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

Oncogene. 2005 Mar 17;24(12):2059-66. doi: 10.1038/sj.onc.1208412.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Actins / metabolism*
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cortactin
  • Gene Expression Regulation*
  • Mice
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism*
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism*
  • Nerve Tissue Proteins / genetics*
  • Platelet-Derived Growth Factor / pharmacology
  • Sequence Deletion
  • Umbilical Veins
  • Wiskott-Aldrich Syndrome Protein, Neuronal


  • Actins
  • Cortactin
  • Cttn protein, mouse
  • Microfilament Proteins
  • Mtss1 protein, mouse
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Platelet-Derived Growth Factor
  • Wasl protein, mouse
  • Wiskott-Aldrich Syndrome Protein, Neuronal