c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses

Abstract

The activation of signalling pathways by ligand engagement with transmembrane receptors is responsible for determining many aspects of cellular function and fate. While these outcomes are initially determined by the nature of the ligand and its receptor, it is also essential that intracellular enzymes, adaptor proteins and transcription factors are correctly assembled to convey the intended response. In recent years, it has become evident that proteins that regulate the amplitude and duration of these signalling responses are also critical in determining the function and fate of cells. Of these, the Cbl family of E3 ubiquitin ligases and adaptor proteins has emerged as key negative regulators of signals from many types of cell-surface receptors. The array of receptors and downstream signalling proteins that are regulated by Cbl proteins is diverse; however, in most cases, the receptors have a common link in that they either possess a tyrosine kinase domain or they form associations with cytoplasmic PTKs (protein tyrosine kinases). Thus Cbl proteins become involved in signalling responses at a time when PTKs are first activated and therefore provide an initial line of defence to ensure that signalling responses proceed at the desired intensity and duration.

A critical role for the E3-ligase activity of c-Cbl in VEGFR-2-mediated PLCγ1 activation and angiogenesis

“…3A shows that PLC␥1 coprecipitates with both the wild-type c-Cbl and 70Z/3-Cbl and its association with c-Cbl is independent of VEGFR-2 activation. Substrates of c-Cbl to be targeted for ubiquitylation interact with either its N-terminal TKB domain or the C-terminal proline-rich region (13). To address the relative contribution of these c-Cbl domains to associate with PLC␥1, we performed in vitro GST pull-down assays using GST alone (GST), GST fused to the Cbl N-terminal TKB domain (GST-Cbl-N) and its TKB-inactivated mutant (GST-Cbl-N/G306E), corresponding to a loss-of-function mutation (14), and GST fused to the c-Cbl C-terminal domain (GST-Cbl-C).…”

c-Cbl-facilitated cytoskeletal effects in v-Abl-transformed fibroblasts are regulated by membrane association of c-Cbl

“…The presence of multiple interaction modules in c-Cbl underlies the versatility of its interactions and the influence of c-Cbl on a variety of biological processes (Schmidt and Dikic, 2005;Thien and Langdon, 2005;Swaminathan and Tsygankov, 2006). c-Cbl is both an E3 ubiquitin ligase involved in the negative regulation of protein tyrosine kinases (PTK) (Levkowitz et al, , 2000Miyake et al, 1999;Waterman et al, 1999;Rao et al, 2001;Yokouchi et al, 2001) and an adaptor protein involved in multiple biological phenomena, including cytoskeletal events (Tanaka et al, 1996;Ojaniemi et al, 1997;Meng and Lowell, 1998;Sanjay et al, 2001;Scaife et al, 2003a, b;Haglund et al, 2004).…”

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).…”