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

Jinxiu Lin, Jiali Liu, Ying Wang, Jianwei Zhu, Kang Zhou, Nicole Smith, Xi Zhan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2059-2066
Number of pages8
JournalOncogene
Volume24
Issue number12
DOIs
StatePublished - Mar 17 2005

Keywords

  • Actin
  • Cell motility
  • Cortactin
  • MIM
  • N-WASP
  • PDGF

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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