| 2005 |
WAVE3/WASF3 localizes to lamellipodia at the leading edge of migrating cells, and its knockdown prevents PDGF-induced lamellipodia formation and cell migration. WAVE3 interacts physically with the PI3K regulatory subunit p85 (mediated by the N-terminal region of WAVE3 and the C-terminal SH2 domain of p85), placing WAVE3 downstream of PI3K signaling. Treatment with PI3K inhibitor LY294002 also abrogated PDGF-induced lamellipodia formation. |
Subcellular localization by microscopy, RNA interference knockdown, yeast two-hybrid screen confirmed by co-immunoprecipitation, pharmacological inhibition |
The Journal of biological chemistry |
High |
15826941
|
| 2005 |
WAVE3/WASF3 knockdown decreases phospho-p38 MAPK levels (but not phospho-AKT, phospho-ERK, or phospho-JNK) and inhibits expression of MMP-1, MMP-3, and MMP-9 (but not MMP-2), leading to inhibition of cell motility and invasion with increased actin stress fiber formation and reorganization of focal adhesion complexes. WAVE1 and WAVE2 expression levels were not affected by loss of WAVE3. |
RNA interference knockdown, Western blotting, invasion assay, actin/focal adhesion staining |
Experimental cell research |
Medium |
15907837
|
| 2005 |
WAVE3/WASF3 includes the Scar/WAVE family proteins in the same kinds of protein complexes as WAVE1 and WAVE2, all three isoforms interacting with previously described binding partners, suggesting participation in the same regulatory complexes for actin assembly. |
Co-immunoprecipitation, interaction assays with multiple binding partners across isoforms |
BMC cell biology |
Medium |
15752430
|
| 2005 |
WAVE3 binds directly to LDOC1 through the verprolin homology (VH) domain of WAVE3. WAVE3 expression induces translocation of LDOC1 from the nucleus to the cytoplasm, inhibiting LDOC1-induced apoptosis (which requires nuclear LDOC1 and p53 stabilization). Thus WAVE3 negatively regulates LDOC1 function. |
Direct binding assay, ectopic expression, subcellular localization (nuclear/cytoplasmic fractionation and microscopy), apoptosis assay |
Journal of biochemistry |
Medium |
16272576
|
| 2007 |
c-Abl tyrosine kinase interacts with WAVE3/WASF3 upon PDGF stimulation, and phosphorylates four tyrosine residues on WAVE3. Abl-mediated phosphorylation of WAVE3 is required for stimulation of lamellipodia formation and cell migration. The Abl inhibitor STI-571 abrogates Abl-mediated phosphorylation of WAVE3. |
Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of tyrosine residues, pharmacological inhibition (STI-571), lamellipodia/migration assays |
The Journal of biological chemistry |
High |
17623672
|
| 2007 |
Stable shRNA-mediated knockdown of WAVE3 in MDA-MB-231 breast cancer cells reduces Matrigel invasion, lung colony formation after tail-vein injection, and primary tumor growth in orthotopic xenograft models. Suppression of p38 MAPK activity by dominant-negative p38 produces comparable phenotypes, establishing the WAVE3-p38 pathway in metastasis. |
shRNA stable knockdown, Matrigel invasion assay, xenograft/orthotopic mouse models, dominant-negative p38 construct |
The American journal of pathology |
High |
17525277
|
| 2009 |
miR-200 family microRNAs directly target the 3'-UTR of WAVE3 mRNA and inhibit its expression. miR-200-mediated downregulation of WAVE3 reduces cancer cell invasiveness and causes morphological changes resembling mesenchymal-to-epithelial transition. Re-expression of a miR-200-resistant WAVE3 reverses these effects, confirming specificity. |
Luciferase 3'-UTR reporter assay, Western blotting, invasion assay, rescue experiment with miR-200-resistant WAVE3 |
The Journal of biological chemistry |
High |
19801681
|
| 2011 |
WAVE3/WASF3 knockdown leads to upregulation of the KISS1 metastasis suppressor gene, elevated IκBα levels in the cytoplasm, and reduced nuclear NF-κB (p65/50). Knockdown of KISS1 in WASF3-silenced cells recovers the invasion phenotype. TNF-α treatment has no effect on invasion or NF-κB nuclear translocation in WASF3 knockdown cells, placing WASF3 upstream of NF-κB/KISS1 in the regulation of MMP-9 production. |
shRNA knockdown, oligonucleotide arrays, luciferase reporter (KISS1 transcription), Western blotting (IκBα/NF-κB), rescue knockdown of KISS1, TNF-α treatment |
International journal of cancer |
High |
21544801
|
| 2011 |
