The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
Feed-forward stimulation of CAMK2 by the oncogenic pseudokinase PEAK1 generates a therapeutically ‘actionable’ signalling axis in triple negative breast cancer
Open accessPreprint — published as 10.1038/s41467-025-57046-8 · Paper page
Abstract
Summary: The PEAK family of pseudokinases, comprising PEAK1-3, are signalling scaffolds that play oncogenic roles in several poor prognosis human cancers, including triple negative breast cancer (TNBC). However, therapeutic targeting of pseudokinases is challenging due to their lack of catalytic activity. To address this, we screened for PEAK1 effectors by affinity purification and mass spectrometry, identifying calcium/calmodulin-dependent protein kinase 2 (CAMK2)D and CAMK2G. PEAK1 promoted CAMK2D/G activation in TNBC cells via a novel feed-forward mechanism involving PEAK1/PLCγ1/Ca 2+ signalling and direct binding via a consensus CAMK2 interaction motif in the PEAK1 N-terminus. In turn, CAMK2 phosphorylated PEAK1 to enhance association with PEAK2, which is critical for PEAK1 oncogenic signalling. To achieve pharmacologic targeting of PEAK1/CAMK2, we repurposed RA306, a second generation CAMK2 inhibitor under pre-clinical development for treatment of cardiovascular disease. RA306 demonstrated on-target activity against CAMK2 in TNBC cells and inhibited PEAK1-enhanced migration and invasion in vitro . Moreover, RA306 significantly attenuated TNBC xenograft growth and blocked metastasis in a manner mirrored by CRISPR-mediated PEAK1 ablation. Overall, these studies establish PEAK1 as a critical cell signalling nexus, identify a novel mechanism for regulation of Ca 2+ signalling and its integration with tyrosine kinase signals, and identify CAMK2 as a therapeutically ‘actionable’ target downstream of PEAK1.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Flagged first, then by citations
Research works printed but not linked: 55
- 10.1016/j.tcb.2014.03.008 · DOI
- 10.1016/j.sbi.2010.10.001 · DOI
- 2019, Prospects for pharmacological targeting of pseudokinases, Nat Rev Drug Discov, 18, 501
- 10.1126/scisignal.abj3554 · DOI
- 10.1111/febs.15087 · DOI
- 10.1158/0008-5472.CAN-12-1472 · DOI
- 10.1371/journal.pone.0135748 · DOI
- 10.1038/s41467-019-13993-7 · DOI · Paper page
- Ding C , et al. Overexpression of PEAK1 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer through modulating ERK1/2 and JAK2 signaling. Cell Death Dis 9, 802 (2018). · DOI
- 10.1158/0008-5472.CAN-11-3552 · DOI
- 10.1158/0008-5472.CAN-08-2354 · DOI · Paper page
- Ounoughene Y , et al. SHED-Dependent Oncogenic Signaling of the PEAK3 Pseudo-Kinase. Cancers (Basel ) 13, (2021). · DOI
- 10.1111/cas.12962 · DOI
- Tactacan CM , et al. The pseudokinase SgK223 promotes invasion of pancreatic ductal epithelial cells through JAK1/Stat3 signaling. Mol Cancer 14, 139 (2015). · DOI
- Lecointre C , et al. Oncogenic Signalling of PEAK2 Pseudokinase in Colon Cancer. Cancers (Basel ) 14, (2022). · DOI
- 10.1074/jbc.M116.748897 · DOI
- 10.1074/jbc.RA117.000751 · DOI
- 10.1038/s41467-017-01279-9 · DOI
- 10.1038/nature12308 · DOI
- Brzozowski JS , Skelding KA . The Multi-Functional Calcium/Calmodulin Stimulated Protein Kinase (CaMK) Family: Emerging Targets for Anti-Cancer Therapeutic Intervention. Pharmaceuticals (Basel ) 12, (2019). · DOI
- Chi M , et al. Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells. Sci Rep 6, 33132 (2016). · DOI
- 10.1126/scisignal.aaf0793 · DOI
- 10.1038/s41467-023-38869-9 · DOI
- Bhattacharyya M , Karandur D , Kuriyan J . Structural Insights into the Regulation of Ca(2+)/Calmodulin-Dependent Protein Kinase II (CaMKII). Cold Spring Harb Perspect Biol 12, (2020). · DOI · Paper page
- 10.1038/290527a0 · DOI
- 10.1016/j.bbcan.2021.188619 · DOI
- 10.1158/0008-5472.CAN-10-0911 · DOI
- 10.1242/jcs.02374 · DOI
- 10.1158/0008-5472.CAN-21-0613 · DOI
- Ozden C , et al. CaMKII binds both substrates and activators at the active site. Cell Rep 40, 111064 (2022). · DOI · Paper page
- 10.1016/J.NEURON.2019.04.012 · DOI · Paper page
- 10.1093/cvr/cvz097 · DOI
- 10.1038/s41388-023-02594-w · DOI
- 10.1016/j.str.2018.01.017 · DOI
- 10.1038/onc.2014.170 · DOI
- 10.1074/jbc.M112.410910 · DOI
- 10.1158/0008-5472.CAN-17-2392 · DOI
- 10.1158/0008-5472.CAN-17-2994 · DOI
- 10.1002/cm.20294 · DOI · Paper page
- Pellicena P , Schulman H . CaMKII inhibitors: from research tools to therapeutic agents. Front Pharmacol 5, 21 (2014). · DOI
- 10.1074/jbc.M509567200 · DOI
- 10.1038/nbt.1511 · DOI · Paper page
- 10.1038/nmeth.3901 · DOI · Paper page
- Evans R , et al. Protein complex prediction with AlphaFold-Multimer. bioRxiv, 2021.2010.2004.463034 (2022).
