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.

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Available from: Guillaume Bompard
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    • "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]. "
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    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.
    Full-text · Article · Mar 2012 · PLoS ONE
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    • "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). "
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    Full-text · Article · Nov 2011 · Oncogene
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    • "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. "
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