?PIX Is a Trafficking Regulator that Balances Recycling and Degradation of the Epidermal Growth Factor Receptor.

ABSTRACT: Endosomal sorting is an essential control mechanism for signaling through the epidermal growth factor receptor (EGFR). We report here that the guanine nucleotide exchange factor ?PIX, which modulates the activity of Rho-GTPases, is a potent bimodal regulator of EGFR trafficking. ?PIX interacts with the E3 ubiquitin ligase c-Cbl, an enzyme that attaches ubiquitin to EGFR, thereby labelling this tyrosine kinase receptor for lysosomal degradation. We show that EGF stimulation induces ?PIX::c-Cbl complex formation. Simultaneously, ?PIX and c-Cbl protein levels decrease, which depends on both ?PIX binding to c-Cbl and c-Cbl ubiquitin ligase activity. Through interaction ?PIX sequesters c-Cbl from EGFR and this results in reduced EGFR ubiquitination and decreased EGFR degradation upon EGF treatment. However, quantitatively more decisive for cellular EGFR distribution than impaired EGFR degradation is a strong stimulating effect of ?PIX on EGFR recycling to the cell surface. This function depends on the GIT binding domain of ?PIX but not on interaction with c-Cbl or ?PIX exchange activity. In summary, our data demonstrate a previously unappreciated function of ?PIX as a strong promoter of EGFR recycling. We suggest that the novel recycling regulator ?PIX and the degradation factor c-Cbl closely cooperate in the regulation of EGFR trafficking: uncomplexed ?PIX and c-Cbl mediate a positive and a negative feedback on EGFR signaling, respectively; ?PIX::c-Cbl complex formation, however, results in mutual inhibition, which may reflect a stable condition in the homeostasis of EGF-induced signal flow.

SUBMITTER: Kortum F 

PROVIDER: S-EPMC4503440 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature