Function and regulation of the Arp2/3 complex during cell migration in diverse environments

Swaney, Kristen F.; Li, Rong

doi:10.1016/j.ceb.2016.04.005

Cited by 97 publications

(93 citation statements)

References 110 publications

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“…In general, migrating cancer cells form actin‐based protrusions, and the Arp2/3 complex mediates actin polymerization during lamellipodium formation and migration in cells. Several studies have shown that the Arp2/3 complex or Arp2/3‐stimulating factors, such as cortactin, are upregulated in malignant gliomas, and inhibition of Arp2/3 activity reduces lamellipodium formation, migration, and invasion . Arp2/3 inhibitors block the migration of both normal and cancer cells; however, ARPC2 inhibitors selectively suppress migration, invasion, and cancer metastasis .…”

Section: Discussionmentioning

confidence: 99%

Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex

et al. 2019

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ARPC2 is a subunit of the Arp2/3 complex, which is essential for lamellipodia, invadopodia and filopodia, and ARPC2 has been identified as a migrastatic target molecule. To identify ARPC2 inhibitors, we generated an ARPC2 knockout DLD‐1 human colon cancer cell line using the clustered regularly interspaced short palindromic repeats/CRISPR‐associated protein 9 (CRISPR/Cas9) system and explored gene signature‐based strategies, such as a connectivity map (CMap) using the gene expression profiling data of ARPC2 knockout and knockdown cells. From the CMap‐based drug discovery strategy, we identified pimozide (a clinically used antipsychotic drug) as a migrastatic drug and ARPC2 inhibitor. Pimozide inhibited the migration and invasion of various cancer cells. Through drug affinity responsive target stability (DARTS) analysis and cellular thermal shift assay (CETSA), it was confirmed that pimozide directly binds to ARPC2. Pimozide increased the lag phase of Arp2/3 complex‐dependent actin polymerization and inhibited the vinculin‐mediated recruitment of ARPC2 to focal adhesions in cancer cells. To validate the likely binding of pimozide to ARPC2, mutant cells, including ARPC2F225A, ARPC2F247A and ARPC2Y250F cells, were prepared using ARPC2 knockout cells prepared by gene‐editing technology. Pimozide strongly inhibited the migration of mutant cells because the mutated ARPC2 likely has a larger binding pocket than the wild‐type ARPC2. Therefore, pimozide is a potential ARPC2 inhibitor, and ARPC2 is a new molecular target. Taken together, the results of the present study provide new insights into the molecular mechanism and target that are responsible for the antitumor and antimetastatic activity of pimozide.

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Section: Discussionmentioning

confidence: 99%

Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex

et al. 2019

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“…We next investigated the source of the physical forces that allow MMPÀ AC invasion. Branched actin networks, driven by Arp2/3 complex actin nucleation, produce migratory and invasive membrane protrusions and have recently been implicated as playing a role in AC invasion (Cá ceres et al, 2018;Swaney and Li, 2016).…”

Section: Loss Of Mmp Function Sensitizes Invasion To Arp2/3 Complex Amentioning

confidence: 99%

Adaptive F-Actin Polymerization and Localized ATP Production Drive Basement Membrane Invasion in the Absence of MMPs

et al. 2019

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“…When activated, the Arp2/3 complex binds to the side of a pre‐existing actin filament, and Arp2 and Arp3, together with an additional actin monomer, form a nucleation core. This trimer then operates as a template for daughter filament elongation . Functionally, the Arp2/3 complex is critical for cell polarity, cell migration and cellular cortex network integrity .…”

Section: Introductionmentioning

confidence: 99%

Partial loss of actin nucleator actin‐related protein 2/3 activity triggers blebbing in primary T lymphocytes

Obeidy

Oehlers

et al. 2019

Immunol Cell Biol

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T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the actin-related protein 2/3 (Arp2/3) complex, a macromolecular machine that nucleates branched actin filaments at the leading edge. The consequences of modulating Arp2/3 activity on the biophysical properties of the actomyosin cortex and downstream T cell function are incompletely understood. We report that even a moderate decrease of Arp3 levels in T cells profoundly affects actin cortex integrity. Reduction in total F-actin content leads to reduced cortical tension and disrupted lamellipodia formation. Instead, in Arp3-knockdown cells, the motility mode is dominated by blebbing migration characterized by transient, balloon-like protrusions at the leading edge. Although this migration mode seems to be compatible with interstitial migration in three-dimensional environments, diminished locomotion kinetics and impaired cytotoxicity interfere with optimal T cell function. These findings define the importance of finely tuned, Arp2/3-dependent mechanophysical membrane integrity in cytotoxic effector T lymphocyte activities.

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Function and regulation of the Arp2/3 complex during cell migration in diverse environments

Cited by 97 publications

References 110 publications

Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex

Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex

Adaptive F-Actin Polymerization and Localized ATP Production Drive Basement Membrane Invasion in the Absence of MMPs

Partial loss of actin nucleator actin‐related protein 2/3 activity triggers blebbing in primary T lymphocytes

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