التفاصيل البيبلوغرافية
| العنوان: |
Feed-forward stimulation of CAMK2 by the oncogenic pseudokinase PEAK1 generates a therapeutically 'actionable' signalling axis in triple negative breast cancer. |
| المؤلفون: |
Yang X, Ma X, Croucher DR, Nguyen EV, Clark KC, Hu C, Latham SL, Zhao T, Bayly-Jones C, Nguyen VCB, Shin SY, Nguyen LK, Cotton TR, Chüeh AC, Kam Sian TCCL, Stratton MM, Ellisdon AM, Daly RJ |
| المصدر: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 15. Date of Electronic Publication: 2024 Feb 15. |
| نوع المنشور: |
Preprint |
| اللغة: |
English |
| بيانات الدورية: |
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: |
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. |
| تواريخ الأحداث: |
Date Created: 20240226 Latest Revision: 20240226 |
| رمز التحديث: |
20240226 |
| مُعرف محوري في PubMed: |
PMC10888886 |
| DOI: |
10.1101/2024.02.14.580406 |
| PMID: |
38405732 |
| قاعدة البيانات: |
MEDLINE |
