A new layer of phosphoinositide‐mediated allosteric regulation uncovered for SHIP2

The Src homology 2 containing inositol 5-phosphatase (SHIP2) is a large multidomain enzyme that catalyzes the dephosphorylation of phospholipid phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3) to form PI(3,4)P2. PI(3,4,5)P3 key lipid second messenger controlling recruitment signaling proteins plasma membrane, thereby regulating plethora cellular events, including proliferation, growth, apoptosis, and cytoskeletal rearrangements. SHIP2, alongside PI3K PTEN, regulates levels at membrane has been heavily implicated in serious diseases such as cancer type diabetes; however, many aspects its regulation mechanism remain elusive. We recently reported an activating effect SHIP2 C2 domain here we describe additional layer via pleckstrin homology-related (PHR) domain. show phosphoinositide-induced transition high activity state increases phosphatase up 10-15 fold. further PI(3,4)P2 directly interacts with PHR trigger this allosteric activation. Modeling PHR-phosphatase-C2 region on suggests no major inter-domain interactions domain, but close contacts between two linkers offer possible path communication. Together, our data acts module catalytic response specific phosphoinositide cell membrane.