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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 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.

Constitutive activation of the Abl nonreceptor tyrosine kinases can occur as a result of structural alterations of the and genes, which leads to the development of leukemia. Tight control of the activities of the endogenous Abl kinases is critical for normal development and maintenance of normal homeostasis. Recent work has revealed that the Abl kinases are activated by diverse cell surface receptors, and function to couple the activated receptors to signaling pathways such as those important for the regulation of cytoskeletal dynamics.

Integrins are cell surface receptors that mediate the interactions of cells with each other and the extracellular matrix. In this chapter, we review experiments indicating that the Abl family of nonreceptor tyrosine kinases, Abl and Arg in vertebrates, are important mediators of cellular responses to integrin engagement. During the early stages of cell spreading, integrins trigger the activation of Abl family kinases and their association with multiple focal adhesion proteins. These events lead to phosphorylation of several cytoskeletal regulatory proteins and changes in cell morphology and motility. Integrins may also utilize Abl family kinases to regulate nuclear processes such as gene expression, cell cycle progression and cell survival. Defects in the proper modulation of cell adhesive responses by Abl family kinases are thought to contribute to the progression of chronic myelogenous leukemia and could potentially underlie other human diseases and behavioral disorders.

The Abl tyrosine kinase contains nuclear-import and -export signals and undergoes nucleo-cytoplasmic shuttling in proliferating cells. The nuclear Abl is activated by DNA damage or tumor necrosis factor to promote cell death through transcription-dependent and -independent mechanisms. The oncogenic BCR-ABL tyrosine kinase is defective in nuclear import and functions as an inhibitor of apoptosis in the cytoplasm. If allowed to function in the nucleus, BCR-ABL also induces cell death. Abl interacts with several different types of death effectors. However, the precise mechanism by which Abl tyrosine kinase regulates cell death remains to be determined.

Abelson (Abl) family nonreceptor tyrosine kinases are essential regulators of cell morphogenesis in developing metazoan organisms. Mutant animals that lack Abl kinases exhibit defects in epithelial and neuronal morphogenesis. In cultured cells, the vertebrate Abl and Abl-related gene (Arg) proteins promote formation of actin-based protrusive structures, such as filopodia and lamellipodia. Abl family kinases act as relays that coordinate changes in cytoskeletal structure in response growth factors and adhesion receptor activation. These cytoskeletal rearrangements are achieved through the ability of these kinases to control the Rho and Rac GTPases and to stimulate assembly of protein complexes that activate nucleation of actin filaments by the Arp2/3 complex. Abl and Arg also contain extended C-termini that bind directly to F-actin and microtubules and may mediate interactions between these cytoskeletal networks in cells. Arg, for instance, can promote the cooperative assembly of an F-actin-rich scaffold in cells, which may serve as a base for the elaboration of actin-rich protrusive structures in cells.

Cell migration is a highly dynamic process that involves regulation of actin-mediated protrusion of a leading lamellipodia and its adhesion to the extracellular matrix, followed by translocation of the cell body and tail retraction at the rear. The migration machinery is regulated in a highly temporal and spatial manner through sophisticated sensing mechanisms that interpret external gradients of chemokines and adhesive proteins present in the extracellular environment. These directional cues are transmitted to the interior of the cell where they couple to the cytoskeletal network. In the following section, we highlight the role of the Abl family of nonreceptor tyrosine kinases, which transmit signals from growth factor and adhesion receptors to the actin and microtubule cytoskeleton of motile cells. These recent findings suggest that Abl kinases may contribute to cell migration processes, including development, wound healing, and immune function, as well as pathological conditions associated with cancer metastasis and inflammation.

Disruption of the auto-inhibitory structure of ABL and ARG activates their kinase activity and oncogenic potential. The oncogenic forms of ABL family kinases, v-ABL, BCR-ABL, TEL-ABL, NUP214-ABL, EML1-ABL, and TEL-ARG, are implicated in a variety of hematological malignancies. The tyrosine kinase activity of all these oncoproteins is essential for the neoplastic transformation, yet additional activities, particularly those of the fusion partners of the ABL kinases, play important roles in determining the lineage and severity of the neoplastic transformation. A better understanding of the mechanism by which the oncogenic forms of ABL family kinases act in leukemogenesis will help to advance therapies for related human leukemias, as well as to understand the mechanism of leukemogenesis and he-matopoiesis in general.

Abl and Arg nonreceptor tyrosine kinases are widely expressed in mammals, where they contribute to the development of diverse organ and tissue systems. Deletion of or in mice reveals roles for the kinases in B and T lymphocyte development, neurulation, neuronal dendrite maintenance, synaptic plasticity, and osteoblast development. Double knockout mice die as embryos, indicating that Abl and Arg also perform essential and overlapping functions during embryonic development. Abl and Arg contain domains for protein-protein interactions (SH3, SH2, proline-rich sequences, PY sequences), cytoskeleton binding (filamentous actin and microtubule binding domains), nuclear translocation (nuclear localization and export sequences), and DNA binding. Although a full understanding of their molecular interactions is still forthcoming, it is clear that Abl and Arg provide many cell types with all-in-one multifunctional signaling tools that serve as links between the cell surface and downstream pathways to both the cytoskeleton and nucleus.

The nervous system is an organ of immense complexity. Neural function and the integration of neural input depend upon the formation of an intricate network of synaptic connections. Building this neural architecture during development involves several aspects of neuronal morphogenesis, from neuronal polarization and the extension of neuronal processes, to the pathfinding of axons across long distances to appropriate target cells and the elaboration of dendritic arbors, resulting in the assembly and maintenance of synapses between each neuron and its targets. Each neuronal subclass relies upon multiple extracellular cues to direct its pathfinding and synaptogenesis to the correct locations within the developing embryo. While much progress has been made in the identification of the extracellular factors and corresponding cell surface receptors that control these aspects of neuronal differentiation, much less is known about the intracellular molecules and signaling pathways that control the process of morphogenesis.