Affinage

BRK1

Protein BRICK1 · UniProt Q8WUW1

Length
75 aa
Mass
8.7 kDa
Annotated
2026-06-09
13 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BRK1 (HSPC300/C3orf10) is a small obligate subunit of the WAVE/SCAR Regulatory Complex (WRC) that couples Rho-GTPase signaling to Arp2/3-driven actin nucleation, and it functions principally to assemble and stabilize the complex (PMID:17894861, PMID:19228419). It physically associates with SCAR/WAVE and Abi/CYFIP family subunits, and the N-terminus of SCAR/WAVE is necessary and sufficient for this interaction and for SCAR's incorporation into the high-molecular-weight complex (PMID:17894861, PMID:17314411). Structurally, free BRK1 forms a homotrimeric parallel triple coiled-coil bundle that closely mirrors the heterotrimeric helical bundle it forms with WAVE1 and Abi2 inside the WRC, and it dissociates as a homotrimer at nanomolar concentrations, identifying it as a homooligomeric precursor for complex assembly (PMID:21701600). Its central role is post-translational stabilization of SCAR/WAVE: loss of BRK1 triggers degradation of SCAR/WAVE2/WAVE3 protein and reduces other complex subunits across Dictyostelium, human cancer cells, and T cells (PMID:19228419, PMID:19576655, PMID:29656550). Functionally, BRK1 is required for lamellipodia/pseudopodia formation, actin filament organization, cell migration and invasion, cytokinesis, neuronal process outgrowth, and immunological synapse formation in T cells (PMID:19576655, PMID:17311301, PMID:23939472, PMID:29656550). A stapled BRK1-mimetic peptide that disrupts the BRK1 binding interface with WASF3 and ABI2 inhibits cancer cell migration and invasion, establishing the assembly interface as druggable (PMID:40832548). BRK1 transcription is positively regulated by Sp1 binding to its promoter and negatively regulated by NRF-1, while miR-181c represses it post-transcriptionally (PMID:24680773, PMID:23939472, PMID:29656550).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2007 High

    Establishing BRK1/HSPC300 as an indispensable physical and genetic component of the WAVE/SCAR complex answered whether it was a true subunit rather than a peripheral associate.

    Evidence Co-IP, loss-of-function and genetic rescue in Drosophila; in vitro binding and deletion mapping in Dictyostelium

    PMID:17314411 PMID:17894861

    Open questions at the time
    • Stoichiometry within the assembled complex not resolved
    • Mechanism of GTPase coupling not addressed
  2. 2009 High

    Demonstrating that BRK1 loss causes post-translational degradation of SCAR/WAVE (but not PIR121) defined its core role as a stabilizer of the complex rather than a catalytic effector.

    Evidence Gene knockout with Western blot protein-level analysis and migration/morphology assays in Dictyostelium; Co-IP and siRNA with WAVE2 degradation in human lung cancer cells

    PMID:19228419 PMID:19576655

    Open questions at the time
    • Degradation pathway (proteasomal/lysosomal) not identified
    • Whether stabilization is purely structural or also regulatory unknown
  3. 2011 High

    The 1.5 A crystal structure showed BRK1 forms a homotrimeric coiled-coil precursor structurally analogous to its heterotrimeric arrangement in the WRC, providing a structural model for how it primes complex assembly.

    Evidence X-ray crystallography, analytical ultracentrifugation, gel filtration, and subunit-exchange assays

    PMID:21701600

    Open questions at the time
    • Kinetics of homotrimer-to-heterotrimer transition in vivo unknown
    • Trigger for incorporation into the WRC not defined
  4. 2014 Medium

    Identifying Sp1 as a direct positive transcriptional regulator (and NRF-1 as a negative regulator) began mapping how BRK1 abundance is controlled, relevant to its dosage-sensitive stabilizing role.

