Actin binding to WH2 domains regulates nuclear import of the multifunctional actin regulator JMY

Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Molecular biology of the cell (Impact Factor: 4.47). 03/2012; 23(5):853-63. DOI: 10.1091/mbc.E11-12-0992
Source: PubMed


Junction-mediating and regulatory protein (JMY) is a regulator of both transcription and actin filament assembly. In response to DNA damage, JMY accumulates in the nucleus and promotes p53-dependent apoptosis. JMY's actin-regulatory activity relies on a cluster of three actin-binding Wiskott-Aldrich syndrome protein homology 2 (WH2) domains that nucleate filaments directly and also promote nucleation activity of the Arp2/3 complex. In addition to these activities, we find that the WH2 cluster overlaps an atypical, bipartite nuclear localization sequence (NLS) and controls JMY's subcellular localization. Actin monomers bound to the WH2 domains block binding of importins to the NLS and prevent nuclear import of JMY. Mutations that impair actin binding, or cellular perturbations that induce actin filament assembly and decrease the concentration of monomeric actin in the cytoplasm, cause JMY to accumulate in the nucleus. DNA damage induces both cytoplasmic actin polymerization and nuclear import of JMY, and we find that damage-induced nuclear localization of JMY requires both the WH2/NLS region and importin β. On the basis of our results, we propose that actin assembly regulates nuclear import of JMY in response to DNA damage.

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Available from: R. Dyche Mullins, Jan 11, 2014
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    • "The ARP2/3 complex leads to actin polymerization [96]. Furthermore, actin assembly regulates nuclear import of Junction-mediating and regulatory protein, that is a regulator of both transcription and actin filament assembly in response to DNA damage [97]. "
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    07/2015; 4(1). DOI:10.2174/2211536604666150707124640
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    • "Similar to the p53-dependent role of JMY in NIH 3T3 Ras or MCF-7 cells [12], JMY may act as a ‘damage sensor’ to relay signals to the nucleus. Recently, JMY translocation into the nucleus has been shown to involve binding of monomeric actin [9], indicating that cytoplasmic unpolymerized actin may regulate JMY translocation. Furthermore, F-actin assembly in cells is regulated by protein MICAL (Molecule Interacting with CasL), which oxidizes actin with hydrogen peroxide, prevents actin polymerization, and increases the unpolymerized actin level in the presence of oxidative stress [30]. "
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    ABSTRACT: Junction-mediating and regulatory protein(JMY) is a multifunctional protein with roles in the transcriptional co-activation of p53 and the regulation of actin nucleation promoting factors and, hence, cell migration; however, its role in the maturation of porcine oocytes is unclear. In the current study, we investigated functional roles of JMY in porcine oocytes. Porcine oocytes expressed JMY mRNA and protein, and the mRNA expression level decreased during oocyte maturation. Knockdown of JMY by RNA interference decreased the rate of polar body extrusion, validating its role in the asymmetric division of porcine oocytes. JMY knockdown also down-regulated the mRNA and protein levels of actin and Arp2/3. Furthermore, JMY accumulated in the nucleus in response to DNA damage, and JMY knockdown suppressed DNA damage-mediated p53 activation. In conclusion, our results show that JMY has important roles in oocyte maturation as a regulator of actin nucleation-promoting factors and an activator of p53 during DNA damage during DNA damages in porcine oocytes.
    PLoS ONE 10/2014; 9(10):e109385. DOI:10.1371/journal.pone.0109385 · 3.23 Impact Factor
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    • "TABLE I. Continued Proteins IDR(s) Functions related to the IDR(s) Role of disorder Refs JMY, MRTF-A or Phactr1 transcriptional cofactors repeats of WH2/ßT or of RPEL-motifs G-actin and importin-a binding , G-actin-concentrationsensing mechanism regulating nuclear localization for transcription signal integrator, mutually exclusive interactions, cooperative G-actin binding [Mouilleron et al., 2012; Zuchero et al., 2012] "
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    ABSTRACT: Many actin-binding proteins (ABPs) use complex multi-domain architectures to integrate and coordinate multiple signals and interactions with the dynamic remodeling of actin cytoskeleton. In these proteins, small segments that are intrinsically disordered in their unbound native state can be functionally as important as identifiable folded units. These functional intrinsically disordered regions (IDRs) are however difficult to identify and characterize in vitro. Here, we try to summarize the state of the art in understanding the structural features and interfacial properties of IDRs involved in actin self-assembly dynamics. Recent structural and functional insights into the regulation of widespread, multi-functional WH2/β-thymosin domains, and of other IDRs such as those associated with WASP/WAVE, formin or capping proteins are examined. Understanding the functional versatility of IDRs in actin assembly requires apprehending by multiple structural and functional approaches their large conformational plasticity and dynamics in their interactions. In many modular ABPs, IDRs relay labile interactions with multiple partners and act as interaction hubs in interdomain and protein-protein interfaces. They thus control multiple conformational transitions between the inactive and active states or between various active states of multi-domain ABPs, and play an important role to coordinate the high turnover of interactions in actin self-assembly dynamics. © 2013 Wiley Periodicals, Inc.
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