Human and mouse Abelson interacting proteins (Abi) are SH3-domain containing proteins that bind to the prolinerich motifs of the Abelson protein tyrosine kinase. We report a new member of this gene family, a Drosophila Abi (dAbi) that is a substrate for Abl kinase and that coimmunoprecipitates with Abl if the Abi SH3 domain is intact. We have identi®ed a new function for both dAbi and human Abi-2 (hAbi-2). Both proteins activate the kinase activity of Abl as assayed by phosphorylation of the Drosophila Enabled (Ena) protein. Removal of the dAbi SH3 domain eliminates dAbi's activation of Abl kinase activity. dAbi is an unstable protein in cells and is present at low steady state levels but its protein level is increased coincident with phosphorylation by Abl kinase. Expression of the antisense strand of dAbi reduces dAbi protein levels and abolishes activation of Abl kinase activity. Modulation of Abi protein levels may be an important mechanism for regulating the level of Abl kinase activity in the cell.

Although Abl functions in mature neurons, work to date has not addressed Abl's role on Cdk5 in neurodegeneration. We found that b-amyloid (Ab42) initiated Abl kinase activity and that blockade of Abl kinase rescued both Drosophila and mammalian neuronal cells from cell death. We also found activated Abl kinase to be necessary for the binding, activation, and translocalization of Cdk5 in Drosophila neuronal cells. Conversion of p35 into p25 was not observed in Ab42-triggered Drosophila neurodegeneration, suggesting that Cdk5 activation and protein translocalization can be p25-independent. Our genetic studies also showed that abl mutations repressed Ab42-induced Cdk5 activity and neurodegeneration in Drosophila eyes. Although Ab42 induced conversion of p35 to p25 in mammalian cells, it did not sufficiently induce Cdk5 activation when c-Abl kinase activity was suppressed. Therefore, we propose that Abl and p35/p25 cooperate in promoting Cdk5-pY15, which deregulates Cdk5 activity and subcellular localization in Ab42-triggered neurodegeneration. Alzheimer's disease (AD), the most frequently diagnosed neurodegenerative disease, is characterized histologically by two hallmark features: senile plaques, which are extracellular deposits of b-amyloid(Ab42), and intracellular neurofibrillary tangles of aggregated hyperphosphorylated tau protein.1 The accumulation of Ab42 has been found to precede the pathological neurodegenerational changes, 2 and the inhibition of Ab42 accumulation by amyloid vaccination can effectively prevent the pathogenesis in mammalian AD animals.3 Less clear is the downstream protein targets of Ab42 toxicity in neurons. Thus, study of the Ab42-induced signaling cascade is of interest because it may provide clues for designing therapeutic strategies for the treatment of AD. AD brain samples show elevated cdk5 activity, 4 and deregulated Cdk5 has been associated with the tau hyperphosphorylation, a state leading to AD.5 Like other Cdk members, Cdk5 needs to bind with its regulatory partners to activate kinase activity. One of Cdk5's activating partners, p35, is expressed primarily in postmitotic neurons.6 Cdk5 also appears to be deregulated by its association with p25, a calpain digestion product of p35 in AD neurons. 7 The Cdk5/ p25 complex is thought to hyperphosphorylate tau and reduce tau's association with microtubules, resulting in neuronal apoptosis.8 Recently, c-Abl has been reported to phosphorylate and activate Cdk5 through the adaptor protein Cables during brain development. 9 The integration of Abl and Cdk5 into the same biological pathway suggests they have similar roles in neuronal cytoskeletal regulation and axon guidance.The Abl kinase, apparently evolutionarily conserved from flies to humans, is involved in the development of the nervous system. 10 Based on genetic studies of mice 11 and Drosophila, 12 abl mutations may lead to neuronal defects. Abl kinase has also been implicated in the regulation of apoptosis. 13Interestingly, the cytotoxicity of Ab42 is considered a crucial stress f...

We targeted expression of human/¯y chimeric Bcr-Abl proteins to the developing central nervous system (CNS) and eye imaginal disc of Drosophila melanogaster. Neural expression of human/¯y chimeric P210 Bcr-Abl or P185 Bcr-Abl rescued abl mutant¯ies from pupal lethality, indicating that P210 and P185 Bcr-Abl can substitute functionally for Drosophila Abl during axonogenesis. However, increased levels of neurally expressed P210 or P185 Bcr-Abl but not Drosophila Abl produced CNS defects and lethality. Expression of P210 or P185 in the eye imaginal disc produced a dominant rough eye phenotype that was dependent on dosage of the transgene. Drosophila Enabled, previously identi®ed 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. Drosophila, therefore, is a suitable model system to identify Bcr-Abl interactions important for signal transduction and oncogenesis.