Abl2/Abl-related Gene Stabilizes Actin Filaments, Stimulates Actin Branching by Actin-related Protein 2/3 Complex, and Promotes Actin Filament Severing by Cofilin

Courtemanche, Naomi; Gifford, Stacey M.; Simpson, Mark A.; Pollard, Thomas D.; Koleske, Anthony J.

doi:10.1074/jbc.m114.608117

Cited by 37 publications

(49 citation statements)

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“…19,20,[35][36][37] The role of Rac and Cdc42 in promoting growth is achieved through actin filament nucleation by ARP2/3 and Pak activities. [39][40][41] We speculate that the role of Pak in retraction may be to promote depolymerization of actin filaments through LIMK activity. Such depolymerization would be necessary to form new actin cytoskeleton in either filopodia or lamellipodia.…”

Section: Discussionmentioning

confidence: 92%

“…5,7,38 LIM kinase is well known to function in regulating actin polymerization in cooperation with the pathways that promote nucleation and extension of new actin filament branches. [39][40][41] Our study therefore also investigates the effect of LIMK inhibition on process outgrowth and explores the possibility that using inhibition of a single kinase, LIMK, can reduce both forms of structural plasticity, axonal retraction and neuritic sprouting.…”

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confidence: 99%

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LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

Wang

Townes‐Anderson

2015

Invest. Ophthalmol. Vis. Sci.

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METHODS. Phosphorylated LIMK (p-LIMK), the active form of LIMK, was examined in salamander retina with Western blot and confocal microscopy. Axon length within the first 7 hours and process growth after 3 days of culture were assessed in isolated rod photoreceptors treated with inhibitors of upstream regulators ROCK and p21-activated kinase (Pak) (Y27632 and IPA-3) and a direct LIMK inhibitor (BMS-5). Porcine retinal explants were also treated with BMS-5 and analyzed 24 hours after detachment. Because Ca 2þ influx contributes to axonal retraction, L-type channels were blocked in some experiments with nicardipine. RESULTS.Phosphorylated LIMK is present in rod terminals during retraction and in newly formed processes. Axonal retraction over 7 hours was significantly reduced by inhibition of LIMK or its regulators, ROCK and Pak. Process growth was reduced by LIMK or Pak inhibition especially at the basal (axon-bearing) region of the rod cells. Combining Ca 2þ channel and LIMK inhibition had no additional effect on retraction but did further inhibit sprouting after 3 days. In detached porcine retina, LIMK inhibition reduced rod axonal retraction and improved retinal morphology.CONCLUSIONS. Thus structural remodeling, in the form of either axonal retraction or neuritic growth, requires LIMK activity. LIM kinase inhibition may have therapeutic potential for reducing pathologic rod terminal plasticity after retinal injury.

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Section: Discussionmentioning

confidence: 92%

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confidence: 99%

LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

Wang

Townes‐Anderson

2015

Invest. Ophthalmol. Vis. Sci.

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“…Notably, effector proteins, which were also shown to be phosphorylated in tonic as well as activated BCR signaling, are not yet linked to the main BCR signaling hub and may point to hitherto unknown BCR-signaling complexes. These effector proteins include components of the cytoskeleton, such as γ-actin (ACTG1) and α-tubulin (TUBA1B), as well as putative cytoskeleton regulators like Abelson protein tyrosine kinase 2 (ABL2) (22) and Leupaxin (LPXN) (23). The latter has also been described as a negative regulator of BCR signaling (24).…”

Section: Bcr Signaling Network In Blmentioning

confidence: 99%

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

Corso

Pan

Walter

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeletonrelated processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments.lymphoma | B-cell receptor | phosphoproteome | cancer biology

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“…Abl family kinases, including Arg, are master regulators of actin structure in diverse biological contexts (Bradley and Koleske, 2009), suggesting that Arg regulates dendritic spine size and stability through direct regulation of the actin cytoskeleton. Arg interacts with actin and the Arp2/3 complex activator cortactin to promote actin branch nucleation and stabilize actin filaments (MacGrath and Koleske, 2012;Courtemanche et al, 2015), and Arg knockdown in cultured hippocampal neurons causes cortactin depletion from spines coincident with spine loss. Tethering cortactin in dendritic spines rescues this spine loss, suggesting that cortactin depletion is a key trigger for spine loss in arg Ϫ/Ϫ spines (Lin et al, 2013).…”

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confidence: 99%

“…It is possible that Arg normally restricts spine enlargement and loss of Arg relieves this brake on spine size. Mechanistically, Arg binding to actin filaments can promote actin filament severing by cofilin (Courtemanche et al, 2015), suggesting that Arg may restrict spine volume by limiting the size or complexity of the actin cytoskeleton of the spine. Alternatively, recent studies (Govindarajan et al, 2011; Makino and Malinow, 2011; Rochefort and Konnerth, 2012) suggest that the size and plasticity of spines clustered along a dendritic segment may be coordinately regulated via their shared use of a limited pool of plasticity-related proteins.…”

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confidence: 99%

Disruption of Coordinated Presynaptic and Postsynaptic Maturation Underlies the Defects in Hippocampal Synapse Stability and Plasticity in Abl2/Arg-Deficient Mice

Xiao

Levy²,

Rosenberg³

et al. 2016

J. Neurosci.

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Immature glutamatergic synapses in cultured neurons contain high-release probability (P r ) presynaptic sites coupled to postsynaptic sites bearing GluN2B-containing NMDA receptors (NMDARs), which mature into low-P r , GluN2B-deficient synapses. Whether this coordinated maturation of high-P r , GluN2B ϩ synapses to low-P r , GluN2B-deficient synapses actually occurs in vivo, and if so, what factors regulate it and what role it might play in long-term synapse function and plasticity are unknown. We report that loss of the integrinregulated Abl2/Arg kinase in vivo yields a subpopulation of "immature" high-P r , GluN2B ϩ hippocampal synapses that are maintained throughout late postnatal development and early adulthood. These high-P r , GluN2B ϩ synapses are evident in arg Ϫ/Ϫ animals as early as postnatal day 21 (P21), a time that precedes any observable defects in synapse or dendritic spine number or structure in arg Ϫ/Ϫ mice. Using focal glutamate uncaging at individual synapses, we find only a subpopulation of arg Ϫ/Ϫ spines exhibits increased GluN2B-mediated responses at P21. As arg Ϫ/Ϫ mice age, these synapses increase in proportion, and their associated spines enlarge. These changes coincide with an overall loss of spines and synapses in the Arg-deficient mice. We also demonstrate that, although LTP and LTD are normal in P21 arg Ϫ/Ϫ slices, both forms of plasticity are significantly altered by P42. These data demonstrate that the integrin-regulated Arg kinase coordinates the maturation of presynaptic and postsynaptic compartments in a subset of hippocampal synapses in vivo, and this coordination is critical for NMDAR-dependent long-term synaptic stability and plasticity.

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Abl2/Abl-related Gene Stabilizes Actin Filaments, Stimulates Actin Branching by Actin-related Protein 2/3 Complex, and Promotes Actin Filament Severing by Cofilin

Cited by 37 publications

References 47 publications

LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

Disruption of Coordinated Presynaptic and Postsynaptic Maturation Underlies the Defects in Hippocampal Synapse Stability and Plasticity in Abl2/Arg-Deficient Mice

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