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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 αPIX, which modulates the activity of Rho-GTPases, is a potent bimodal regulator of EGFR trafficking. αPIX 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 αPIX::c-Cbl complex formation. Simultaneously, αPIX and c-Cbl protein levels decrease, which depends on both αPIX binding to c-Cbl and c-Cbl ubiquitin ligase activity. Through interaction αPIX 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 αPIX on EGFR recycling to the cell surface. This function depends on the GIT binding domain of αPIX but not on interaction with c-Cbl or αPIX exchange activity. In summary, our data demonstrate a previously unappreciated function of αPIX as a strong promoter of EGFR recycling. We suggest that the novel recycling regulator αPIX and the degradation factor c-Cbl closely cooperate in the regulation of EGFR trafficking: uncomplexed αPIX and c-Cbl mediate a positive and a negative feedback on EGFR signaling, respectively; αPIX::c-Cbl complex formation, however, results in mutual inhibition, which may reflect a stable condition in the homeostasis of EGF-induced signal flow.
Highlights
The identification of ARHGEF6 encoding αPIX as a disease gene for a non-syndromic form of intellectual disability has brought this molecule into scientific focus [1]. αPIX belongs to the Dbl-related guanine nucleotide exchange factor (GEF) protein family [2, 3]
The role of Cbl as a negative regulator of receptor tyrosine kinase (RTK) signaling has been extensively studied [33, 37] and epidermal growth factor receptor (EGFR; Entrez Gene ID: 1956) has been the primary experimental model to examine the contribution of Cbl proteins to endocytic sorting of RTKs
If a cell needs to become desensitized for EGFR ligands, internalized receptors can be directed to the lysosome for degradation; alternatively, if signaling should be sustained or a cell needs to be resensitized for EGFR ligands, endocytozed EGFRs are recycled back to the plasma membrane [58]
Summary
The identification of ARHGEF6 encoding αPIX ( known as Cool-2; Entrez Gene ID: 9459) as a disease gene for a non-syndromic form of intellectual disability has brought this molecule into scientific focus [1]. αPIX belongs to the Dbl-related guanine nucleotide exchange factor (GEF) protein family [2, 3]. The role of Cbl as a negative regulator of receptor tyrosine kinase (RTK) signaling has been extensively studied [33, 37] and epidermal growth factor receptor (EGFR; Entrez Gene ID: 1956) has been the primary experimental model to examine the contribution of Cbl proteins to endocytic sorting of RTKs. Upon ligand binding, EGFR is rapidly internalized and sorted into endosomes; from there EGFR can be either recycled back to the cell surface or transported to lysosomes for degradation—a process called receptor downregulation [38]. Whereas ubiquitination seems to be dispensable for EGFR internalization, this modification strongly affects the postendocytic EGFR fate by lysosomal targeting and subsequent degradation of ubiquitinated receptors [38, 39]
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