PI(3,5)P(2) controls the signaling activity of class I PI3K.

PI(3,5)P(2) on lysosomes and late endosomes inhibits class I PI3K activity, with a key interaction involving the p85 subunit, revealing a new regulatory mechanism.

• Why it matters: Understanding how PI(3,5)P(2) regulates PI3K signaling is crucial because dysregulation is linked to cancer and tissue regeneration, yet its specific role remains unclear.
• What they did: Using a novel ratiometric sensor, the study quantified PI(3,5)P(2) dynamics, showing its formation by class II PI3KC2β and PIKfyve and its interaction with p85 to control class I PI3K activity.
• The result: Disrupting the p85-PI(3,5)P(2) interaction leads to sustained PI3K activation and promotes neurite growth, suggesting potential therapeutic strategies for p85-mutant cancers and regenerative medicine.