CK-666 and CK-869 differentially inhibit Arp2/3 iso-complexes.
LuYan Cao1, Shaina Huang2, Angika Basant2
1The Francis Crick Institute, London, UK. luyan.cao@crick.ac.uk.
EMBO Reports
|July 15, 2024
Summary
The Arp2/3 complex inhibitors CK-666 and CK-869 show differential activity against mammalian iso-complexes. Their effectiveness in inhibiting actin nucleation and branching depends on specific subunit composition, impacting cell functions like migration.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The Arp2/3 complex is crucial for actin nucleation and cellular processes.
- CK-666 and CK-869 are common chemical probes for Arp2/3 complex function.
- Mammalian Arp2/3 complex exists as multiple iso-complexes due to gene duplication.
Purpose of the Study:
- To investigate the differential activity of CK-666 and CK-869 against distinct Arp2/3 iso-complexes.
- To determine how iso-complex composition affects inhibitor efficacy in actin nucleation and branching.
- To clarify the implications of iso-complex heterogeneity for interpreting experimental results.
Main Methods:
- Utilized recombinant Arp2/3 complexes with defined subunit compositions.
- Assessed the activity of CK-666 and CK-869 on linear actin filament formation and branching.
- Examined inhibitor effects on phagocytosis and cell migration in bone marrow-derived macrophages.
Main Results:
- Both CK-666 and CK-869 inhibit linear actin formation across different ArpC1 iso-complexes.
- Actin branching inhibition is iso-complex dependent: both drugs inhibit ArpC1A complexes, but only CK-869 inhibits ArpC1B complexes.
- CK-869, but not CK-666, impaired macrophage phagocytosis and migration, correlating with low ArpC1A expression.
Conclusions:
- The efficacy of CK-666 and CK-869 is significantly influenced by Arp2/3 iso-complex composition.
- CK-869 exhibits broader inhibitory activity against ArpC1 and Arp3 iso-complexes compared to CK-666.
- Findings necessitate careful consideration of Arp2/3 iso-complex expression when interpreting studies using these inhibitors.
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