Activation of CAMK2 by pseudokinase PEAK1 represents a targetable pathway in triple negative breast cancer
Open accessPublished version of a preprint
Abstract
The PEAK family of pseudokinases, comprising PEAK1-3, 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 screen for PEAK1 effectors and identify calcium/calmodulin-dependent protein kinase 2 (CAMK2)D and CAMK2G. PEAK1 promotes CAMK2 activation in TNBC cells via PLCγ1/Ca 2+ signalling and direct binding to CAMK2. In turn, CAMK2 phosphorylates PEAK1 to enhance association with PEAK2, which is critical for PEAK1 oncogenic signalling. To achieve pharmacologic targeting of PEAK1/CAMK2, we repurpose RA306, a second generation CAMK2 inhibitor. RA306 inhibits PEAK1-enhanced migration and invasion of TNBC cells in vitro and significantly attenuates TNBC xenograft growth and metastasis in a manner mirrored by PEAK1 ablation. Overall, these studies establish PEAK1 as a critical cell signalling nexus that integrates Ca 2+ and tyrosine kinase signals and identify CAMK2 as a therapeutically ‘actionable’ target downstream of PEAK1.
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Cites
Highly accurate protein structure prediction with AlphaFold
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Reciprocal Activation within a Kinase-Effector Complex Underlying Persistence of Structural LTP
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- 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, B. V., Budnar, S., Shin, S.-Y., Nguyen, L. K., Cotton, T. R., Chüeh, A. C., Lim Kam Sian, T. C. C., 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, Bao V.
- Budnar, Srikanth
- Shin, Sung-Young
- Nguyen, Lan K.
- Cotton, Thomas R.
- Chüeh, Anderly C.
- Lim Kam Sian, Terry C. C.
- Stratton, Margaret M.
- Ellisdon, Andrew M.
- Daly, Roger J.
- Venue
- Nature Communications
- Published
- 2025-02-22
- Volume
- 16
- Issue
- 1
- Pages
- 1871-1871
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11845518
- OpenAlex
- W4407820132
- Cited by
- 9
- References
- 3
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 1
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- 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
- Department of Health | National Health and Medical Research Council (Ideas Grant 2003599)
- Department of Education and Training | Australian Research Council (DP220103638, DP190103672, DE240100992)
- National Breast Cancer Foundation (NBCF Fellowship IIRS-20-032)
- UMASS | University of Massachusetts Amherst (National Research Service Award T32 GM139789)
- U.S. Department of Health & Human Services | National Institutes of Health (NIH R35GM145376)
- Victorian Cancer Agency (MCRF21036)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pathology and Forensic Medicine › 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
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