Dark kinase annotation, mining, and visualization using the Protein Kinase Ontology

Area of Science:

• Biochemistry
• Bioinformatics
• Genomics

Background:

• Protein kinases are crucial in cell signaling and are implicated in various diseases.
• Existing knowledge resources often lack integrated data on kinase sequence, structure, function, and disease associations.
• The Protein Kinase Ontology (ProKinO) provides a framework for organizing complex kinase information.

Purpose of the Study:

• To significantly expand the ProKinO knowledge graph with expression patterns and drug interaction data.
• To develop a new, interactive web browser for visualizing and exploring the ProKinO knowledge graph.
• To enhance ProKinO's utility as a discovery tool for understudied protein kinases and their roles in disease.

Main Methods:

• Integrated additional data on expression patterns and drug interactions into the ProKinO knowledge graph.
• Developed a new web-based browser for interactive visualization of the knowledge graph.
• Utilized graph mining and SPARQL queries to analyze kinase data.
• Incorporated kinase ligand binding sites, expression patterns, and functional features into ProKinO.
• Integrated ProtVista for interactive mining of kinase sequence annotations in 3D structures and AlphaFold models.

Main Results:

• ProKinO was significantly expanded with new classes and relationships, including kinase ligand binding sites and expression patterns.
• A new interactive web browser was developed for ProKinO, enhancing accessibility and usability.
• Graph mining identified p21-activated protein kinase 5 (PAK5) as a frequently mutated "dark kinase" in cancers, with abnormal expression in acute myeloid leukemia.
• Recurrent oncogenic mutations in PAK5 and common ligand/drug binding residues in PAK family kinases were identified.
• The updated ProKinO database and browser are publicly accessible.

Conclusions:

• The expanded ProKinO knowledge graph and its interactive browser offer a valuable resource for the signaling community.
• ProKinO facilitates the discovery of novel insights into protein kinases, particularly understudied ones like PAK5.
• The findings highlight ProKinO's potential in cancer research and drug discovery by identifying key mutations and drug-binding sites.