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Mechanisms of Activation of Abl Family Kinases

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Abl Family Kinases in Development and Disease

Part of the book series: Molecular Biology Intelligence Unit ((MBIU))

Abstract

Evidence that has accumulated over the last years points to c-Abl and Arg (ABL1 and ABL2) as being particular forms of the Src family of kinases. Just as much as or even more than the Src kinases, Abl members are built to be able to couple protein-protein interaction with protein tyrosine kinase catalytic output. This stems from the constant competition between self-inhibitory intramolecular interactions (mostly via the SH3 and SH2 domains) and generally activating intermolecular interactions with ligands. Ligand engagement both regulates and, in turn, is regulated by the level of activity of the kinase domain. A series of post-translational modifications act on this balance and allows the integration of catalytic activity, localization and multiprotein complex assembly functions. Most excitingly, the majority of the principles appearing to govern c-Abl and Arg are still operational in the Bcr-Abl oncogenic counterpart and affect the efficacy of small molecular ATP-competitors.

The Abl family of tyrosine kinases is regulated by a complex set of intramolecular interactions that impinge both directly and indirectly on the Abl kinase domain and lead to effective inhibition of tyrosine kinase activity both in vitro and in vivo. Even a partial, albeit persistent, disruption of these autoinhibitory constraints results in cell transformation and different forms of cancer in humans. The fusion-proteins Bcr-Abl, Tel-Abl and v-Abl are three well-characterized examples in this respect. Here, the kinase activity is mostly switched on, contributing to the deregulation of cell growth. On the other hand, the controlled activation of Abl kinases is required for a large number of normal cellular processes. The most important ones are of central interest to many research groups and are discussed extensively in other chapters of this book. In this chapter, we provide an overview of the mechanisms by which multiple cellular proteins transiently activate Abl kinases to perform cellular functions. We present the entire set of mechanisms that lead to Abl activation, grouping the numerous studies on physiological stimuli acting on Abl into distinct activation categories. The recently obtained insights into the structure of autoinhibited Abl is integrated and is used as guide to explain the different molecular mechanisms.

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  1. Center for Molecular Medicine of the Austrian, Academy of Sciences, Lazarettgasse 19/3, 1090, Vienna, Austria

    Oliver Hantschel & Giulio Superti-Furga

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  1. Oliver Hantschel
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  2. Giulio Superti-Furga
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Hantschel, O., Superti-Furga, G. (2006). Mechanisms of Activation of Abl Family Kinases. In: Abl Family Kinases in Development and Disease. Molecular Biology Intelligence Unit. Springer, New York, NY. https://doi.org/10.1007/978-0-387-68744-5_1

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