Receptor and Phosphoinositide Signaling in Control of Proliferation, Survival and Autophagy
Richard Anderson, Ph.D.
William R. Kellett Professor
University of Wisconsin-Madison
School of Medicine and Public Health
Hosts: Arne Gericke, Ph.D. and Suzanne Scarlata, Ph.D.
The EGF receptor plays key roles in both proliferation and autophagy. Upon receptor stimulation by EGF the EGF receptor (EGFR) is activated and rapidly endocytosed upon internalization it continues signaling until sorted to the lysosome. Lysosomal sorting is tightly regulated by a novel phosphoinositide-sorting pathway involving the lysosome associated protein transmembrane 4B (LAPTM4B) that is an oncogene. Remarkably the inactive EGFR upon cell stress also signals and this controls autophagy. Both the proliferative and autophagy pathways are regulated by phosphoinositides and LAPTM4B.
The active EGFR also activates PI 3-kinase signaling on the endosome generating of the lipid messenger phosphatidylinositol 3,4,5-trisphosphate (PI3,4,5P3) that is crucial for development, cell growth and survival, motility and becomes dysfunctional in many diseases including cancers. This reveals a mechanism for PI3,4,5P3 generation by scaffolded phosphoinositide kinases. In this pathway class I phosphoinositide 3-kinase (PI3K) is assembled by IQGAP1 with PI4KIIIa and PIPKIa, that sequentially generate PI3,4,5P3 from phosphatidylinositol. By scaffolding these kinases into functional proximity the PI4,5P2 generated is selectively used by PI3K for PI3,4,5P3 generation, which then signals to PDK1 and Akt that are also in the complex. Moreover, multiple receptor types stimulate the assembly of this IQGAP1-PI3K signaling complex. Blockade of IQGAP1 interaction with PIPKIa or PI3K inhibited PI3,4,5P3 generation and signaling, and selectively diminished cancer cell survival, revealing a novel target for cancer chemotherapy.