Involvement of Rac in actin cytoskeleton rearrangements induced by MIM-B

School of Biosciences, Division of Molecular Cell Biology, University of Birmingham, Edgbaston, Birmingham, B15 2TT UK.
Journal of Cell Science (Impact Factor: 5.43). 12/2005; 118(Pt 22):5393-403. DOI: 10.1242/jcs.02640
Source: PubMed


Numerous scaffold proteins coordinate signals from the environment with actin-based protrusions during shape change and migration. Many scaffolds integrate signals from Rho-family GTPases to effect the assembly of specific actin structures. Here we investigate the mechanism of action MIM-B (missing in metastasis-B) on the actin cytoskeleton. MIM-B binds actin monomer through a WASP homology 2 motif, bundles actin filaments via an IRSp53/MIM domain, and is a long isoform of MIM, a proposed metastasis suppressor. We analysed the activity of MIM-B toward the actin cytoskeleton as well as its potential link to cancer metastasis. Endogenous MIM-B protein is widely expressed and its expression is maintained in various metastatic cell lines. MIM-B induces lamellipodia-like actin-rich protrusions. The IRSp53/MIM domain of MIM-B, as well as Rac activity are required to induce protrusions, but not the WASP homology 2 motif. MIM-B binds and activates Rac via its IRSp53/MIM domain, but this is not sufficient to induce lamellipodia. Finally, our data revealed that actin bundling and Rac-binding properties of MIM-B are not separable. Thus, MIM-B is unlikely to be a metastasis suppressor but acts as a scaffold protein that interacts with Rac, actin and actin-associated proteins to modulate lamellipodia formation.

