A novel role for WAVE1 in controlling actin network growth rate and architecture

Sweeney, Meredith O.; Collins, Agnieszka; Padrick, Shae B.; Goode, Bruce L.

doi:10.1091/mbc.e14-10-1477

Cited by 20 publications

(24 citation statements)

References 60 publications

(83 reference statements)

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“…We also confirmed that WH2 binding does not significantly alter the dissociation rate of ATP‐bound monomers from the barbed ends (Fig EV2), further supporting that the inhibitory effect originates from reduced association. These data reveal that, although soluble WAVE1 WH2 domains slow actin filament elongation [consistent with previous observations by Sweeney et al ()], the same WH2 domains immobilized at high density on a surface actually accelerate filament growth by providing a high local density of polymerization‐competent WH2‐bound actin monomers.…”

Section: Resultssupporting

confidence: 90%

“…Secondly, the proline‐rich domains might help promote filament elongation. This idea is supported by a few recent studies suggesting that WASP‐family NPFs modulate actin filament elongation, but both stimulatory (Khanduja & Kuhn, ) and inhibitory (Sweeney et al , ) effects have been reported. Interestingly, filament elongation factors such as Ena/VASP proteins also contain proline‐rich domains located on the N‐terminal side of WH2‐like sequences, and these proline‐rich domains clearly contribute to actin polymerase activity (Hansen & Mullins, ).…”

Section: Introductionmentioning

confidence: 74%

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WH2 and proline‐rich domains of WASP‐family proteins collaborate to accelerate actin filament elongation

et al. 2017

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WASP‐family proteins are known to promote assembly of branched actin networks by stimulating the filament‐nucleating activity of the Arp2/3 complex. Here, we show that WASP‐family proteins also function as polymerases that accelerate elongation of uncapped actin filaments. When clustered on a surface, WASP‐family proteins can drive branched actin networks to grow much faster than they could by direct incorporation of soluble monomers. This polymerase activity arises from the coordinated action of two regulatory sequences: (i) a WASP homology 2 (WH2) domain that binds actin, and (ii) a proline‐rich sequence that binds profilin–actin complexes. In the absence of profilin, WH2 domains are sufficient to accelerate filament elongation, but in the presence of profilin, proline‐rich sequences are required to support polymerase activity by (i) bringing polymerization‐competent actin monomers in proximity to growing filament ends, and (ii) promoting shuttling of actin monomers from profilin–actin complexes onto nearby WH2 domains. Unoccupied WH2 domains transiently associate with free filament ends, preventing their growth and dynamically tethering the branched actin network to the WASP‐family proteins that create it. Collaboration between WH2 and proline‐rich sequences thus strikes a balance between filament growth and tethering. Our work expands the number of critical roles that WASP‐family proteins play in the assembly of branched actin networks to at least three: (i) promoting dendritic nucleation; (ii) linking actin networks to membranes; and (iii) accelerating filament elongation.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 74%

WH2 and proline‐rich domains of WASP‐family proteins collaborate to accelerate actin filament elongation

et al. 2017

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“…Although the array contained over 1300 proteins, the notable phospho-proteins that were altered dramatically in response to 15α-MP are shown in Supplementary Figure 2. These include targets whose functions impact cellular structurally-directed processes, such as pY731VE-cadherin, a glycoprotein of the cadherin superfamily involved in endothelial cell-cell adhesion (26), pY125WAVE1 (Wiskott-Aldrich syndrome protein), WASP family member involved in regulating the actin cytoskeletal organization (27), pS339CXCR4 a member of the chemokine receptors that regulates morphogenesis, angiogenesis and immune responses (28), and pS10merlin levels, which all increased in response to the treatment with 15α-MP, compared to control (Supplementary Figure 2). Other targets include pY478ezrin, pS147cyclinB1, and pY1507Alk levels, which decreased (Supplementary Figure 2).…”

Section: Resultsmentioning

confidence: 99%

“…Studies using the GBM cell model also reveal the modulation of other putative targets, including VE-cadherin (26), WAVE1 (27), pS339CXCR4 (28), merlin, ezrin, CyclinB1, Erk1/2, and Alk, which would constitute part of the mechanism leading to the antitumor responses to 15α-MP. Functionally, CyclinB1 is a known regulator of the cell cycle (40), Alk promotes growth and anti-apoptotic pathways (41), while ezrin, radixin, moesin (ERM), and merlin comprise the ERM family of proteins, which link membrane proteins to the actin cytoskeleton (34).…”

Section: Discussionmentioning

confidence: 99%

15α-methoxypuupehenol Induces Antitumor Effects In Vitro and In Vivo against Human Glioblastoma and Breast Cancer Models

