Richard Anderson Lab

Research: Agonist stimulated PI 3-kinase and ERK signaling control proliferation

The agonist signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)-Akt signaling pathways are key mechanisms for controlling cell survival, proliferation, differentiation, metabolism, motility, stemness, and are often deregulated in human cancers. Generation of the lipid messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) 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)P3 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 and PIPKI, which sequentially generate PtdIns(3,4,5)P3 from phosphatidylinositol. By scaffolding these kinases into functional proximity, the PtdIns(4,5)P2 generated is selectively used by PI(3)K for PtdIns(3,4,5)P3 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 or PI(3)K inhibited PtdIns(3,4,5)P3 generation and signalling, and selectively diminished cancer cell survival, revealing a target for cancer chemotherapy.

In cancers ERK and (PI3K)-Akt signaling are inversely correlated. Yet, the precise molecular mechanism for cross-inhibition has remained unclear. However, it is known that when Akt is turned on, its phosphorylated cytoplasmic substrate FOXO1 turns off ERK activity by reshaping the Ras-ERK scaffold IQGAP1. This is critical in many cancers as therapeutic treatment with Akt or PI 3-kinase inhibitors lead to cancer resistance by up regulating ERK signaling. Inversely, inhibition of ERK signaling often increases PI 3-kinase and Akt signaling that maintains survival and proliferation.

Figure 1

Figure 1. Agonist stimulated PI 3-kinase signaling