Gene name - Abl tyrosine kinase
Cytological map position - 73B3--73B4
Function - signaling protein
Symbol - Abl
FlyBase ID: FBgn0000017
Genetic map position - 3-
Classification - Protein tyrosine kinases
Cellular location - cytoplasmic
|Recent literature||Jodoin, J. N. and Martin, A. C. (2016). Abl suppresses cell extrusion and intercalation during epithelium folding. Mol Biol Cell [Epub ahead of print]. PubMed ID: 27440923
Tissue morphogenesis requires control over cell shape changes and rearrangements. In the Drosophila mesoderm, linked epithelial cells apically constrict, without cell extrusion or intercalation, to fold the epithelium into a tube that will then undergo a epithelial-to-mesenchymal transition (EMT). Apical constriction drives tissue folding or cell extrusion in different contexts, but the mechanisms that dictate the specific outcomes are poorly understood. Using live-imaging, this study found that Abelson (Abl) tyrosine kinase depletion during gastrulation causes apically constricting cells to undergo aberrant basal cell extrusion and cell intercalation. abl depletion disrupted apical-basal polarity and adherens junction organization in mesoderm cells, suggesting that extruding cells undergo premature EMT. The polarity loss was associated with abnormal basolateral contractile actomyosin and Enabled (Ena) accumulation. Depletion of the Abl effector Enabled (Ena) in abl depleted embryos suppressed the abl phenotype, consistent with cell extrusion resulting from misregulated abl. This work provides new insight as to how Abl loss and Ena misregulation promote cell extrusion and EMT.
| Rogers, E.M, Spracklen, A.J., Bilancia, C.G.,
Sumigray, K.D., Allred, S.C., Nowotarski, S.H., Schaefer, K.N., Ritchie,
B.J. and Peifer, M. (2016). Abelson
kinase acts as a robust, multifunctional scaffold in regulating
embryonic morphogenesis. Mol Biol Cell [Epub ahead of print].
PubMed ID: 27385341
Abelson family kinases (Abl) are key regulators of cell behavior and the cytoskeleton during development and in leukemia. Abl's SH3, SH2, and tyrosine kinase domains are joined via a linker to an F-actin-binding domain (FABD). Research on Abl's roles in cell culture have led to several hypotheses for its mechanism of action: 1) Abl phosphorylates other proteins, modulating their activity. 2) Abl directly regulates the cytoskeleton via its cytoskeletal interaction domains, and/or 3) Abl is a scaffold for a signaling complex. The importance of these roles during normal development remains untested. This study tested these mechanistic hypotheses during Drosophila morphogenesis using a series of mutants to examine Abl's many cell biological roles. Strikingly, Abl lacking the FABD fully rescues morphogenesis, cell shape change, actin regulation, and viability, while kinase dead Abl, though reduced in function, retains substantial rescuing ability in some but not all Abl functions. The function of four conserved motifs in the linker region was also tested, revealing a key role for a conserved PXXP motif known to bind Crk and Abi. The study proposes that Abl acts as a robust multi-domain scaffold with different protein motifs and activities contributing differentially to diverse cellular behaviors.
The Philadelphia chromosomal translocation is responsible for the fusion of two genes, ABL and BCR. Recognized as a frequently occuring aberrant chromosome in acute lymphoblastic leukemia, it was understood more than a decade ago that the Philadelphia chromosome occurs as a result of a recombination between two genes: the cellular ABL gene on chromosome 9, and BCR (breakpoint cluster region) gene located on chromosome 22. The Drosophila Abelson (Abl) protein is a homolog of mammalian c-Abl the wild-type gene coding for the ABL sequence found in the BRC/ABL hybrid protein. The BCR/ABL oncogene product, derived from this specific chromosomal translocation is present in Philadelphia chromosome-postive acute lymphoblastic leukemia. Despite its homology to c-Abl, the wild type mammalian protein, Drosophila ABL protein shows distinct properties and functional differences from c-Abl that suggest the two proteins are not strictly comparable. Notably, the Drosophila protein shows no nuclear localization; this suggests that the functions listed below, found for the mammalian protein, are absent in Drosophila:
Assuming that no other Abl type proteins are found in Drosophila, and no nuclear function can be found for Drosophila Abl, Abl can be used to illustrate the extent of an evolutionary divergence of nuclear function.