Hilliard

Miklóssy

Chock

et al. 2017

Molecular Cancer Therapeutics

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Studies with 15α-methoxypuupehenol (15α-MP), obtained from the extracts of Hyrtios sp., identified putative targets that are associated with its antitumor effects against human glioblastoma (GBM) and breast cancer. In the human GBM (U251MG) or breast cancer (MDA-MB-231) cells, treatment with 15α-MP repressed pY705Stat3 (Signal Transducer and Activator of Transcription 3), pErk1/2 (extracellular signal-regulated kinase), pS147CyclinB1, pY507Alk (Anaplastic lymphoma kinase), and pY478ezrin levels, and induced pS10merlin, without inhibiting pJAK2 (Janus kinase) or pAkt induction. 15α-MP treatment induced loss of viability of breast cancer (MDA-MB-231, MDA-MB-468) and GBM (U251MG) lines and GBM patient-derived xenograft cells (G22) that harbor aberrantly-active Stat3, with only moderate or little effect on the human breast cancer, MCF7, colorectal adenocarcinoma Caco-2, normal human lung fibroblast, WI-38, or normal mouse embryonic fibroblast (MEF Stat3fl/fl) lines that do not harbor constitutively-active Stat3, or the Stat3 null (Stat3−/−) mouse astrocytes. 15α-MP-treated U251MG cells have severely impaired F-actin organization and altered morphology, including the cells rounding up, and undergo apoptosis, compared to a moderate, reversible morphology change observed for similarly-treated mouse astrocytes. Treatment further inhibited U251MG or MDA-MB-231 cell proliferation, anchorage-independent growth, colony formation, and migration in vitro, while only moderately or weakly affecting MCF7 cells or normal mouse astrocytes. Oral gavage delivery of 15α-MP inhibited the growth of U251MG subcutaneous tumor xenografts in mice, associated with apoptosis in the treated tumor tissues. Results together suggest the modulation of Stat3, CyclinB1, Alk, ezrin, merlin, and Erk1/2 functions contributes to the antitumor effects of 15α-MP against GBM and breast cancer progression.

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“…While SCAR alone can promote protrusion formation and fusion at adhesion sites, the additional activities of the WASp/WIP complex permit formation of a broad contact zone and a large, robust focus. These different properties may arise from previously described inherent differences in the NPF and branching activities of WASp and SCAR [Zalevsky et al 2001; Yarar et al 2002; Kang et al 2010; Sweeney et al 2014], from additional effects on the actin network (e.g. barbed end capping by WASp [Co et al 2007; Khanduja and Kuhn 2014]), or perhaps on differential efficiency or spatial control of activation for each NPF.…”

Section: Case Studies In Drosophila Cell Biologymentioning

confidence: 99%

Drosophila comes of age as a model system for understanding the function of cytoskeletal proteins in cells, tissues, and organisms

2015

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For the last 100 years, Drosophila melanogaster has been a powerhouse genetic system for understanding mechanisms of inheritance, development, and behavior in animals. In recent years, advances in imaging and genetic tools have led to Drosophila becoming one of the most effective systems for unlocking the subcellular functions of proteins (and particularly cytoskeletal proteins) in complex developmental settings. In this review, written for non‐Drosophila experts, we will discuss critical technical advances that have enabled these cell biological insights, highlighting three examples of cytoskeletal discoveries that have arisen as a result: (1) regulation of Arp2/3 complex in myoblast fusion, (2) cooperation of the actin filament nucleators Spire and Cappuccino in establishment of oocyte polarity, and (3) coordination of supracellular myosin cables. These specific examples illustrate the unique power of Drosophila both to uncover new cytoskeletal structures and functions, and to place these discoveries in a broader in vivo context, providing insights that would have been impossible in a cell culture model or in vitro. Many of the cellular structures identified in Drosophila have clear counterparts in mammalian cells and tissues, and therefore elucidating cytoskeletal functions in Drosophila will be broadly applicable to other organisms. © 2015 Wiley Periodicals, Inc.

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A novel role for WAVE1 in controlling actin network growth rate and architecture

Cited by 20 publications

References 60 publications

WH2 and proline‐rich domains of WASP‐family proteins collaborate to accelerate actin filament elongation

WH2 and proline‐rich domains of WASP‐family proteins collaborate to accelerate actin filament elongation

15α-methoxypuupehenol Induces Antitumor Effects In Vitro and In Vivo against Human Glioblastoma and Breast Cancer Models

Drosophila comes of age as a model system for understanding the function of cytoskeletal proteins in cells, tissues, and organisms

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