    Evidence Promoter reporter, site-directed mutagenesis, EMSA, ChIP and siRNA in NSCLC cells; reporter and KD in neurons for NRF-1

    PMID:23939472 PMID:24680773

    Open questions at the time
    • Physiological conditions controlling each regulator unknown
    • Interplay between Sp1 and NRF-1 not addressed
  5. 2018 Medium

    Showing miR-181c represses BRK1 and that BRK1 loss collapses immunological synapse formation extended its stabilizing function to an immune-cell context and added a post-transcriptional control layer.

    Evidence miRNA target validation, siRNA/overexpression, actin polymerization assay, synapse imaging and Western blot in CD3+ T cells

    PMID:29656550

    Open questions at the time
    • Single lab; direct miR-181c:BRK1 binding not structurally validated
    • Breadth of miR-181c effects beyond BRK1 not controlled
  6. 2025 Medium

    A stapled BRK1-mimetic peptide that binds WASF3 and ABI2 and blocks migration/invasion established the BRK1 assembly interface as a druggable target for anti-metastatic intervention.

    Evidence Stapled peptide design, cell permeability and binding assays, migration/invasion assays in cancer cells

    PMID:40832548

    Open questions at the time
    • In vivo efficacy not shown
    • Selectivity against the full WRC interactome not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BRK1 mechanistically transduces upstream Rac1/Rho-GTPase signals into regulated Arp2/3 activation, beyond stabilizing the complex, remains unresolved in the available corpus.
  • No direct GTPase-coupling mechanism shown for BRK1
  • Dynamics of complex assembly/disassembly in living cells not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0140313 molecular sequestering activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 1
Partners
ABI2CYFIP1SCARWASF2WASF3
Complex memberships
WAVE/SCAR Regulatory Complex (WRC)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 HSPC300 (BRK1) physically associates with CYFIP (PIR121/Sra1) and SCAR (WAVE) as an indispensable component of the WAVE/SCAR complex in Drosophila; loss of HSPC300 causes identical axonal and neuromuscular junction growth defects as mutations in other complex subunits, and defects are rescued by presynaptic expression of wild-type HSPC300. Co-immunoprecipitation/physical association assay, genetic rescue, loss-of-function mutant analysis in Drosophila Neural development High 17894861
2007 The N-terminus of Dictyostelium Scar (first 96 amino acids) is necessary and sufficient for interaction with HSPC300 (BRK1) and Abi1/2 in vitro; this interaction is required for Scar's participation in a large-molecular-weight protein complex and for proper localization and regulation of Scar. In vitro binding assay, deletion mutagenesis, cell morphology/motility analysis in Dictyostelium mutants Molecular biology of the cell High 17314411
2009 Loss of HSPC300 (BRK1) in Dictyostelium results in post-translational degradation/loss of SCAR protein (but not PIR121), causing a scar-like phenotype (slow migration, roundness, lack of large pseudopods), establishing that HSPC300 is essential for SCAR complex stability and function. Gene disruption (knockout), Western blot (protein level analysis), cell migration and morphology assays in Dictyostelium BMC cell biology High 19228419
2009 HSPC300 (BRK1) interacts with WAVE2 protein in human lung cancer cells; siRNA silencing of HSPC300 results in WAVE2 protein degradation, reorganization of actin filaments, decreased pseudopodium formation, and inhibition of cell migration. Co-immunoprecipitation, siRNA knockdown, Western blot, cell migration assay Lung cancer (Amsterdam, Netherlands) Medium 19576655
2011 Free BRK1/HSPC300 forms a homotrimeric parallel triple coiled-coil bundle (determined at 1.5 Å resolution by X-ray crystallography); this structure is highly similar to the heterotrimeric α-helical bundle of HSPC300/WAVE1/Abi2 within the human WAVE complex, and BRK1 dissociates as a homotrimer at nanomolar concentrations suggesting it serves as a homooligomeric precursor for WAVE complex assembly. X-ray crystallography (1.5 Å), analytical ultracentrifugation, gel filtration, subunit exchange assay PloS one High 21701600
2007 Depletion of HSPC300 (BRK1) by RNA interference in tumor cell lines (including ccRCC cells) results in cytoskeleton abnormalities and cytokinesis arrest, demonstrating a required role for HSPC300 in actin dynamics and tumor cell proliferation. siRNA knockdown, cytoskeletal morphology analysis, cell proliferation/cytokinesis assay Human mutation Medium 17311301
2013 NRF-1 negatively regulates C3orf10 (BRK1) transcription in human neuroblastoma IMR-32 cells and primary rat cortical neurons; knockdown of C3orf10/BRK1 in primary rat hippocampal neurons increases the number of axonal collaterals and dendrites. siRNA knockdown, promoter reporter assay, neuronal morphology analysis Gene Medium 23939472
2018 miR-181c targets BRK1 for translational inhibition; BRK1 silencing in CD3+ T cells inhibits T cell activation, actin polymerization, lamellipodia formation, and immunological synapse formation, and reduces expression of other WAVE2 complex proteins, indicating BRK1 stabilizes the WAVE2 complex in T cells. Dual selection functional assay (miRNA target identification), siRNA knockdown, overexpression, actin polymerization assay, immunological synapse imaging, Western blot Journal of leukocyte biology Medium 29656550
2014 Sp1 transcription factor directly binds the BRK1 promoter at -73 to -64 nt and positively regulates BRK1 transcription in non-small cell lung cancer cells; mutation of the Sp1 binding site suppresses BRK1 promoter activity and Sp1 siRNA knockdown reduces BRK1 mRNA. Promoter deletion/reporter assay, site-directed mutagenesis, EMSA, ChIP assay, siRNA knockdown Gene Medium 24680773
2025 BRK1 binds WASF3 (WAVE3) and ABI2 within the WASF Regulatory Complex (WRC); a stapled BRK1 mimetic peptide (BASH-2) designed to disrupt BRK1's binding interface permeates cells, binds WASF3 and ABI2, and inhibits cancer cell migration and invasion in a dose-dependent manner. Stapled peptide design and cell permeability assay, binding assay (WASF3 and ABI2), cell migration and invasion assay ACS medicinal chemistry letters Medium 40832548

