Phosphoinositides at 50: From minor lipids to master organizers of polarity

Phosphoinositides (PIs) have been at the center of cell signaling and membrane biology since Michell's proposal of the PI-cycle in 1975. Over the past fifty years, these quantitatively minor lipids have emerged as versatile molecular organizers, defining membrane identity, generating spatial cues, coordinating cytoskeletal dynamics and thus playing pivotal role in polarity. Studies in yeast, amoebae, and neutrophils demonstrated how localized PI pools regulate polarity and chemotaxis, providing a conceptual advance to tissue-level organization. In epithelia, PIs now stand as central determinants of apico-basal polarity and lumen morphogenesis through their cooperation with Rho GTPases, polarity complexes, and septins. This review highlights how these lipids shape our understanding of membrane dynamics and epithelial tissue organization. To conclude, this review underscores how alterations in the activities of these polarity regulators lead to abnormal epithelial morphogenesis and severe diseases such as cancer.