Download full-text


Available from: Guillaume Bompard,
  • Source
    • "Mtss1 expression (or IRSp53, IRTKS expression) induces a dramatic F-actin accumulation at the rudimentary cell-cell contacts made by fibroblastic cells [20], [21] that was not fully investigated in these previous studies. Neither ΔIMD nor K4D mutants of Mtss1 localized to or induced this phenotype, suggesting the IMD is critical for this activity [20], [21]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell-cell junctions are an integral part of epithelia and are often disrupted in cancer cells during epithelial-to-mesenchymal transition (EMT), which is a main driver of metastatic spread. We show here that Metastasis suppressor-1 (Mtss1; Missing in Metastasis, MIM), a member of the IMD-family of proteins, inhibits cell-cell junction disassembly in wound healing or HGF-induced scatter assays by enhancing cell-cell junction strength. Mtss1 not only makes cells more resistant to cell-cell junction disassembly, but also accelerates the kinetics of adherens junction assembly. Mtss1 drives enhanced junction formation specifically by elevating Rac-GTP. Lastly, we show that Mtss1 depletion reduces recruitment of F-actin at cell-cell junctions. We thus propose that Mtss1 promotes Rac1 activation and actin recruitment driving junction maintenance. We suggest that the observed loss of Mtss1 in cancers may compromise junction stability and thus promote EMT and metastasis.
    PLoS ONE 03/2012; 7(3):e31141. DOI:10.1371/journal.pone.0031141 · 3.23 Impact Factor
  • Source
    • "Because the BAR domains of MIM and IRSp53 have a unique zeppelin-like structure with the membrane binding surface on the convex face (Lee et al 2007, Millard et al 2005, Scita et al 2008), they have been recently used to define a subfamily of the BAR domain proteins as inverse BAR (I-BAR) domain family, including MIM, Abba, IRSp53, IRTKS and FLJ22582. In vitro studies have documented the role of MIM in membrane curvature, which is broadly related to cell migration, endocytosis and cell-substratum interactions (Bompard et al 2005, Lin et al 2005, Mattila et al 2007, Woodings et al 2003). Recent studies with other MIM knockout murine strains also indicated a role of MIM in the intercellular interaction in the kidney cells (Saarikangas et al 2011, Xia et al 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Missing in metastasis (MIM) is a member of newly emerged inverse Bin-Amphiphysin-Rvs (BAR) domain protein family and a putative metastasis suppressor. Although reduced MIM expression has been associated with bladder, breast and gastric cancers, evidence for the role of MIM in tumor progression remains scarce and controversial. Herein we characterized a MIM knockout mouse strain and observed that MIM-deficient mice often developed enlarged spleens. Autopsy and histological analysis revealed that nearly 78% of MIM(-/-) mice developed tumors with features similar to diffuse large B lymphoma during a period from 1 to 2 years. MIM(-/-) mice also exhibited abnormal distribution of B cells in lymphoid organs with decrease in the spleen but increase in the bone marrow and the peripheral blood. Furthermore, the bone marrow of MIM(-/-) mice contained a higher percentage of pre-B2 cells but fewer immature B-cells than wild-type mice. In response to CXCL13, a B-cell chemokine released from splenic stromal cells, MIM-deficient B-cells did not undergo chemotaxis or morphological changes in response to the chemokine and also did not internalize CXCR5, the receptor of CXCL13. Microarray analyses demonstrated that MIM is the only member of the I-BAR domain family that was highly expressed in human B cells. However, low or absent MIM expression was common in either primary B-cell malignancies or established B-cell acute lymphocytic leukemia or lymphomas. Thus, our data demonstrate for the first time an important role for MIM in B-cell development and suggest that predisposition of MIM-null mice to lymphomagenesis may involve aberrant interactions between B lineage cells and the lymphoid microenvironment.
    Oncogene 11/2011; 31(30):3561-8. DOI:10.1038/onc.2011.509 · 8.46 Impact Factor
  • Source
    • "Why Mtss1 is overexpressed during the early development of cancer and then lost during the later metastatic stages is unclear. Mtss1 is a scaffolding protein linking the actin cytoskeleton and the plasma membrane (Bompard et al., 2005; Gonzalez-Quevedo et al., 2005; Lee et al., 2007; Lin et al., 2005; Mattila et al., 2007; Mattila et al., 2003; Woodings et al., 2003). Through this ability, Mtss1 antagonizes EGFR endocytosis during Drosophila oocyte border cell migration (Quinones et al., 2010) and regulates signaling during cilliogenesis suggesting Mtss1 might influence EGFR signaling in cancer. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mtss1 is located within chromosomal region 8q23-24, which is one of the three most commonly amplified regions in head and neck squamous cell carcinoma (HNSCC). Mtss1 is lost in metastatic cells, but confusingly is commonly overexpressed in primary tumors. Here we address possible reasons why Mtss1 is positively selected for in primary tumors. We find that Mtss1 enhances the localization of the epidermal growth factor (EGF) receptor to the plasma membrane, prolonging EGF signaling and resulting in enhanced proliferation in HNSCC. Depletion of Mtss1 results in decreased EGF receptor levels and decreased phosphorylation of Erk1/2 and Akt. However, when cells are at high density and adherent to each other, analogous to conditions in a solid tumor, Mtss1 does not confer any growth advantage, either in basal conditions or following EGF stimulation. This could indicate why Mtss1 might be lost in metastases, but preserved in early primary tumors. This is supported by an organotypic assay showing that Mtss1-expressing cells display a less proliferative more epithelial-like morphology on top of a collagen matrix. Furthermore, xenograft tumors expressing Mtss1 initially grow more rapidly, but later show less proliferation and more differentiation. Mtss1 positively modulates EGF signaling at low cell densities to promote proliferation and, therefore, may be beneficial for the early stages of primary HNSCC tumor growth. However, at high cell densities, Mtss1 impacts negatively on EGF signaling and this suggests why it inhibits metastasis.
    Oncogene 09/2011; 31(14):1781-93. DOI:10.1038/onc.2011.376 · 8.46 Impact Factor
Show more