Disease relevance of Abl

• To assess functional conservation between the two gene products, we constructed Drosophila abl/v-abl-chimeric Abelson murine leukemia viruses [1].
• Can clues to the molecular defects in chronic myelogenous leukemia come from genetic studies on the Abelson tyrosine kinase in fruit flies [2]?

High impact information on Abl

• Both Abl and Ena can directly bind to Robo's cytoplasmic domain [3].
• Genetic analysis of a Drosophila neural cell adhesion molecule: interaction of fasciclin I and Abelson tyrosine kinase mutations [4].
• The Drosophila Abelson (abl) proto-oncogene homolog encodes a cytoplasmic tyrosine kinase that is expressed during embryogenesis primarily in developing CNS axons; abl mutants show no gross defects in CNS morphogenesis [4].
• During Drosophila embryogenesis, the Abelson tyrosine kinase (abl) is localized in the axons of the central nervous system (CNS) [5].
• The Drosophila Abelson proto-oncogene homolog: identification of mutant alleles that have pleiotropic effects late in development [6].

Biological context of Abl

• We have identified the Drosophila trio gene through a mutation that exacerbates the Abl mutant phenotype [7].
• In addition, tyrosine phosphorylation of Trio and Fra is elevated in S2 cells when Abl levels are increased [8].
• The Abelson tyrosine kinase (Abl) is integrated into signal transduction networks regulating axon outgrowth [7].
• The function of Abl in this pathway is dependent on an intact catalytic domain [9].
• We discuss possible models for Abl function during epithelial morphogenesis in light of these data [10].

Anatomical context of Abl

• These observations suggest a mechanism by which Abl-mediated signaling networks influence the actin cytoskeleton in neuronal growth cones [7].
• Phenotypic analysis demonstrates that trio and Abl cooperate in regulating axon outgrowth in the embryonic central nervous system (CNS) [7].
• These results suggest Ama/Nrt-mediated adhesion may be part of signaling networks involving the Abl tyrosine kinase in the growth cone [11].
• Here we report a novel role for Drosophila Abl in epithelial cells, where it is critical for morphogenesis [10].
• Finally, loss of Abl reduces Arm and alpha-catenin accumulation in adherens junctions, while having little or no effect on other components of the cytoskeleton or cell polarity machinery [10].

Associations of Abl with chemical compounds

• Two novel dosage-sensitive modifiers of the Abelson tyrosine kinase (Abl) mutant phenotype have been identified [11].
• Mutations in Abl and trio dominantly enhance fra and Netrin mutant CNS phenotypes, and fra;Abl and fra;trio double mutants display a dramatic loss of axons in a majority of commissures [8].
• We report that the proline-rich region of Ena is responsible for this interaction as well as for mediating binding to the src homology 3 domain of the Abelson tyrosine kinase [12].
• Drosophila Enabled, previously identified as a suppressor of the abl mutant phenotype and substrate for Drosophila Abl kinase, had markedly increased phosphotyrosine levels in Bcr-Abl expressing Drosophila, indicating that it is a substrate for Bcr-Abl as well [13].
• The complete coding sequence of arg defines the Abelson subfamily of cytoplasmic tyrosine kinases [14].

Physical interactions of Abl

• Fra interacts physically with Abl and Trio in GST-pulldown assays and in co-immunoprecipitation experiments [8].
• To induce the turning of ISNb axons, Notch interacts genetically with multiple components of a signal transduction pathway that includes the Abl tyrosine kinase and its affiliated accessory proteins [15].

Enzymatic interactions of Abl

• We conclude that a critical function of Drosophila Abl is to phosphorylate and negatively regulate ena protein during neural development [16].

Regulatory relationships of Abl

• Heterozygous null alleles of nrt dominantly enhance the Abl mutant phenotype, also affecting axon pathfinding [11].
• Modulation of Abi protein levels may be an important mechanism for regulating the level of Abl kinase activity in the cell [17].
• The fax gene encodes a novel 47-kD protein expressed in a developmental pattern similar to that of Abl in the embryonic mesoderm and axons of the central nervous system [18].
• Our genetic studies also showed that abl mutations repressed Abeta42-induced Cdk5 activity and neurodegeneration in Drosophila eyes [19].

Other interactions of Abl

• Genetic screens for dominant second-site mutations that suppress the lethality of Abl mutations in Drosophila identified alleles of only one gene, enabled (ena) [16].
• Drosophila abelson interacting protein (dAbi) is a positive regulator of abelson tyrosine kinase activity [17].
• We now demonstrate that the Drosophila Abl tyrosine kinase functions in the intersegmental nerve b (ISNb) motor choice point pathway as an antagonist of the RPTP Dlar [9].
• Activation of the nonreceptor tyrosine kinase Abelson (Abl) contributes to the development of leukemia, but the complex roles of Abl in normal development are not fully understood [10].
• Genetic interactions between capt and slit support a model where Capt and Abl collaborate as part of the repellent response [20].

Analytical, diagnostic and therapeutic context of Abl

• These observations identify an important morphogenetic role for Abl and suggest a conserved mechanism for this kinase during apical cell constriction [21].

References