Research: Receptor Control of Autophagy

A Kinase Independent Role for EGF Receptor in Autophagy Initiation

The Epidermal Growth Factor Receptor (EGFR) is over-expressed and/or over-activated in numerous human cancers. EGFR activation suppresses autophagy in tumor cells, and inhibition of EGFR signaling induces autophagy. We have discovered an unanticipated role for the inactive EGFR in autophagy initiation

Model for initiation of autophagy by the inactive EGF receptor. EGFR is continuously cycling between the plasma membrane and intracellular membrane compartments. Upon serum starvation EGFR directly interacts with LAPTM4B and this initiates autophagy by modulating the Beclin 1 complex(Cell, In press).

(Cell, in press). Inactive EGFR directly interacts with the oncoprotein LAPTM4B that is required for the endosomal accumulation of EGFR upon serum starvation. Inactive EGFR and LAPTM4B stabilize each other at endosomes and recruit the Exocyst subcomplex containing Sec5. We show that inactive EGFR, LAPTM4B, and the Sec5 subcomplex are all required for basal and starvation induced autophagy. LAPTM4B and Sec5 promote EGFR association with Rubicon (an autophagy inhibitor), and this controls Beclin 1 disassociation from Rubicon to initiate autophagy. Thus, the oncoprotein LAPTM4B facilitates the role of inactive EGFR in autophagy initiation (see Figure). This pathway is selective (perhaps specific) for the EGF receptor and positioned to control tumor metabolism and promote tumor cell survival upon serum deprivation or metabolic stress. Remarkably, the inhibition of EGFR with specific kinase inhibitors also induces autophagy and may be a mechanism that impedes the effective use of these drugs in most cancer therapies(Cell, In press).

These combined results indicate that the EGF receptor is uniquely regulated by endosomal mechanisms that both enhance and prolong its spatial signaling and control key metabolic pathway that enhance cell survival upon stress or inhibition of activity. These discoveries have opened unexpected mechanisms for EGFR in the proliferation and cell survival that appear specific for this receptor.