Coronin 1B Antagonizes Cortactin and Remodels Arp2/3-Containing Actin Branches in Lamellipodia

Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Cell (Impact Factor: 32.24). 10/2008; 134(5):828-42. DOI: 10.1016/j.cell.2008.06.054
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The dendritic actin network generated by the Arp2/3 complex in lamellipodia underlies formation of protrusions, directional sensing, and migration. While the generation of this network is well studied, the mechanisms regulating network disassembly are poorly understood. We report that Coronin 1B disassembles Arp2/3-containing actin filament branches by inducing Arp2/3 dissociation. This activity is antagonized by Cortactin, a filament branch stabilizer. Consistent with this biochemical competition, depletion of both proteins partially rescues defects in lamellipodial dynamics observed upon depletion of either protein alone. Coronin 1B targets actin branches in a manner that is mutually exclusive with the Arp2/3 complex and alters the branch angle. We conclude that Coronin 1B replaces the Arp2/3 complex at actin filament branches as the dendritic network matures and drives the turnover of branched actin networks.

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    • "g control of WAVE2 - mediated actin polymerization by PI ( 3 , 4 , 5 ) P 3 ( Oikawa et al . , 2004 ) . In ad - dition , disassembly of lamellipodial branched actin networks may rely on other molecular mechanisms that promote deb - ranching such as antagonism of cortactin by coronin and of antagonism of Arp2 / 3 complex by glial maturation factor ( Cai et al . , 2008 ; Gandhi et al . , 2010 ; Luan and Nolen , 2013 ; Yden - berg et al . , 2013 ) . Endosomal actin turnover is also likely to be controlled by actin severing factors such as cofilin . Although we cannot rule out a role for such factors in PI ( 3 , 5 ) P 2 - mediated regulation of actin stability , inhibition of PI ( 3 , 5 ) P 2 synthesis "
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    ABSTRACT: Branched actin critically contributes to membrane trafficking by regulating membrane curvature, dynamics, fission, and transport. However, how actin dynamics are controlled at membranes is poorly understood. Here, we identify the branched actin regulator cortactin as a direct binding partner of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) and demonstrate that their interaction promotes turnover of late endosomal actin. In vitro biochemical studies indicated that cortactin binds PI(3,5)P2 via its actin filament-binding region. Furthermore, PI(3,5)P2 competed with actin filaments for binding to cortactin, thereby antagonizing cortactin activity. These findings suggest that PI(3,5)P2 formation on endosomes may remove cortactin from endosome-associated branched actin. Indeed, inhibition of PI(3,5)P2 production led to cortactin accumulation and actin stabilization on Rab7(+) endosomes. Conversely, inhibition of Arp2/3 complex activity greatly reduced cortactin localization to late endosomes. Knockdown of cortactin reversed PI(3,5)P2-inhibitor-induced actin accumulation and stabilization on endosomes. These data suggest a model in which PI(3,5)P2 binding removes cortactin from late endosomal branched actin networks and thereby promotes net actin turnover. © 2015 Hong et al.
    The Journal of Cell Biology 08/2015; 210(5):753-69. DOI:10.1083/jcb.201412127 · 9.83 Impact Factor
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    • "We speculate that both up-and downregulation of Src and cortactin affect actin networks and bundles, resulting in an imbalance of actin-driven forces that controls the positioning of filopodia within lamellipodia compared with control conditions. These results indicate that Src and cortactin play a critical role in integrating filopodia within the lamellipodial actin network (Figure 9, process 2; most likely via Arp2/3), as well as in stabilizing actin bundles in filopodia (Figure 9, process 3; most likely via dynamin), consistent with recent studies proposing that cortactin and dynamin stabilize actin bundles in growth cone filopodia (Yamada et al., 2013) and that cortactin stabilizes actin branches in nonneuronal cells (Weaver et al., 2001; Cai et al., 2008). The fact that CortF but not CASrc2 expression alone affected large-scale lateral movement of filopodia, whereas the combinatorial expression restored the phenotype to control levels, could suggest that CASrc2 acts through an additional pathway in this case. "
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    ABSTRACT: Src tyrosine kinases have been implicated in axonal growth and guidance; however, the underlying cellular mechanisms are not well understood. Specifically, it is unclear which aspects of actin organization and dynamics are regulated by Src in neuronal growth cones. Here, we investigated the function of Src2 and one of its substrates, cortactin, in lamellipodia and filopodia of Aplysia growth cones. We found that up-regulation of Src2 activation state or cortactin increased lamellipodial length, protrusion time, and actin network density, whereas down-regulation had opposite effects. Furthermore, Src2 or cortactin up-regulation increased filopodial density, length, and protrusion time, whereas down-regulation promoted lateral movements of filopodia. Fluorescent speckle microscopy revealed that rates of actin assembly and retrograde flow were not affected in either case. In summary, our results support a model whereby Src and cortactin regulate growth cone motility by increasing actin network density and protrusion persistence of lamellipodia by controlling the state of actin-driven protrusion versus retraction. In addition, both proteins promote the formation and stability of actin bundles in filopodia. © 2015 by The American Society for Cell Biology.
    Molecular biology of the cell 07/2015; 26(18). DOI:10.1091/mbc.E15-03-0142 · 4.47 Impact Factor
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    • "SSH dephosphorylates Coronin 1B and Cofilin (step 5; Cai et al., 2007; this paper). Dephosphorylated Coronin 1B binds Arp2/3 complex and removes it from the branch (step 6; Cai et al., 2008). The destabilized branch is then severed by active Cofilin (Pollard and Borisy, 2003). "
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    ABSTRACT: We previously identified Waf1 Cip1 stabilizing protein 39 (WISp39) as a binding partner for heat shock protein 90 (Hsp90). We now report that WISp39 has an essential function in the control of directed cell migration, which requires WISp39 interaction with Hsp90. WISp39 knockdown (KD) resulted in the loss of directional motility of mammalian cells and profound changes in cell morphology, including the loss of a single leading edge. WISp39 binds Coronin 1B, known to regulate the Arp2/3 complex and Cofilin at the leading edge. WISp39 preferentially interacts with phosphorylated Coronin 1B, allowing it to complex with Slingshot phosphatase (SSH) to dephosphorylate and activate Cofilin. WISp39 also regulates Arp2/3 complex localization at the leading edge. WISp39 KD-induced morphological changes could be rescued by overexpression of Coronin 1B together with a constitutively active Cofilin mutant. We conclude that WISp39 associates with Hsp90, Coronin 1B, and SSH to regulate Cofilin activation and Arp2/3 complex localization at the leading edge. © 2015 Howell et al.
    The Journal of Cell Biology 03/2015; 208(7). DOI:10.1083/jcb.201410095 · 9.83 Impact Factor
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