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The Cbl interactome and its functions

Nature Reviews Molecular Cell Biology volume 6, pages 907–919 (2005)Cite this article

Key Points

  • Cbl proteins are multifunctional adaptor proteins that are implicated in the regulation of signal transduction in response to different stimuli. Cbl-associated proteins form interactomes that can generate signal-competent networks that control many physiological processes. These interactomes determine the functional outcome of Cbl interactions.

  • Cbl proteins have been implicated in receptor-tyrosine kinase (RTK) regulation by mediating receptor internalization and downregulation. This function largely depends on Cbl-interacting proteins, which cause negative membrane curvature and the E3-ligase activity of Cbl that leads to target ubiquitylation. The latter is an important step in sorting receptor cargo towards lysosomal degradation.

  • Similarly, Cbl molecules have been implicated in T-cell receptor regulation. Activation of the T-cell-receptor complex (TCR) by an antigen-presenting cell (APC) eventually leads to degradation of the activated TCR. This function largely depends on Cbl molecules.

  • The function of the Cbl proteins is also negatively regulated by various molecular mechanisms, including sequestration of Cbl away from the activated receptor or inefficient coupling of Cbl binding to receptors with a low-phosphorylation status.

  • Cbl fulfils adaptor functions in focal adhesions. Subsequent to activation of integrins, for example, adhesion of macrophages to fibronectin or vitronectin, Cbl is attracted into focal adhesion structures and supports the stability of the multiprotein complex by its modular structure.

Abstract

Cbl proteins are ubiquitin ligases and multifunctional adaptor proteins that are implicated in the regulation of signal transduction in various cell types and in response to different stimuli. Cbl-associated proteins can assemble together at a given time or space inside the cell, and such an interactome can form signal competent networks that control many physiological processes. Dysregulation of spatial or temporal constraints in the Cbl interactome results in the development of human pathologies such as immune diseases, diabetes and cancer.

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Figure 1: The domain structure of Cbl proteins.
Figure 2: The Cbl interactome.
Figure 3: Inhibitors of Cbl functions.
Figure 4: Selective roles of c-Cbl and Cbl-b interactomes in T-cell receptor signalling.
Figure 5: The Cbl interactome in the regulation of the actin cytoskeleton.

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Acknowledgements

We are very grateful to B.-J. Breitkreutz and M. Tyers for critical advice in creating Cbl interaction maps and for making the Osprey version of the Cbl interactome presented in Figure 2. We also thank V. Heissmeyer, D. Höller, W. Langdon, K. Rittinger, I. Szymkiewicz and S. Urbe for critical comments on the manuscript. We apologize to colleagues whose work could not be cited owing to space limitations. M.H.H.S. is a fellow of the European Molecular Biology Organization. I.D. gratefully acknowledges support from the Deutsche Forschungsgemeinschaft and the Boehringer Ingelheim Foundation.

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Authors and Affiliations

  1. Institute for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, Frankfurt am Main, D-60590, Germany

    Mirko H.H. Schmidt & Ivan Dikic

  2. Mediterranean Institute for Life Sciences (MedILS), Mazuranicevo setaliste bb, Split, HR-21000, Croatia

    Ivan Dikic

Authors
  1. Mirko H.H. Schmidt
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Correspondence to Ivan Dikic.

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DATABASES

Swiss-Prot

Alix1

Cbl-b

Cbl-c

c-Cbl

CD2AP

CD4

CD8

Cdc42

CIN85

EEA1

EGFR

EPS15

Grb2

PKC

Sprouty2

VAV

ZAP70

FURTHER INFORMATION

The Cbl interactome

The Cbl-b interactome

GRID

Osprey

BIND

Ivan Dikic's laboratory

Glossary

SIGNALOSOME

A supramolecular-protein assembly that initiates signalling cascades and promotes signal transduction within the cell.

TKB DOMAIN

The TKB domain of Cbl proteins is a modified SH2 domain and mediates binding to phosphorylated tyrosines in Cbl-target molecules.

RING FINGER

A protein domain that consists of two loops that are held together at their base by cysteine and histidine residues that form a complex with two zinc ions. Many RING fingers function in protein degradation by facilitating protein ubiquitylation.

