Protein tyrosine kinase regulation by ubiquitination: Critical roles of Cbl-family ubiquitin ligases

Abstract

Protein tyrosine kinases (PTKs) coordinate a broad spectrum of cellular responses to extracellular stimuli and cell–cell interactions during development, tissue homeostasis, and responses to environmental challenges. Thus, an understanding of the regulatory mechanisms that ensure physiological PTK function and potential aberrations of these regulatory processes during diseases such as cancer are of broad interest in biology and medicine. Aside from the expected role of phospho-tyrosine phosphatases, recent studies have revealed a critical role of covalent modification of activated PTKs with ubiquitin as a critical mechanism of their negative regulation. Members of the Cbl protein family (Cbl, Cbl-b and Cbl-c in mammals) have emerged as dominant “activated PTK-selective” ubiquitin ligases. Structural, biochemical and cell biological studies have established that Cbl protein-dependent ubiquitination targets activated PTKs for degradation either by facilitating their endocytic sorting into lysosomes or by promoting their proteasomal degradation. This mechanism also targets PTK signaling intermediates that become associated with Cbl proteins in a PTK activation-dependent manner. Cellular and animal studies have established that the relatively broadly expressed mammalian Cbl family members Cbl and Cbl-b play key physiological roles, including their critical functions to prevent the transition of normal immune responses into autoimmune disease and as tumor suppressors; the latter function has received validation from human studies linking mutations in Cbl to human leukemia. These newer insights together with embryonic lethality seen in mice with a combined deletion of Cbl and Cbl-b genes suggest an unappreciated role of the Cbl family proteins, and by implication the ubiquitin-dependent control of activated PTKs, in stem/progenitor cell maintenance. Future studies of existing and emerging animal models and their various cell lineages should help test the broader implications of the evolutionarily-conserved Cbl family protein-mediated, ubiquitin-dependent, negative regulation of activated PTKs in physiology and disease.

Transformation of polarized epithelial cells by apical mistrafficking of epiregulin

“…3C). Y1045-EGFR phosphorylation is recognized by the E3 ligase casitas B-lineage lymphoma protooncogene (CBL), which then targets EGFR for K63-mediated lysosomal degradation (30). We also observed ubiquitylation of EGFR after basolateral EREG stimulation, but not after apical EREG stimulation (Fig.…”

Ubiquitin ligase Cbl‐b acts as a negative regulator in discoidin domain receptor 2 signaling via modulation of its stability

“…However, they also display different expression pattern and in vivo function [18]. As for the role of Cbl and Cbl-b in some PTK signaling, it can be different or even opposite [26,29].…”

“…Although our current data supported the notion that collagen-induced ubiquitination of DDR2 was predominantly facilitated by Cbl-b, we cannot exclude the possibility that Cbl may also play some important roles in DDR2 signaling, given that we identified an interaction between Cbl and DDR2 as well (data not shown). In addition, aside from possessing ubiquitin ligase activity, Cbl has been well documented as an adaptor protein [18,26]. As such, whether and how Cbl is involved in DDR2 signaling still awaits further investigation.…”

“…Because ubiquitin-modified tyrosine kinases can be degraded in either lysosome or proteasome [18], we then examined which pathway is linked to DDR2 ubiquitination. HEK293T cells coexpressing Myc-DDR2, HA-Ub and Xpress-Cbl-b were stimulated with collagen II for 2 h, and then treated with proteasome or lysosome inhibitor for 30 min.…”

“…Cbl family, which consists of three homologues known as Cbl (or c-Cbl), Cbl-b and Cbl-c (or Cbl-3) in mammals, belongs to RING-type E3 ubiquitin ligases [17]. Cbl proteins-mediated ubiquitination can target activated tyrosine kinases for degradation, either by facilitating their endocytic sorting into lysosomes or by promoting their proteasomal degradation [18]. In contrast to the wide expression pattern of Cbl and Cbl-b, Cbl-c expression was reported to be limited in epithelial cells [19], in which DDR2 is always not expressed [4,5].…”