Chapter 69 - Receptor Tyrosine Kinase Signaling and Ubiquitination

Abstract

This chapter discusses how ubiquitination regulates receptor tyrosine kinases and how tyrosine kinase signaling pathways control ubiquitination processes. It describes the molecular interplay between receptor tyrosine kinase signaling and protein ubiquitination networks that are critical for the regulation of physiological and pathological conditions. In particular, there is a link between constitutive receptor tyrosine kinase (RTK) signaling and the loss of ubiquitin-dependent negative regulation of RTKs, which can cause cell transformation and cancer. Besides protein phosphorylation that serves as the major posttranslational modification to convey signals in the cell, ubiquitination of the receptor as well as several downstream effectors has emerged as an important modification that modulates signaling events. First, the attachment of ubiquitin provides the sorting signal for lysosomal degradation of the receptor leading to permanent termination of signaling. Second, ubiquitination can change the activity, the localization as well as the stability of downstream effectors. Ligand binding to receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR), leads to receptor dimerization, activation, and phosphorylation at multiple tyrosines within their intracellular part. Proteins that are responsible for the endocytic sorting of the ubiquitinated receptor are subjected to a special type of ubiquitination, the so-called coupled monoubiquitination. However, besides regulating receptor sorting and degradation, ubiquitination emerges as a potent signal regulating localization, activity, and binding-competence of a great variety of proteins, not only in RTK signaling. Ub-binding proteins that recognize ubiquitinated effectors play a key role in the establishment of these signaling networks.