Co-Regulation Analysis of Domain-Specific Phosphosites Reveals Insights into the Phosphoregulation-Directed Functional Diversity of Nucleolin
- 1Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to Be University), Mangalore 575018, Karnataka, India
Abstract
Nucleolin (NCL) is a highly phosphorylated, multilocalized, pleiotropic nucleolar protein involved in chromatin organization, DNA damage response, the cell cycle, RNA metabolism, and ribosome biogenesis. A large-scale integration of publicly available human cellular phosphoproteome datasets led to the identification of 18 frequently detected/reported phosphosites across 1266 profiling and 507 differential datasets. Amidst various strategies currently being considered to target NCL in cancers, multi-domain distribution of these phosphosites differentially regulated across distinct cancers highlighted its plausible involvement in tumor-associated regulatory mechanisms. This demands the exploration of the potential kinases and interactors associated with these phosphorylation events. We performed a co-occurrence analysis to explore potential coordinated phosphorylation events among them and across other phosphoproteins. An integrative analysis of phosphosite-specific co-regulation, upstream kinases, and interaction networks was employed to explore potential phosphosite-specific signaling associations. Intriguingly, our analysis inferred the association of the predominant phosphosites within the acidic tract with chromatin organization and histone-related functions, whereas TPxKK motif phosphosites were linked to NCL localization, chromosome segregation, and nucleolar reorganization. Phosphosites in the RRM domain showed a potential association with RNA-binding proteins and metabolic pathways. Collectively, these findings suggest a domain-specific phosphosite-centric regulatory network of NCL, providing a valuable reference framework for future experimental studies and phosphosite-directed therapeutic strategies in cancers.
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BibTeX
@article{shaji2026coregulation,
title = {{Co-Regulation Analysis of Domain-Specific Phosphosites Reveals Insights into the Phosphoregulation-Directed Functional Diversity of Nucleolin}},
author = {Megha Shaji and Jaytha Thomas and Pathiyil Sajini Sekhar and Suhail Subair and Althaf Mahin and Leona Dcunha and Alimath Sambreena and Rajesh Raju and Sowmya Soman},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209132},
url = {https://www.mdpi.com/1422-0067/27/20/9132},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Co-Regulation Analysis of Domain-Specific Phosphosites Reveals Insights into the Phosphoregulation-Directed Functional Diversity of Nucleolin
AU - Megha Shaji
AU - Jaytha Thomas
AU - Pathiyil Sajini Sekhar
AU - Suhail Subair
AU - Althaf Mahin
AU - Leona Dcunha
AU - Alimath Sambreena
AU - Rajesh Raju
AU - Sowmya Soman
PY - 2026
DA - 2026/10/15
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209132
UR - https://www.mdpi.com/1422-0067/27/20/9132
AB - Nucleolin (NCL) is a highly phosphorylated, multilocalized, pleiotropic nucleolar protein involved in chromatin organization, DNA damage response, the cell cycle, RNA metabolism, and ribosome biogenesis. A large-scale integration of publicly available human cellular phosphoproteome datasets led to the identification of 18 frequently detected/reported phosphosites across 1266 profiling and 507 differential datasets. Amidst various strategies currently being considered to target NCL in cancers, multi-domain distribution of these phosphosites differentially regulated across distinct cancers highlighted its plausible involvement in tumor-associated regulatory mechanisms. This demands the exploration of the potential kinases and interactors associated with these phosphorylation events. We performed a co-occurrence analysis to explore potential coordinated phosphorylation events among them and across other phosphoproteins. An integrative analysis of phosphosite-specific co-regulation, upstream kinases, and interaction networks was employed to explore potential phosphosite-specific signaling associations. Intriguingly, our analysis inferred the association of the predominant phosphosites within the acidic tract with chromatin organization and histone-related functions, whereas TPxKK motif phosphosites were linked to NCL localization, chromosome segregation, and nucleolar reorganization. Phosphosites in the RRM domain showed a potential association with RNA-binding proteins and metabolic pathways. Collectively, these findings suggest a domain-specific phosphosite-centric regulatory network of NCL, providing a valuable reference framework for future experimental studies and phosphosite-directed therapeutic strategies in cancers.
SN - 1422-0067
ER -