miR-31 directly targets the 3'-UTR of WAVE3 mRNA and inhibits its expression. Loss of miR-31 correlates with increased WAVE3 in invasive breast cancer. Re-expression of miR-31-resistant WAVE3 reverses miR-31-mediated inhibition of cancer cell invasion. |
3'-UTR targeting validation, Western blotting, invasion assay, rescue with miR-31-resistant WAVE3 |
International journal of cancer |
High |
21105030
|
| 2012 |
HSP90 is present in the WASF3/WAVE3 immunocomplex from prostate cancer cells. Inactivation of HSP90 does not affect WASF3 stability but prevents its phosphoactivation by destabilizing ABL kinase. HSP70 is also present in the WASF3 immunocomplex; inactivation of HSP70 leads to WASF3 destabilization through proteasome degradation. Overexpression of HSP70 in WASF3-null cells does not enhance invasion. |
Mass spectrometry, co-immunoprecipitation, pharmacological inhibition of HSP90/70, shRNA knockdown, proteasome inhibition assay |
The Journal of biological chemistry |
High |
22315230
|
| 2012 |
HIF1A binds to hypoxia response elements (HRE) in the WASF3 promoter under hypoxic conditions, as shown by ChIP assay, and induces WASF3 transcription. Hypoxia also increases WASF3 phosphoactivation. WASF3 knockdown cells show no motility response to hypoxia. |
Chromatin immunoprecipitation (ChIP), luciferase reporter assay, scratch wound motility assay, Western blotting for phospho-WASF3 |
International journal of cancer |
High |
22581642
|
| 2012 |
Loss of WAVE3 in cancer cells leads to inhibition of NFκB signaling through decreased nuclear translocation of NFκB, resulting in loss of activation of NFκB target genes (including MMP9), inhibition of invadopodia formation and ECM degradation, and sensitization of cancer cells to TNFα-induced apoptosis through inhibition of the AKT pro-survival pathway. Conversely, overexpression of WAVE3 enhances NFκB activity. |
WAVE3 knockdown/overexpression, NFκB nuclear translocation assay, invadopodia formation assay, ECM degradation assay, MMP9 expression analysis, apoptosis assay |
PloS one |
Medium |
25329315
|
| 2013 |
WASF3/WAVE3 overexpression increases ZEB1/2 levels, which suppress the miR-200a/200b/429 cluster. This occurs through WASF3-mediated downregulation of KISS1, which releases IκBα inhibition of NFκB, and ZEB1 expression is regulated by NFκB. Knockdown of WASF3 leads to reduced ZEB1 levels, increased miR-200 and E-cadherin levels, and loss of invasion. |
WASF3 overexpression/knockdown, Western blotting, luciferase reporter, NFκB pathway analysis |
Oncogene |
Medium |
23318438
|
| 2013 |
IL-6 induces WASF3 expression and phosphoactivation through the JAK2/STAT3 pathway in two ways: (1) STAT3 directly binds the WASF3 promoter and increases transcription; (2) JAK2 interacts with WASF3 and directly activates (phosphorylates) it. Inhibition of STAT3 (shRNA, dominant negative, or S3I-201) reduces WASF3 levels and migration. Inhibition of JAK2 (shRNA or AG490) reduces WASF3 activation and prevents its membrane localization. |
ChIP demonstrating STAT3 binding to WASF3 promoter, Co-IP (JAK2-WASF3), shRNA, dominant-negative constructs, pharmacological inhibition, migration assay, membrane localization assay |
Carcinogenesis |
High |
23677069
|
| 2013 |
TGF-β selectively and robustly induces WAVE3 expression in metastatic breast cancer cells through a Smad2- and β3 integrin-dependent mechanism. WAVE3 is required for TGF-β-induced EMT: stable depletion of WAVE3 prevents TGF-β from inducing EMT programs, lamellipodia formation, and cell migration. |
TGF-β treatment with downstream Western blotting, stable WAVE3 knockdown, EMT marker analysis, lamellipodia assay, 3D organotypic culture, in vivo syngeneic mouse model |
Breast cancer research and treatment |
High |
24197660
|
| 2015 |
ATAD3A (mitochondrial membrane protein) interacts with WASF3/WAVE3 as demonstrated by mass spectrometry. ATAD3A knockdown decreases WASF3 protein levels. HSP70 stabilizes WASF3 in the cytoplasm, but inactivation of HSP70 does not destabilize WASF3 at the mitochondrial membrane where ATAD3A protects it. GRP78 upregulation (during ER stress) increases WASF3 levels, and ATAD3A is present in a WASF3-GRP78 complex. Suppression of GRP78 leads to ATAD3A-dependent destabilization of WASF3 at the mitochondrial membrane. The N-terminal end of WASF3 is within the mitochondria and is the interaction site with the N-terminal end of ATAD3A. |
