Tes, a Specific Mena Interacting Partner, Breaks the Rules for EVH1 Binding

Boëda, Batiste; Briggs, Deg; Higgins, Theresa; Garvalov, Boyan K.; Fadden, Andrew J.; McDonald, Neil Q.; Way, Michael

doi:10.1016/j.molcel.2007.10.033

Cited by 66 publications

(81 citation statements)

References 47 publications

(70 reference statements)

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“…It is well understood that a variety of ligands can interact with a single EVH1 domain (Prehoda et al 1999;Boeda et al 2007), and three observations suggest that Dcp1 conforms to this paradigm. First, the Dcp1 PRS-binding site interacts with both Edc1 and Edc2, which promotes a similar coactivating response in Dcp2 (Figs.…”

Section: Discussionmentioning

confidence: 99%

Dcp1 links coactivators of mRNA decapping to Dcp2 by proline recognition

Borja

Piotukh²,

Freund³

et al. 2010

RNA

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Cap hydrolysis is a critical step in several eukaryotic mRNA decay pathways and is carried out by the evolutionarily conserved decapping complex containing Dcp2 at the catalytic core. In yeast, Dcp1 is an essential activator of decapping and coactivators such as Edc1 and Edc2 are thought to enhance activity, though their mechanism remains elusive. Using kinetic analysis we show that a crucial function of Dcp1 is to couple the binding of coactivators of decapping to activation of Dcp2. Edc1 and Edc2 bind Dcp1 via its EVH1 proline recognition site and stimulate decapping by 1000-fold, affecting both the K M for mRNA and rate of the catalytic step. The C-terminus of Edc1 is necessary and sufficient to enhance the catalytic step, while the remainder of the protein likely increases mRNA binding to the decapping complex. Lesions in the Dcp1 EVH1 domain or the Edc1 prolinerich sequence are sufficient to block stimulation. These results identify a new role of Dcp1, which is to link the binding of coactivators to substrate recognition and activation of Dcp2.

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Section: Discussionmentioning

confidence: 99%

Dcp1 links coactivators of mRNA decapping to Dcp2 by proline recognition

Borja

Piotukh²,

Freund³

et al. 2010

RNA

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“…The c-Src-binding site contains two repeats of PPXXP, and mutating either of these to PAXXA blocks the interaction with c-Src and tyrosine phosphorylation. xPMR60 has neither FP4 or similar proline-rich peptides nor a Lim-3-like domain (Boeda et al 2007), so it is unlikely that the Ena/VASP proteins bind through their EVH1 domains. We used Western blotting of protein recovered with the battery of N-and C-terminal deletion ere treated without (À) or with (+) cytochalasin D (CD) prior to lysis.…”

Section: Recovery Of Cytoskeleton-associated Proteins With Xpmr60°-tapmentioning

confidence: 99%

The cytoskeleton-associated Ena/VASP proteins are unanticipated partners of the PMR1 mRNA endonuclease

Peng

Murray²,

Sarkar³

et al. 2009

RNA

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The PMR1 mRNA endonuclease catalyzes the selective decay of a limited number of mRNAs. It participates in multiple complexes, including one containing c-Src, its activating kinase, and one containing its substrate mRNA. This study used tandem affinity purification (TAP) chromatography to identify proteins in HeLa cell S100 associated with the mature 60-kDa form of Xenopus PMR1 (xPMR60). Unexpectedly, this identified a number of cytoskeleton-associated proteins, most notably the Ena family proteins mammalian Enabled (Mena) and vasodilator-stimulated phosphoprotein (VASP). These are regulators of actin dynamics that distribute throughout the cytoplasm and concentrate along the leading edge of the cell. xPMR60 interacts with Mena and VASP in vivo, overexpression of Mena has no impact on mRNA decay, and Mena and VASP are recovered together with xPMR60 in each of the major complexes of PMR1-mRNA decay. In a wound-healing experiment induced expression of active xPMR60 in stably transfected cells resulted in a twofold increase in cell motility compared with uninduced cells or cells expressing inactive xPMR60°. Under these conditions xPMR60 colocalizes with VASP along one edge of the cell.

