|Part of Fig. 1 from Panjarian et al minireview in The Journal of Biological Chemistry: domain organization of Abl kinases and crystal structure of the downregulated c-Abl core. Click on the image to see a larger version.
Tyrosine kinases function in a number of processes and pathways in the body and are responsible for regulating numerous cellular functions such as growth, development, signaling and activation. Mutations that leave these kinases constitutively active are associated with various types of cancer; indeed, clinical research over the past 20 years has shown targeting rogue kinases to be beneficial in the fight against cancer. To target these kinases effectively, researchers have focused on understanding the structure and regulation of the various families of tyrosine kinases.
The active forms of Abl family tyrosine kinases play a role in the development and progression of a number of human leukemias, leading researchers to explore how Abl kinases are regulated to develop effective cancer drug treatments. This has led to the development of several pharmacological inhibitors of Bcr-Abl, which have been remarkably successful in the treatment of chronic myelogenous leukemia.
In a recent minireview in The Journal of Biological Chemistry, Shoghag Panjarian and Thomas E. Smithgall at the University of Pittsburgh School of Medicine and Roxana E. Iacob, Shugui Chen and John R. Engen at Northeastern University discuss how the structure and regulation of Abl kinases influence inhibitor compatibility. This minireview explores how the Ncap region and the SH2 and SH3 domains function to regulate Abl kinase activity, the kinase domain and how its interaction with other proteins is controlled, and the conformational changes that the kinase undergoes upon activation or inhibition. The authors also discuss how the lessons learned about the Abl family from structural studies can be applied to the oncogenic fusion protein Bcr-Abl; it lacks the Ncap regulatory region and possesses a coiled-coil domain at the N- terminus that is believed to play a role in activation.
“Future drug-discovery efforts targeting allosteric mechanisms unique to this kinase system may provide a path to exceptional inhibitor sensitivity,” the authors write in the minireview, titled “Structure and dynamic regulation of Abl kinases.”
Kyeorda Kemp (email@example.com) is a postdoctoral researcher at Northwestern University.