Molecular mechanisms underlying endocytosis and sorting of ErbB receptor tyrosine kinases

Abstract

The major process that regulates the amplitude and kinetics of signal transduction by tyrosine kinase receptors is endocytic removal of active ligand^receptor complexes from the cell surface, and their subsequent sorting to degradation or to recycling. Using the ErbB family of receptor tyrosine kinases we exemplify the diversity of the down regulation process, and concentrate on two sorting steps whose molecular details are emerging. These are the Eps15-mediated sorting to clathrincoated regions of the plasma membrane and the c-Cbl-mediated targeting of receptors to lysosomal degradation. Like in yeast cells, sorting involves not only protein phosphorylation but also conjugation of ubiquitin molecules. The involvement of other molecules is reviewed and recent observations that challenge the negative regulatory role of endocytosis are described. Finally, we discuss the relevance of receptor down regulation to cancer therapy. ß

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

“…c-Cbl, a ubiquitin E3 ligase, is recruited to EGFR upon ligand stimulation, and then initiates the ubiquitylation of the activated receptor (Joazeiro et al, 1999;Levkowitz et al, 1999). The ubiquitylated EGFR is internalized into early endosomes, from where it is either recycled to plasma membrane, or delivered to multivesicular bodies and late endosomes for degradation (Waterman and Yarden, 2001;Ravid et al, 2004). In our study, we reported for the first time that ephrinA5 could enhance c-Cbl association with EGFR and subsequent ubiquitylation of the receptor, and thereby promote EGFR degradation.…”

Epidermal growth factor receptor double targeting by a tyrosine kinase inhibitor (Iressa) and a monoclonal antibody (Cetuximab). Impact on cell growth and molecular factors

“…The underlying mechanism of this upregulation of the EGFR target produced by the two drugs is not easy to elucidate. Receptor downregulation has been studied most effectively for tyrosine kinase receptor and especially for EGFR (Waterman and Yarden, 2001). Thus, subsequent to its ubiquitination, EGFR is subject to lysosomal degradation (Citri et al, 2002).…”

Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding

“…Genetic defects that disrupt ubiquitin-controlled sorting are often linked to aberrations in cell growth and may result in oncogenic transformation. Examples include c-Cbl, an E3 ubiquitin ligase involved in sorting growth factor receptors to endocytosis (for review, see Waterman and Yarden 2001), and Tsg101, an E2-like molecule originally isolated in a random screen for tumor suppressor genes (Li and Cohen 1996). Cbl proteins attach ubiquitin moieties to tyrosine-phosphorylated receptors for the epidermal growth factor (EGF), thereby accelerating their internalization and delivery to the lysosome for degradation.…”