Mass spectrometry, co-immunoprecipitation, shRNA knockdown, mitochondrial fractionation with proteolysis protection assay, in vivo xenograft |
Oncogene |
High |
25823022
|
| 2015 |
Genetic knockdown of CYFIP1 in cancer cells destabilizes the WASF3 complex, causes loss of WASF3 function, and suppresses invasion. Stapled peptides (WAHM) targeting the α-helical interface between WASF3 and CYFIP1 suppress motility and invasion in breast and prostate cancer cells, suppress Rac interaction with the WASF3 complex, and dysregulate downstream targets MMP-9 and KISS1. Depletion of WASF1 and WASF2, which also bind CYFIP1, did not affect invasion, demonstrating specificity for WASF3. |
shRNA knockdown of CYFIP1, stapled peptide treatment, invasion/motility assay, Rac interaction assay (Co-IP), MMP-9 and KISS1 expression analysis |
Cancer research |
High |
26676744
|
| 2016 |
WASF3 is present in the HER2 immunocomplex. Suppression of WASF3 suppresses invasion even in the presence of HER2 expression. WASF3's ability to promote invasion is highly dependent on the HER2/HER3 heterodimer. The HER2/HER3 complex facilitates WASF3 phospho-activation and transcriptional upregulation through HER2/HER3 activation of JAK/STAT signaling. |
Co-immunoprecipitation, WASF3 suppression/overexpression, invasion assays with HER2/HER3 manipulation, Western blotting (phospho-WASF3) |
Oncogene |
Medium |
26804171
|
| 2016 |
NCKAP1 is required for WASF3 complex stability and function: silencing NCKAP1 destabilizes the WASF3 complex and suppresses invasive capacity of breast, prostate, and colon cancer cells and metastasis in vivo. Activation of the WASF3 complex requires RAC1 interaction, and inactivation of NCKAP1 prevents RAC1 association with the WASF3 complex. Stapled peptides (WANT3) targeting the NCKAP1-CYFIP1 interface destabilize the WASF3 complex and suppress RAC1 binding and invasion. |
shRNA knockdown of NCKAP1, Co-IP (RAC1-WASF3 complex), in vivo spontaneous metastasis model, stapled peptide treatment |
Cancer research |
High |
27432794
|
| 2017 |
WAVE3 interacts with YB1 (Y-box binding protein 1), and this interaction is required for YB1 nuclear translocation in cancer cells and activation of transcription of cancer stem cell-specific genes. WAVE3 is enriched in the CSC subpopulation. CRISPR/Cas9 knockout of WAVE3 attenuates the CSC subpopulation and inhibits transcription of CSC transcription factors. |
CRISPR/Cas9 knockout, Co-immunoprecipitation (WAVE3-YB1 interaction), nuclear/cytoplasmic fractionation, CSC marker analysis, transcription factor activity assays |
Oncotarget |
Medium |
29262622
|
| 2017 |
p63α transcriptionally upregulates HSP70 (Hsp70) expression via E2F1, and HSP70 promotes bladder cancer cell invasion through the Hsp70/WASF3/MMP-9 axis. |
Western blotting, invasion assay, transcription analysis (E2F1/p63α-mediated Hsp70 upregulation), pathway inhibition |
The Journal of biological chemistry |
Medium |
28794159
|
| 2017 |
Mutant RAS promotion of invasion and metastasis is dependent on WASF3 activation in a PI3K and AKT-dependent manner. AKT is present in the WASF3 immunocomplex and this association is enhanced by mutant RAS overexpression. Mutant RAS promotes dissociation of p85 from the WASF3 complex, promoting activation of p110. ERK1/2 activation is not affected by loss of WASF3. |
Co-immunoprecipitation (AKT in WASF3 complex), proteomics analysis, WASF3 knockdown epistasis, p85/p110 dissociation assay |
Genes, chromosomes & cancer |
Medium |
28233357
|
| 2019 |
Wasf3 null mice (generated by deletion of exons 4 and 5) are viable with no visible morphological or behavioral abnormalities and no abnormal mammary gland development or brain development. In the MMTV-polyoma middle-T oncogene breast cancer model, Wasf3 is upregulated in metastatic lesions, and Wasf3 null background reduces the number and size of metastatic lung lesions without affecting primary tumor development. |
Conditional knockout mouse model (Cre-lox deletion), MMTV-PyMT spontaneous breast cancer model, histological analysis of metastases |
The American journal of pathology |
High |
31542393
|
| 2020 |
