Llorente A, Arora GK, Loughran RM, Murad R, Maurya S, Crabtree S, Portillo B, Chapagain P, Huluka H, Eron S, Goodman K, Ye G, Blind RD, Emerling BM

Phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) have emerged as candidate drug targets in cancer, neurological, inflammatory, and infectious diseases. Although their canonical function is to phosphorylate PI(5)P to generate PI(4,5)P2, growing evidence points to additional catalytic-independent roles, but how these functions are organized within protein interaction networks remains unclear. Here, we use proximity-dependent ...

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biotin identification (BioID) in HeLa cells to map isoform-resolved interactomes of human PI5P4K?, PI5P4K?, and PI5P4K?. This approach captures PI5P4K-proximal proteins in intact cells and reveals interaction networks positioning these kinases within trafficking-associated signaling modules. Importantly, BioID analysis indicates that PI5P4K? has the most extensive set of proximal interactors among the three PI5P4Ks, consistent with its comparatively low catalytic activity and a prominent scaffold-like function. Among PI5P4K?-enriched partners, we highlight the endosomal cargo adaptor SNX17 as a proximal interactor that links PI5P4K? to ?1-integrin recycling and to cell migration and invasion. By providing a proximity map for all three PI5P4Ks, this study offers a framework to help define contexts in which targeted protein degradation may offer advantages over catalytic inhibition and provides a resource for future mechanistic studies on these phosphoinositide kinases.

Date: Apr. 24, 2026

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