domain, which is required for an optimal binding to cortactin, substantiated the MIM-mediated inhibition of cell motility. These data imply that MIM regulates cell motility by modulating different Arp2/3 activators in a distinguished manner.

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Acknowledgements

We thank Dr Pekka Lappalainen for providing plasmids encoding murine MIM. We also thank Drs Jian-Jiang Hao and Takehito Uruno for the critical reading of the manuscript. This work was supported by NIH Grants R01 HL 52753-10, R01 CA-91984-02 (to XZ).

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  1. Jinxiu Lin

    Present address: Department of Cardiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China

  2. Nicole Smith

    Present address: National Cancer Institute, SAIC-Frederick, MD, 21702, USA

Authors and Affiliations

  1. Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD, 20855, USA

    Jinxiu Lin & Nicole Smith

  2. Department of Pathology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    Jiali Liu, Ying Wang, Jianwei Zhu, Kang Zhou & Xi Zhan

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Correspondence to Xi Zhan.

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Lin, J., Liu, J., Wang, Y. et al. Differential regulation of cortactin and N-WASP-mediated actin polymerization by missing in metastasis (MIM) protein. Oncogene 24, 2059–2066 (2005). https://doi.org/10.1038/sj.onc.1208412

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