CBL

CBL Full Name

Cbl proto-oncogene, E3 ubiquitin protein ligase

CBL Introduction

CBL proteins constitute a family of key negative regulators in signal transduction pathways with their primary function being that of E3 ubiquitin-protein ligases. There are three major CBL proteins in mammals: c-Cbl, Cbl-b and Cbl-c. These proteins are differentially distributed in tissues and have specific as well as overlapping functions, but have a similar domain structure and identical central biochemical activity. All CBL proteins have a multi-domain architecture with several functionally conserved domains that act in a coordinated manner to achieve high specificity of substrate recognition and ubiquitination. The N-terminal half of the protein contains a highly conserved Tyrosine Kinase Binding domain (TKB) that mediates specific recognition and binding to the phosphorylated tyrosine residue(s) on the target protein. This is key to their substrate specificity. Following the TKB domain are a Linker region and a RING finger domain. The RING domain is the core catalytic module for E3 ligase activity of CBL proteins and is responsible for recruiting E2 ubiquitin-conjugating enzymes that carry ubiquitin and for promoting the transfer of ubiquitin onto the substrate protein. In addition to the RING domain, the C-terminal domain of CBL proteins also contains a Proline-Rich Region (PRR), which can mediate interaction with other signaling proteins, allowing for even further diversification and modulation of signaling.

Figure 1. CBL family structure. (Source: Ren J, et al. 2024)

As E3 ubiquitin ligases, the best-known function of CBL proteins is to facilitate target protein degradation through the ubiquitin-proteasome system or lysosomal pathway, with the end result of "switching off" or attenuating cellular signalling. The prototypical function of CBL proteins is in the negative regulation of Receptor Tyrosine Kinase (RTK) signalling pathways, for example EGFR. In the presence of an agonist ligand and following autophosphorylation, CBL proteins bind to activated RTKs through their TKB domain. They then use their RING domain to recruit and catalyse ubiquitination of the receptor, which is eventually sorted into the endocytic pathway for lysosomal degradation. This "switches off" the downstream RTK signalling and prevents overstimulation of cell growth and proliferation. In addition to this regulation of RTKs, CBL proteins also help control the activity of a variety of other non-receptor tyrosine kinases and signalling adaptor proteins. As key regulators of intracellular signalling, CBL family members also play crucial roles in the immune system. In particular, Cbl-b is important for maintaining tolerance and preventing autoimmune reactions, by setting the activation threshold for T-cell receptor (TCR) signalling. Loss of Cbl-b significantly lowers the activation threshold for T cells, leading to hyperactivation of the immune system. Similarly, in NK cells, Cbl-b also suppresses their activation and anti-tumor functions. Consequently, targeting Cbl-b has emerged as a promising strategy to enhance the anti-cancer activity of immune cells.

The aberrations in CBL family members are implicated in human diseases, particularly in the two broad research areas of cancer and autoimmune disorders, due to their important functions in cell signaling and maintenance of immune homeostasis. CBL mutations have been identified as a major pathogenic cause of hematologic malignancies. For example, somatic or germline mutations of CBL is one of the most frequent genetic alterations in Juvenile Myelomonocytic Leukemia (JMML). The majority of these mutations are loss-of-function mutations which occur at the RING domain or the linker region of CBL, and cause the loss of CBL's E3 ligase activity. The resulting mutant CBL protein would therefore be unable to mediate turnover of its downstream targets (predominantly kinases, such as FLT3 and c-Kit) via degradation, and hence leads to their sustained and aberrant activation (such as of RAS pathway), which eventually contributes to the malignant proliferation of the myeloid cells. Mutations in CBL have also been found to occur in Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML) and Acute Myeloid Leukemia (AML), which are also often associated with poor prognosis. On the contrary, functional loss of Cbl-b is instead strongly associated with a susceptibility to autoimmune diseases. As a major tolerance maintenance molecule, the functional loss of Cbl-b would lead to a reduced T-cell activation threshold and compromised ability of the immune system in self-regulation, thus promoting the development of autoimmune diseases such as Type 1 diabetes, Systemic Lupus Erythematosus and Multiple Sclerosis.

Alternate Names for CBL

CBL; Cbl proto-oncogene, E3 ubiquitin protein ligase; CBL2; NSLL; C-CBL; RNF55; FRA11B; E3 ubiquitin-protein ligase CBL; oncogene CBL2; proto-oncogene c-Cbl

• 1. Ren J, et al. The role of CBL family ubiquitin ligases in cancer progression and therapeutic strategies. Front Pharmacol. 2024 Jul 26;15:1432545.
  2. Ahmed SF, et al. E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK-CBL-CIN85 axis. Oncogene. 2021 Mar;40(12):2149-2164.