Structure, regulation, signaling, and targeting of abl kinases in cancer

Abstract

Abl kinases are prototypic cytoplasmic tyrosine kinases and are involved in a variety of chromosomal aberrations in different cancers. This causes the expression of Abl fusion proteins, such as Bcr-Abl, that are constitutively activated and drivers of tumorigenesis. Over the past decades, biochemical and functional studies on the molecular mechanisms of Abl regulation have gone hand in hand with progression of our structural understanding of autoinhibited and active Abl conformations. In parallel, Abl oncoproteins have become prime molecular targets for cancer therapy, using adenosine triphosphate (ATP)-competitive kinase inhibitors, such as imatinib. Abl-targeting drugs serve as a paradigm for our understanding of kinase inhibitor action, specificity, and resistance development. In this review article, I will review the molecular mechanisms that are responsible for the regulation of Abl kinase activity and how oncogenic Abl fusions signal. Furthermore, past and ongoing efforts to target Abl oncoproteins using ATP-competitive and allosteric inhibitors, as well as future possibilities using combination therapy, will be discussed.

Keywords: Bcr-Abl; kinase inhibitor; kinase structure; tyrosine kinase.

Figure 1.

Timeline of Abl structural insights. A schematic domain representation of Abl is shown on top of the figure. Below, the structures, staggered by the time when they were published, of the different Abl domains and domain combinations are shown in cartoon representation. The structures are colored as in the schematic domain representation on top. Once different structures of the same domains (e.g., obtained with different methods, different crystal forms, mutants, drugs) were published simultaneously, only one representative structure is shown for graphical convenience. The PDB entries from which the representations were derived are shown next to the respective structure.

Figure 2.

Structure of autoinhibited Abl and Src. Cartoon representation of autoinhibited Abl in complex with the adenosine triphosphate (ATP)–competitive inhibitor PD166326 (left; PDB entry 1OPK, 18) compared with autoinhibited Src in complex with the ATP analogue AMP-PNP (right; PDB entry 2SRC, 14). Below the cartoon representations of the crystal structures, more schematic representation are used that should illustrate global conformation differences of the 2 kinases. In both kinases, the SH3-SH2 domain unit forms a clamp that inhibits the kinase domain. In Src, the tyrosine-phosphorylated tail binding to the SH2 domain latches the clamp. The myristoyl group of Abl serves as a latch for the SH3-SH2 clamp by inducing a conformational switch in the C-terminal kinase domain helix that gates clamp binding.

Figure 3.

ABL1 and ABL2 fusions in cancer. Schematic domain representation of the proto-oncogene products of the ABL1 and ABL2 genes, as well as the known fusion gene products that mainly arise through chromosomal translocations. Known phosphorylation sites are indicated. The phosphorylation events on Tyr-177 in Bcr-Abl isoforms and Tyr-314 in Etv6-Abl that are discussed in more detail are indicated in red. Sizes of the proteins are approximately to scale. Domain abbreviations are as follows: TyrK, tyrosine kinase; FABD, F-actin binding; CC, coiled-coil; DH, Dbl-homolgy; PH, Pleckstrin-homology; RHOGAP, Rho GTPase-activating protein; WD40, Trp-Asp (W-D) terminating domain of ~40 amino acid length; PNT, pointed dimerization domain; RRM, RNA recognition motif.