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“…The INV exon is inserted just after the EVH1 domain, which is primarily responsible for the subcellular localization of Ena/VASP proteins and interactions with several signaling proteins such as Lamellipodin (Gertler et al, 1996;Urbanelli et al, 2006;Pula and Krause, 2008). It is therefore possible that the INV exon might influence the function of Mena INV by regulating its EVH1-mediated interactions (Niebuhr et al, 1997;Boeda et al, 2007). The 11a exon is inserted within the EVH2 domain between the F-actin binding motif and the coiled-coil tetramerization site.…”

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confidence: 99%

Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer

Roussos

Balsamo

Alford

et al. 2011

Journal of Cell Science

167

255

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SummaryWe have shown previously that distinct Mena isoforms are expressed in invasive and migratory tumor cells in vivo and that the invasion isoform (Mena INV ) potentiates carcinoma cell metastasis in murine models of breast cancer. However, the specific step of metastatic progression affected by this isoform and the effects on metastasis of the Mena11a isoform, expressed in primary tumor cells, are largely unknown. Here, we provide evidence that elevated Mena INV increases coordinated streaming motility, and enhances transendothelial migration and intravasation of tumor cells. We demonstrate that promotion of these early stages of metastasis by Mena INV is dependent on a macrophage-tumor cell paracrine loop. Our studies also show that increased Mena11a expression correlates with decreased expression of colony-stimulating factor 1 and a dramatically decreased ability to participate in paracrine-mediated invasion and intravasation. Our results illustrate the importance of paracrine-mediated cell streaming and intravasation on tumor cell dissemination, and demonstrate that the relative abundance of Mena INV and Mena11a helps to regulate these key stages of metastatic progression in breast cancer cells. Journal of Cell Science metastatic progression. Mena is a member of the Ena/VASP family of proteins and binds actin to regulate the geometry and assembly of filament networks through: (1) an anti-capping protein activity (Bear et al., 2002;Barzik et al., 2005; Hansen and Mullins, 2010) that involves binding to profilin and both G-and F-actin; (2) Mena tetramerization, and (3) reduction in the density of actin-related proteins 2 and 3 (Arp2/3)-mediated branching (Gertler et al., 1996;Barzik et al., 2005;Ferron et al., 2007;Pasic et al., 2008;Bear and Gertler, 2009; Hansen and Mullins, 2010). Alternative splicing for the Mena gene has been reported: a 19 amino acid residue insertion just after the EVH1 domain generates the Mena invasion isoform (Mena INV , formerly Mena +++ ) (Gertler et al., 1996;Philippar et al., 2008), whereas a 21 residue insertion in the EVH2 domain generates the Mena11a isoform (Di Modugno et al., 2007). A comparison of the invasive and migratory tumor cells collected in vivo, with primary tumor cells isolated from mouse, rat and human cell-line-derived mammary tumors, revealed that Mena INV expression is upregulated and Mena11a is downregulated selectively in the invasive and migrating carcinoma cell population (Goswami et al., 2009). The differential regulation of Mena isoforms across species suggests that these two isoforms have important roles in invasion and metastasis.In previous studies, we showed that expression of Mena INV in a xenograft mouse mammary tumor promotes increased formation of spontaneous lung metastases from orthotopic tumors and alters the sensitivity of tumor cells to epidermal growth factor (EGF) . We undertook the current study to identify the step(s) in the metastatic cascade that are affected by Mena INV expression and investigate the effect of expression of...

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Tes, a Specific Mena Interacting Partner, Breaks the Rules for EVH1 Binding

Cited by 66 publications

References 47 publications

Dcp1 links coactivators of mRNA decapping to Dcp2 by proline recognition

Dcp1 links coactivators of mRNA decapping to Dcp2 by proline recognition

The cytoskeleton-associated Ena/VASP proteins are unanticipated partners of the PMR1 mRNA endonuclease

Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer

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