- 10.1038/S41592-022-01488-1 · DOI · Paper page
- 10.1002/prot.21123 · DOI
- 10.1093/nar/25.17.3389 · DOI · Paper page
- 10.1038/nbt.3988 · DOI · Paper page
- 10.1093/nar/gkt376 · DOI
- Sievers F , et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7, 539 (2011). · DOI
- 1994, Fitting a mixture model by expectation maximization to discover motifs in biopolymers, Proc Int Conf Intell Syst Mol Biol, 2, 28
- 10.1128/MCB.00249-10 · DOI
- 10.1038/sj.onc.1210928 · DOI
- Pereira B , et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun 7, 11479 (2016). · DOI
- 10.1093/NAR/GKAB1038 · DOI · Paper page
Metadata
- Authors
- Yang, X., Ma, X., Zhao, T., Croucher, D. R., Nguyen, E. V., Clark, K. C., Hu, C., Latham, S. L., Bayly-Jones, C., Nguyen, V. C. B., Budnar, S., Shin, S.-Y., Nguyen, L. K., Cotton, T. R., Chüeh, A. C., Sian, T. C. C. L. K., Stratton, M. M., Ellisdon, A. M., & Daly, R. J.
- Affiliations
- Monash University (AU)
- Garvan Institute of Medical Research (AU)
- University of Massachusetts Amherst (US)
- Corresponding author
- Daly, Roger J
- ORCID
- Yang, Xue
- Ma, Xiuquan
- Croucher, David R
- Nguyen, Elizabeth V.
- Clark, Kimberley C.
- Hu, Changyuan
- Latham, Sharissa L
- Bayly-Jones, Charles
- Nguyen, Viet Chi Bao
- Budnar, Srikanth
- Shin, Sung-Young
- Nguyen, Lan K.
- Cotton, Thomas R.
- Chüeh, Anderly C.
- Sian, Terry C C Lim Kam
- Stratton, Margaret M.
- Ellisdon, Andrew M.
- Daly, Roger J
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2024-02-15
- Volume
- 16
- Issue
- 1
- Pages
- 1871-1871
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11845518
- OpenAlex
- W4407820132
- Cited by
- 9
- References
- 1
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 1
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- U.S. Department of Health and Human Services (NIH R35GM145376)
- University of Massachusetts
- Victorian Cancer Agency (MCRF21036)
- Marshfield Clinic Research Foundation
- National Breast Cancer Foundation (NBCF Fellowship IIRS-20-032, IIRS-20-032)
- Monash University
- Department of Health, State Government of Victoria
- Department of Education and Training (DP190103672, DE240100992, DP220103638)
- National Institutes of Health
- University of Massachusetts Amherst
- Medical Research Council
- Australian Research Council (DP190103672, DE240100992, DP220103638)
- National Health and Medical Research Council (2003599)
- National Institute of General Medical Sciences (R35GM145376, T32GM139789)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- PEAK1, pseudokinase, CAMK2D, triple-negative breast cancer, PLCγ1, calcium signaling, tyrosine kinase signaling, cell migration and invasion, metastasis, therapeutic target, oncogenic signaling
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