PCARE (C2orf71) interacts with WASF3/WAVE3 and efficiently recruits it to the primary cilium. Ectopic coexpression of PCARE and WASF3 in ciliated cells causes remarkable expansion of the ciliary tip via actin polymerization. This expansion is disrupted by siRNA knockdown of actin regulators, pharmacological inhibition of actin polymerization, or PCARE with a retinal dystrophy-associated missense mutation. In mouse retina and human retinal organoids, PCARE and WASF3 colocalize with actin at the outer segment base where this process drives disk formation initiation. |
Co-immunoprecipitation (PCARE-WASF3), ectopic co-expression in ciliated cells, siRNA knockdown, pharmacological actin inhibition, mouse retinal imaging, human retinal organoids |
Proceedings of the National Academy of Sciences of the United States of America |
High |
32312818
|
| 2020 |
WAVE3 tyrosine phosphorylation (downstream of PI3K) is also achieved downstream of TGF-β and EGF signaling, and is required for oncogenic activity including migration, tumorsphere growth, and invasion. Loss of WAVE3 phosphorylation also inhibits the activation of PI3K, TGF-β, and EGF signaling downstream effectors, identifying a positive feedback loop between WAVE3 phosphorylation and these pathways. |
Phospho-mutant WAVE3 constructs, Western blotting for pathway effectors, migration assay, 3D tumorsphere assay, mouse xenograft model |
Oncogenesis |
Medium |
33012785
|
| 2021 |
Phosphorylation of the proline-rich domain (PRD) of WAVE3 is essential for its interaction with YB1. Loss of PRD phosphorylation inhibits WAVE3-YB1 interaction, prevents YB1-mediated activation of CSC markers, and inhibits WAVE3-mediated EMT activation. PRD phosphorylation is required for migration and invasion in vitro and tumor growth/metastasis in vivo. |
Phospho-mutant PRD constructs, co-immunoprecipitation (WAVE3-YB1), invasion/migration assays, CSC marker analysis, in vivo xenograft |
Scientific reports |
Medium |
33594155
|
| 2021 |
SHOX2 directly activates WASF3 transcription and recruits STAT3 to the WASF3 promoter, where SHOX2 and STAT3 form a functional immunocomplex that cooperatively promotes WASF3 transcriptional activity. WASF3 knockdown abrogates SHOX2-induced metastasis but not SHOX2-dependent tumorigenesis. |
ChIP-qPCR and ChIP/re-ChIP (SHOX2 and STAT3 at WASF3 promoter), co-immunoprecipitation (SHOX2-STAT3 complex), shRNA knockdown epistasis, in vivo orthotopic mouse model |
Journal of experimental & clinical cancer research |
High |
34465361
|
| 2023 |
Overexpression of WASF3 disrupts mitochondrial respiratory supercomplex formation and is associated with ER stress. In transgenic mice with increased WASF3 expression, treadmill running capacity was markedly decreased with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. ER stress-induced WASF3 upregulation (by endotoxin) also decreased skeletal muscle complex IV levels. Pharmacologic inhibition of ER stress decreased WASF3 levels and improved mitochondrial function in patient cells. |
WASF3 transgenic mouse model, treadmill exercise testing, mitochondrial supercomplex assembly analysis (BN-PAGE or equivalent), complex IV activity measurement, pharmacological ER stress inhibition, patient skeletal muscle biopsy analysis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
37579159
|
| 2023 |
WAVE3/WASF3 phosphorylation is required for β-catenin stabilization; loss of WAVE3 expression or phosphorylation inhibits β-catenin activity and expression. Dual blocking of WAVE3 expression or phosphorylation in combination with chemotherapy suppresses chemoresistant TNBC cell behavior in vitro and in vivo. Re-expression of phospho-active WAVE3 restores oncogenic activity, while phospho-mutant WAVE3 does not. |
CRISPR/Cas9 KO, phospho-mutant rescue, Western blotting (β-catenin), 2D/3D invasion assay, xenograft assay |
Breast cancer research |
Medium |
36949468
|
| 2025 |
METTL3 mediates m6A modification of WASF3 mRNA. IGF2BP2 binds to the m6A site in the 3'-UTR of WASF3 mRNA and enhances WASF3 translation. Highly expressed WASF3 activates the MAPK signaling pathway by interacting with phosphorylated p38 (p-p38). Removal of m6A modification of WASF3 mRNA inhibited WASF3 expression and abolished WASF3's ability to bind p-p38 and activate MAPK signaling. |
Co-immunoprecipitation (METTL3-WASF3, WASF3-p-p38), m6A modification assay, Western blotting, m6A inhibition experiments, ESCC cell functional assays |
MedComm |
Medium |
41127505
|