Agonist-stimulated phosphatidylinositol-3,4,5-trisphosphate generation by scaffolded phosphoinositide kinases

Generation of the lipid messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P-3) is crucial for development, cell growth and survival, and motility, and it becomes dysfunctional in many diseases including cancers. Here we reveal a mechanism for PtdIns(3,4,5)P-3 generation by scaffolded phosphoinositide kinases. In this pathway, class I phosphatidylinositol-3-OH kinase (PI(3)K) is assembled by IQGAP1 with PI(4)KIII alpha and PIPKI alpha, which sequentially generate PtdIns(3,4,5) P3 from phosphatidylinositol. By scaffolding these kinases into functional proximity, the PtdIns(4,5)P-2 generated is selectively used by PI(3)K for PtdIns(3,4,5)P-3 generation, which then signals to PDK1 and Akt that are also in the complex. Moreover, multiple receptor types stimulate the assembly of this IQGAP1-PI(3) K signalling complex. Blockade of IQGAP1 interaction with PIPKI alpha or PI(3)K inhibited PtdIns(3,4,5)P-3 generation and signalling, and selectively diminished cancer cell survival, revealing a target for cancer chemotherapy.