c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor

Abstract

Ligand-induced down-regulation of two growth factor receptors, EGF receptor (ErbB-1) and ErbB-3, correlates with differential ability to recruit c-Cbl, whose invertebrate orthologs are negative regulators of ErbB. We report that ligand-induced degradation of internalized ErbB-1, but not ErbB-3, is mediated by transient mobilization of a minor fraction of c-Cbl into ErbB-1-containing endosomes. This recruitment depends on the receptor's tyrosine kinase activity and an intact carboxy-terminal region. The alternative fate is recycling of internalized ErbBs to the cell surface. Cbl-mediated receptor sorting involves covalent attachment of ubiquitin molecules, and subsequent lysosomal and proteasomal degradation. The oncogenic viral form of Cbl inhibits down-regulation by shunting endocytosed receptors to the recycling pathway. These results reveal an endosomal sorting machinery capable of controlling the fate, and, hence, signaling potency, of growth factor receptors.

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

“…It is believed that ubiquitination has a key role in 'tagging' EGFR for endocytosis. Cbl, a ring-finger domain E3 ubiquitin ligase, is mainly responsible for EGFR ubiquitination (Levkowitz et al, 1998). One of our novel findings is that inhibition of ERK activity further promotes the association between Cbl and EGFR, which strongly correlates with the augmented ubiquitination of EGFR by PD98059.…”

“…The ERK pathway affects EGFR trafficking by threonine phosphorylation of EGFR Consequent to EGF stimulation, activated EGFR is rapidly ubiquitinated by c-Cbl, an SH2 domain-containing ubiquitin ligase that itself becomes phosphorylated and binds to EGFR, which promotes postinternalization of EGFR and sorting to endosomes and lysosomes for degradation (Levkowitz et al, 1998;Joazeiro et al, 1999;Waterman et al, 1999). In DU145 cells, EGF stimulation led to EGFR ubiquitination (Figure 3a, upper panel, lane 2), which was enhanced by PD98059 (lane 4 vs 2), but not by LY294002 (lane 6 vs 2).…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Binding of Grb2 to EGFR appears necessary for receptor internalization [86]. Activated, tyrosine phosphorylated EGFR uniquely binds the E3 ubiquitin ligase Cbl, which is capable of ubiquitinylating EGFR leading to lysosomal degradation of the receptor [87]. Cbl appears to be recruited to EGFR by Grb2, and this complex alone may be sufficient for endocytosis of the receptor [88].…”

Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation

“…The domain structure of c-Cbl consists of a tyrosine kinase binding (TKB) domain through which it binds tyrosinephosphorylated targets, a RING finger domain, which binds E2-conjugating enzymes, and a C-terminal ubiquitin-associated (UBA) domain. Additional studies demonstrated that c-Cbl facilitates ligand-induced ubiquitylation of the EGFR [11,12], as well as several other RTKs (reviewed in [13]) by means of RING finger-dependant recruitment of E2 ubiquitin-conjugating enzymes to the receptor's vicinity. Receptor ubiquitylation results in accelerated removal from the cell surface and to subsequent receptor degradation in the lysosomal compartment, thereby terminating RTK signaling.…”