LEUCINE ZIPPER MOTIF

A leucine-rich protein domain that mediates interactions with other proteins that have a similar domain.

E3 UBIQUITIN PROTEIN LIGASE

An enzyme that functions together with a ubiquitin-conjugating enzyme (E2) to couple the small protein ubiquitin to Lys residues on a target protein. This marks that protein for destruction by the proteasome.

INTERACTOME

A protein network that surrounds a certain protein at a given time and space in a cell.

FOCAL ADHESION

An integrin-mediated cell–substrate adhesion structure that anchors the ends of actin filaments (stress fibres) and mediates strong attachments to substrates. It also functions as an integrin-signalling platform.

SH3 DOMAIN

(Src-homology-3 domain). A protein–protein interaction domain that recognizes a unique proline-rich peptide motif. This domain is found in many proteins that are involved in signal transduction and membrane–cytoskeleton interactions.

ENDOSOME

A membranous transport vesicle that is involved in endocytosis.

ARP2/3 COMPLEX

(actin-related protein 2/3). A multi-protein complex that consists of seven different proteins and initiates new actin filaments on pre-existing ones.

DYNAMIN

A mechanical GTPase that promotes the detachment of clathrin-coated vesicles from the plasma membrane.

MULTIVESICULAR BODY

(MVB). An endocytic intermediate organelle in the lysosomal-degradative pathway that contains small vesicles (often containing ubiquitylated cargo) and is surrounded by a limiting membrane.

SH2 DOMAIN

(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and therefore has a key role in relaying cascades of signal transduction.

FYVE DOMAIN

(Fab1, YOTB, Vac1, EEA1 domain). A zinc-finger-containing protein motif that binds the membrane lipid phosphatidylinositol-3-phosphate. The protein that contains FYVE is therefore targeted to the membrane.

RHO-FAMILY GTPASES

A subfamily of small (∼21 kDa) GTP-binding proteins that are related to Ras, and that regulate the cytoskeleton.

ESCRT

(endosomal sorting complex required for transport). The multiprotein ESCRT machinery (ESCRT-I, -II and -III) promotes inward vesiculation at the limiting membrane of the sorting endosome, and selects cargo proteins for delivery to the intralumenal vesicles of multivesicular bodies.

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). A complex of genetic loci in higher vertebrates that encodes a family of cellular antigens that allow the immune system to recognize self from non-self.

THYMOCYTES

Lymphocytes that are found in the thymus.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

(GEF). A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

ANERGY

A state in which T cells cannot respond to antigen.

14-3-3 PROTEINS

A family of proteins and protein domains that bind to serine/threonine-phosphorylated residues in a context-specific manner. They bind and regulate key proteins that are involved in various physiological processes.

LAMELLIPODIA

Thin, flat extensions at the cell periphery that are filled with a branching meshwork of actin filaments.

PSEUDOPODIA

Temporary projections of the cytoplasm of certain cells, such as neutrophils, or of certain unicellular organisms, especially amoebae, that function in locomotion.

GROWTH CONE

Motile tip of the axon or dendrite of a growing nerve cell, which spreads out into a large cone-shaped appendage.

LEADING EDGE

The thin margin of a lamellipodium that spans the area of the cell from the plasma membrane to a depth of about 1 μm into the lamellipodium.

OSTEOCLAST

A mesenchymal cell that can differentiate into a bone-degrading cell.

LIPID RAFTS

Membrane microdomains that are enriched in cholesterol, sphingolipids and lipid-modified proteins such as GPI-linked proteins and palmitoylated proteins. These microdomains often function as platforms for signalling events.

CAVEOLAE

Specialized membrane domains that contain high amounts of cholesterol and sphingolipids. They represent one starting point of non-clathrin-mediated endocytosis.

SORBIN HOMOLOGY (SOHO) DOMAIN

A motif within a protein that targets the molecule to lipid rafts.

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Schmidt, M., Dikic, I. The Cbl interactome and its functions. Nat Rev Mol Cell Biol 6, 907–919 (2005). https://doi.org/10.1038/nrm1762

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