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  • Review Article
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Regulation of the c-Abl and Bcr–Abl tyrosine kinases

Key Points

  • Abl is a non-receptor tyrosine kinase that contains a Src-homology-3 (SH3)- and a Src-homology-2 (SH2)-domain. Abl participates in many signalling pathways in the cytoplasm and the nucleus. The oncogenic fusion Bcr–Abl, which is caused by reciprocal chromosomal translocations, leads to different forms of leukaemia in humans.

  • The crystal structure of regulated Abl closely resembles that seen in structures of regulated Src-family kinases, but with unique differences: binding of myristate to a hydrophobic pocket in the kinase domain induces a defined conformational change that enables intramolecular docking of the SH2 domain to the kinase domain, thereby enforcing an autoinhibited conformation.

  • Phosphorylation sites have recently been mapped in Bcr–Abl by mass spectrometry. Taking the crystal structure and functional data into consideration, these new results have implications for Abl regulation.

  • The amino-terminal autoinhibitory 'Cap' region did not show interpretable electron density in the crystal structure, but a detailed functional analysis identified a region that is evolutionarily conserved and essential for autoinhibition and a second region that is not conserved and is dispensable.

  • An unsuspected link between mutations that confer resistance to the small-molecule inhibitor STI-571 and enzyme activation indicates that Abl-like regulatory constraints are also operational in the oncoprotein Bcr–Abl.

Abstract

The prototypic non-receptor tyrosine kinase c-Abl is implicated in various cellular processes. Its oncogenic counterpart, the Bcr–Abl fusion protein, causes certain human leukaemias. Recent insights into the structure and regulation of the c-Abl and Bcr–Abl tyrosine kinases have changed the way we look at these enzymes.

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Figure 1: Domain structures of the SH3- and SH2-domain-containing tyrosine-kinase superfamily.
Figure 2: Structures of regulated c-Abl and c-Src.
Figure 3: Phosphorylation sites in Abl.
Figure 4: Functional classification of the Cap region.
Figure 5: STI-571-resistant mutations.

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Acknowledgements

We are particularly grateful to K. Dorey and G. Neubauer for the unpublished data on Abl phosphorylation sites and K. Dorey for the sequence of Xenopus Abl. We would like to thank B. Nagar, K. Dorey, M. Schwab, A. Nebreda and K. Scheffzek for critical reading of the manuscript and J. Kuriyan and members of the Superti-Furga laboratory for insightful discussions. O.H. is supported by fellowships from the EMBL and the Aventis Foundation and is a fellow of the German National Merit Foundation. Work in the G.S.F. laboratory is supported by the EMBL and Cellzome.

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DATABASES

Interpro

PH domain

SH2

SH3

TH domain

OMIM

ALL

CML

Swiss-Prot

Abi1

Abl

Arg

ATM

Bcr

Cables

Cbl

Crk

Grb2

c-jun

Nck

p53

p73

γ-PAK

paxillin

Prdx1

Rb

Src

FURTHER READING

Protein Data Bank

Glossary

PARALOGUE

A gene product on the opposite branch of a duplicated gene family. Orthologues are on the same branch of a family (for example, FLNa, FLNb and FLNc). Paralogues and orthologues are homologues.

PALMITOYLATION

Protein palmitoylation is a common protein modification in which a 16-carbon-atom saturated fatty acid (palmitate) is covalently attached to a cysteine residue through a thioester bond.

SH2 DOMAIN

(Src-homology-2 domain). A protein module that recognizes and binds tyrosine-phosphorylated sequences in a sequence-specific context and thereby has a key role in relaying cascades of signal transduction.

SH3 DOMAIN

(Src-homology-3 domain). A protein module of about 50 amino acids that recognizes and binds to sequences typically rich in proline.

TEC-HOMOLOGY DOMAIN

A characteristic protein module found on Tec-family kinases, consisting of a highly conserved Zn2+ -binding Btk motif and a proline-rich region.

PLECKSTRIN HOMOLOGY DOMAIN

A module of 100 amino acids that is present in many signalling molecules and binds to lipid products of phosphatidylinositol 3-kinase.

ADAPTOR PROTEINS

Proteins that modulate cellular responses by recruiting other proteins to a complex. They usually contain several protein–protein interaction domains.

ACTIVE SITE

The part of an enzyme where the substrates are brought into close proximity and the chemical reaction happens.

POLYPROLINE TYPE II HELIX

A preferred conformation for proline-rich regions of protein sequences, with an axial translation of 3.2 Å and three residues in each turn of a left-handed helix. Other common polypeptide conformations are α-helix and β-sheet.

ACTIVATION LOOP

A conserved structural motif in kinase domains, which needs to be phosphorylated for full activation of the kinase.

SF9 CELLS

A commonly used insect cell line, derived from the fall armyworm (Spodoptera frugiperda), and used for baculovirus-mediated expression of recombinant proteins in insect cells.

RT-LOOP

A variable loop in SH3 domains that is positioned close to conserved residues and is implicated in the binding of proline-rich (PXXP) motifs. It is responsible for differential binding affinity and specificity of SH3 domains.

310 HELIX

A tighter, less stable helix than the α-helix, with three residues per turn, forming hydrogen-bonded loops of 10 atoms.

YEAST TWO-HYBRID

A technique used to test if two proteins physically interact with each other. One protein is fused to the GAL4 activation domain and the other to the GAL4 DNA-binding domain, and both fusion proteins are introduced into yeast. Expression of a GAL4-regulated reporter gene indicates that the two proteins physically interact.

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Hantschel, O., Superti-Furga, G. Regulation of the c-Abl and Bcr–Abl tyrosine kinases. Nat Rev Mol Cell Biol 5, 33–44 (2004). https://doi.org/10.1038/nrm1280

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