Systems-level phosphoproteomics reveals calcium/calmodulin-dependent protein kinase kinase 2-driven kinase signaling underlying malignant phenotypes in gastric cancer.
- 1Center for Systems Biology and Molecular Medicine Yenepoya (Deemed to be University) Mangalore India.
- 2Department of Biochemistry Nitte (Deemed to be University) Center for Omics & Systems Medicine (C-OSM) K.S. Hegde Medical Academy (KSHEMA) Mangalore Karnataka India.
Abstract
Gastric cancer (GC) is driven by aberrant kinase signaling that promotes uncontrolled proliferation and malignant progression. Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is overexpressed in GC; however, the global phosphorylation networks downstream of CAMKK2 remain incompletely defined. In this study, we investigated the functional and signaling consequences of CAMKK2 inhibition in GC cells using an integrated phenotypic and quantitative phosphoproteomics approach. Pharmacological inhibition of CAMKK2 using STO-609 in AGS cells significantly suppressed proliferation, clonogenic growth, migration, and invasion and induced defects in nuclear morphology indicative of impaired cell cycle progression. Tandem mass tag-based phosphoproteomic profiling identified over 10,500 phosphopeptides and revealed extensive phosphoproteome remodeling after CAMKK2 inhibition, characterized predominantly by hypophosphorylation of proteins involved in nuclear signaling, RNA processing, and cell cycle regulation. Kinase-substrate enrichment and motif analyses demonstrated coordinated attenuation of cyclin-dependent kinase, mitogen-activated protein kinase, and mitotic kinase-associated signaling pathways, with convergence on E2F-regulated transcriptional programs. Collectively, these findings establish CAMKK2 as a central regulator of kinase signaling networks that sustain proliferative and malignant phenotypes in GC and highlight CAMKK2 inhibition as a potential therapeutic strategy.
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BibTeX
@article{najar2026systemslevel,
title = {{Systems-level phosphoproteomics reveals calcium/calmodulin-dependent protein kinase kinase 2-driven kinase signaling underlying malignant phenotypes in gastric cancer.}},
author = {Mohd Altaf Najar and T S Keshava Prasad and Prashant Kumar Modi},
journal = {Journal of cell communication and signaling},
year = {2026},
month = oct,
doi = {10.1002/ccs3.70112},
url = {https://europepmc.org/article/MED/42948434},
note = {CC BY},
}
RIS
TY - JOUR
TI - Systems-level phosphoproteomics reveals calcium/calmodulin-dependent protein kinase kinase 2-driven kinase signaling underlying malignant phenotypes in gastric cancer.
AU - Mohd Altaf Najar
AU - T S Keshava Prasad
AU - Prashant Kumar Modi
PY - 2026
DA - 2026/10/27
JO - Journal of cell communication and signaling
DO - 10.1002/ccs3.70112
UR - https://europepmc.org/article/MED/42948434
AB - Gastric cancer (GC) is driven by aberrant kinase signaling that promotes uncontrolled proliferation and malignant progression. Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is overexpressed in GC; however, the global phosphorylation networks downstream of CAMKK2 remain incompletely defined. In this study, we investigated the functional and signaling consequences of CAMKK2 inhibition in GC cells using an integrated phenotypic and quantitative phosphoproteomics approach. Pharmacological inhibition of CAMKK2 using STO-609 in AGS cells significantly suppressed proliferation, clonogenic growth, migration, and invasion and induced defects in nuclear morphology indicative of impaired cell cycle progression. Tandem mass tag-based phosphoproteomic profiling identified over 10,500 phosphopeptides and revealed extensive phosphoproteome remodeling after CAMKK2 inhibition, characterized predominantly by hypophosphorylation of proteins involved in nuclear signaling, RNA processing, and cell cycle regulation. Kinase-substrate enrichment and motif analyses demonstrated coordinated attenuation of cyclin-dependent kinase, mitogen-activated protein kinase, and mitotic kinase-associated signaling pathways, with convergence on E2F-regulated transcriptional programs. Collectively, these findings establish CAMKK2 as a central regulator of kinase signaling networks that sustain proliferative and malignant phenotypes in GC and highlight CAMKK2 inhibition as a potential therapeutic strategy.
SN - 1873-9601
SN - 1873-961X
ER -