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 BRK1, a Bub1-related kinase, is essential for generating proper tension between homologous kinetochores at metaphase I of rice meiosis. The Plant cell 43 23243128
2007 Loss of the actin regulator HSPC300 results in clear cell renal cell carcinoma protection in Von Hippel-Lindau patients. Human mutation 34 17311301
2007 HSPC300 and its role in neuronal connectivity. Neural development 27 17894861
2009 Metastatic potential of lung squamous cell carcinoma associated with HSPC300 through its interaction with WAVE2. Lung cancer (Amsterdam, Netherlands) 22 19576655
2013 Novel genes FAM134C, C3orf10 and ENOX1 are regulated by NRF-1 and differentially regulate neurite outgrowth in neuroblastoma cells and hippocampal neurons. Gene 17 23939472
2007 The N-terminus of Dictyostelium Scar interacts with Abi and HSPC300 and is essential for proper regulation and function. Molecular biology of the cell 14 17314411
2009 Loss of Dictyostelium HSPC300 causes a scar-like phenotype and loss of SCAR protein. BMC cell biology 13 19228419
2023 Transgenic sugarcane with higher levels of BRK1 showed improved drought tolerance. Plant cell reports 10 37578541
2011 High-resolution X-ray structure of the trimeric Scar/WAVE-complex precursor Brk1. PloS one 10 21701600
2018 miR-181c-BRK1 axis plays a key role in actin cytoskeleton-dependent T cell function. Journal of leukocyte biology 9 29656550
2014 Sp1 transcriptionally regulates BRK1 expression in non-small cell lung cancer cells. Gene 7 24680773
2023 Pan-cancer analysis of BRK1 as a potential immunotherapeutic target. Biotechnology & genetic engineering reviews 1 36989393
2025 Development of an All-Hydrocarbon Stapled Peptide Targeting BRK1 in Triple-Negative Breast Cancer. ACS medicinal chemistry letters 0 40832548

Missed literature

Know a paper Affinage missed for BRK1? Flag it for the maintainers and the community.

No submissions yet.