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  • Review Article
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Cbl: many adaptations to regulate protein tyrosine kinases

Nature Reviews Molecular Cell Biology volume 2, pages 294–307 (2001)Cite this article

Key Points

  • c-Cbl is a multidomain signalling protein that was first identified as part of an oncogenic mouse retrovirus. Other mammalian homologues (Cbl-b and Cbl-3), and Cbl proteins in Drosophila melanogaster and Caenorhabditis elegans have since been identified.

  • Loss-of-function mutations in Cbl from C. elegans (known as SLI-1) restore signalling from a weakly active LET-23 receptor tyrosine kinase (RTK), a finding that defined Cbl proteins as negative regulators of RTKs.

  • All Cbl proteins have a unique tyrosine-kinase-binding (TKB) domain that recognizes phosphorylated tyrosines on activated RTKs, and a RING finger domain that recruits ubiquitin-conjugating enzymes. These two domains are primarily responsible for Cbl proteins functioning as ubiquitin protein ligases that direct multi-ubiquitylation and downregulation of RTKs.

  • c-Cbl can also target and negatively regulate non-receptor tyrosine kinases such as Syk and ZAP-70, but whether the mechanism involves E3 activity remains uncertain.

  • Cbl proteins have additional regions that mediate binding to numerous proteins that contain Src homology region 2 and 3 (SH2 and SH3) domains and 14-3-3 proteins. These regions are associated with the formation of protein complexes at the site of activated tyrosine kinases, some of which are involved in bone resorption, glucose uptake and cell spreading.

  • Cbl proteins can be made oncogenic by overexpressing the TKB domain alone (v-Cbl) or by deleting amino acids within an α-helix in a small domain that links the TKB domain to the RING finger. These mutations disrupt TKB domain interactions with the linker α-helix and abolish E3 activity.

  • Loss of E3 activity alone is insufficient for transformation as not all mutations that abolish RTK multi-ubiquitylation are transforming. Transformation also requires an undefined deregulation of TKB domain function, which results in the constitutive activation of RTKs.

  • c-Cbl- and Cbl-b-deficient mice show enhanced signalling in thymocytes and peripheral T cells, respectively. In both c-Cbl and Cbl-b mutant mice, T-cell-receptor responses are uncoupled from a requirement for co-receptor stimulation.

Abstract

Responses to extracellular stimuli are often transduced from cell-surface receptors to protein tyrosine kinases which, when activated, initiate the formation of protein complexes that transmit signals throughout the cell. A prominent component of these complexes is the product of the proto-oncogene c-Cbl, which specifically targets activated protein tyrosine kinases and regulates their signalling. How, then, does this multidomain protein shape the responses generated by these signalling complexes?

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Figure 1: The Cbl protein family.
Figure 2: c-Cbl interacts with many signalling proteins.
Figure 3: The genetic pathway of vulval induction in Caenorhabditis elegans is negatively regulated by sli-1.
Figure 4: Proposed model for the role of c-Cbl in directing multi-ubiquitylation and downregulation of the epidermal growth factor receptor.
Figure 5: Cbl proteins negatively regulate T-cell-receptor-coupled signalling pathways.
Figure 6: Structure of the complex between c-Cbl and UBCH7.

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Acknowledgements

We thank N. Zheng and N. Pavletich for providing the structural figures, and H. Gu, D. Bowtell and M. Murphy for providing unpublished results on the Cbl-knockout mice.

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Authors and Affiliations

  1. Department of Pathology, University of Western Australia, 35 Stirling Highway, Crawley, 6009, Western Australia, Australia

    Christine B. F. Thien & Wallace Y. Langdon

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  1. Christine B. F. Thien
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Related links

Related links

DATABASE LINKS

c-Cbl

Cbl family

Cbl-b

Cbl-3

D-Cbl

SLI-1

EGFR

PDGFR

ZAP-70

Syk

EF hand

SH2 domain

RING finger

Sprouty

FGFR

SH3-domain

14-3-3 protein

Fyn

Yes

Lyn

Abl

Vav1

Cdc42

UBA domain

LET-23

LET-60

Grb2

SEM-5

colony-stimulating factor 1 receptor

UBCH7

ErbB2

Fos

Jun

NF-AT

CrkL

C3G

Rap1

CD28

Akt

Met

scatter factor

CAP

ENCYCLOPEDIA OF LIFE SCIENCES

Antigen recognition by lymphocytes

Ubiquitin pathway

Glossary

UBIQUITIN-CONJUGATING ENZYME (E2)

An enzyme that accepts ubiquitin from a ubiquitin-activating enzyme and transfers it to a ubiquitin ligase which, in turn, transfers it to a substrate protein.

MULTI-UBIQUITYLATION

The sequential addition of the small protein ubiquitin to a target protein, to form a chain of isopeptide-linked ubiquitin molecules. This is a signal for proteolytic cleavage in the proteasome.

BONE RESORPTION

The digestion of mineralized bone tissue by specialized cells called osteoclasts.

ECOTROPIC

A classification for viruses that only replicate in cells of the species from which they were derived, for example, mouse ecotropic retroviruses replicate in mouse but not foreign cells.

C3HC4 RING FINGER

A protein domain containing two interleaved zinc-coordinating sites. In the first site, the zinc is coordinated by three cysteines and a histidine (C3H), whereas in the second it is coordinated by four cysteines (C4).

UBIQUITIN PROTEIN LIGASE (E3)

An enzyme that couples the small protein ubiquitin to lysine residues on a target protein, marking that protein for destruction by the proteasome.

SH3 DOMAINS

(Src-homology region 3). Protein sequence of about 50 amino acids that recognizes and binds sequences rich in proline.

CRK

Adaptor protein first described as the product of an avian oncogene, v- Crk, that contains an amino-terminal SH2 domain and two SH3 domains that function as binding sites for a diverse set of signalling proteins.

VULVAL INDUCTION

A readily accessible genetic system in Caenorhabditis elegans for studying the induction and regulation of epidermal growth factor receptor signalling pathways in vivo.

R7 PHOTORECEPTOR CELLS

A readily accessible genetic system in Drosophila melanogaster for studying the induction and regulation of epidermal growth factor receptor signalling pathways in vivo.

ANERGY

A state in which T cells cannot respond to antigen.

T-CELL CO-RECEPTOR

Receptor on T cells that binds accessory molecules on antigen-presenting cells and, when engaged along with the T-cell receptor (TCR), provides either a co-stimulatory (for example, CD28) or an inhibitory (for example, CTLA-4) signal with respect to T-cell activation.

LIPID RAFTS

Dynamic assemblies of cholesterol and sphingolipids in the plasma membrane.

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Thien, C., Langdon, W. Cbl: many adaptations to regulate protein tyrosine kinases. Nat Rev Mol Cell Biol 2, 294–307 (2001). https://doi.org/10.1038/35067100

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