Richard Anderson Lab

Research: Spatial and Receptor Signaling in the Endosome

EGF receptor signaling and down regulation

Figure 1

Sorting to the lysosome terminates EGF receptor signaling. Remarkably, this pathway requires PIPKIi5 and the generation of PI4,5P2. The PI4,5P2 modulates effectors that control EGFR sorting into ILVs of the MVB(Dev. Cell, 25, 144–155). Loss of PIPKIi5 or pathway components result in enhanced and prolonged EGFR signaling.

PI4,5P2 is generated at the late endosome(J. Biol. Chem., 274:17794-17805) and endosomal targeted PIPKIgi5 selectively controls epidermal growth factor receptor (EGFR) sorting to the lysosome (Dev. Cell, 25, 144–155). Endosomal trafficking and degradation of the EGFR play an essential role in control of its signaling. PI4,5P2 is an established regulator of endocytosis, whereas PI3P modulates endosomal trafficking. Yet, PIPKIgi5, an enzyme that synthesizes PI4,5P2, controls endosome to lysosome sorting of EGFR (see Figure). PIPKIgi5 is targeted to the endosomal where it interacts with sorting nexins, proteins that bind PIPn isomers. The loss of PIPKIgi5, sorting nexin 5 (SNX5), or other PI4,5P2 effector proteins in this pathway block EGFR sorting into intraluminal vesicles (ILVs) of the multivesicular body (MVB). Loss of ILV sorting enhances and prolongs EGFR signaling. These findings reveal that PIPKIgi5 and PI4,5P2 form a unique signaling nexus that represents a paradigm shift in understanding the role of phosphoinositides in endosomal sorting (see Figure. Remarkably, the PIPKIgi5 pathway is selective for EGFR and possibly E-cadherin degradation.


We are defining other components in this pathway, the receptor specificity and underlying mechanisms. The PIPKIgi5 pathway has exciting implications for cancer therapeutics as simple over expression of PIPKIgi5 leads to a large reduction of cellular EGFR and enhanced down regulation upon EGF stimulus. In addition, PIPKIgi5 directly associates with lysosomal-associated transmembrane protein 4B (LAPTM4B). LAPTM4B is a known oncogene that is over expressed in many cancers and stimulates proliferation and anti-cancer drug resistance. We have shown that LAPTM4B blocks EGFR down regulation and enhances signaling by blocking sorting into ILVs(Dev. Cell, in revision). Our results indicate that the PIPKIgi5 pathway is a key regulator of EGFR signaling that has broad implications for EGFR dependent cancer progression.