Nevertheless, the cytoplasmic functions of Abl appear to be conserved. Both fly and mammalian proteins have a conserved actin interaction domain and both proteins show genetic or physical interaction with a conserved protein known as Disabled (Dab). The Drosophila Disabled protein colocalizes with Abl in cell bodies and axons of embryonic CNS neurons. Dab is essential for normal CNS development, even in the presence of Drosophila Abl. Dab is tyrosine phosphorylated in insect cells and given its co-localization with Abl in the CNS, it has been suggested that Dab may be a physiological substrate of Abl. Identification of Abl substrates is important in building a picture of the role of Abl in the CNS. Drosophila Abl is required in disabled heterozygotes after the time of cell fate specification and during the time of axonogenesis in the embryonic CNS (Gertler, 1993). Murine Disabled is expressed in certain neuronal and hematopoietic cell lines and is localized to the growing nerves of embryonic mice. During mouse embryogenesis, murine Disabled is tyrosine phosphorylated when the nervous system is undergoing dramatic expansion, but when nerve tracts are established, murine Disabled lacks detectable phosphotyrosine. The properties of murine Disabled and genetic analysis of Disabled in Drosophila suggest that these molecules function in key signal transduction pathways involved in a function downstream of Abl in axonogenesis (Howell, 1997). The involvement of Abl in axonogenesis does not require Abl's kinase domain (Henkemeyer, 1990).
The importance of Abl in neurogenesis is also evidenced by Abl's interaction with another conserved protein, Enabled. Enabled is a member of the rapidly expanding VASP family of cytoskeletal associated proteins. The well studied migration of neuronal growth cones serves as a model for the actin-driven formation of membrane protrusions. Establishment of proper connections in the central nervous system depends on the ability of neuronal growth cones to guide neurites to their final targets. The ABL-ENA-Profilin pathway is implicated in the process of axonal outgrowth and fasciculation. Genetic screens for dominant second-site mutations that suppress the lethality of Abl mutations in Drosophila identify alleles of only one gene, enabled. The ENA protein contains proline-rich motifs and binds to ABL and Src SH3 domains. ENA is (as Disabled has been suggested to be) also a substrate for the Abl kinase. Tyrosine phosphorylation of ENA is increased when it is coexpressed in cells with human or Drosophila Abl, and endogenous ENA tyrosine phosphorylation is reduced in Abl mutant animals. Like Abl, ena is expressed at highest levels in the axons of the embryonic nervous system and ena mutant embryos show defects in axonal architecture. Therefore, it has been concluded that a critical function of Drosophila ABL is to phosphorylate and negatively regulate ENA protein during neural development (Gertler, 1995).
Drosophia Abl interacts with four other fly genes: prospero, failed axon connections, and Fasciclin 1 and Fasciclin 2, two genes coding for cell adhesion proteins. The interaction with prospero has not been explored further since the non-uniform cytoplasmic distribution of Prospero protein was discovered. The action of Inscuteable, a cytoskeleton associated protein, suggests an involvement of cytoskeleton in providing cues for Prospero and Numb subcellular localization. Cytochalasin D, which disrupts Actin filaments, eliminates Inscuteable crescents and results in incorrect Prospero crescent positioning (Kraut, 1996). Since the highest levels of Abl are not in neuroblasts but in postmitiotic neurons (Bennett, 1992), the relation between Prospero and Abl is currently unknown.
The interaction of Abl with Fas1, Fas2, and failed axon connections suggests the involvement of Abl in a feedback mechanism in which the cytoskeleton of the cell is given information about cell adherence events occurring during axonogenesis. This might be the Drosophila function of Abl with greatest relevance to vertebrate neurobiology. Abl also seems to be involved in signaling in early embryonic development both in Drosophila and Xenopus. The nature of this involvement has not yet been documented.
The proto-oncogenic kinase Abelson (Abl) regulates actin in response to cell signaling. Drosophila Abl is required in the nervous system, and also in epithelial cells, where it regulates adherens junction stability and actin organization. Abl acts at least in part via the actin regulator Enabled (Ena), but the mechanism by which Abl regulates Ena is unknown. A novel role is described for Abl in early Drosophila development, where it regulates the site and type of actin structures produced. In Abl's absence, excess actin is polymerized in apical microvilli, whereas too little actin is assembled into pseudocleavage and cellularization furrows. These effects involve Ena misregulation. In abl mutants, Ena accumulates ectopically at the apical cortex where excess actin is observed, suggesting that Abl regulates Ena's subcellular localization. Other actin regulators were also examined. Loss of Abl leads to changes in the localization of the Arp2/3 complex and the formin Diaphanous, and mutations in diaphanous or capping protein beta enhance abl phenotypes (Grevengoed, 2003).
Genetic analysis suggests that in the early Drosophila embryo, the primary means by which Abl influences the cytoskeleton is through Ena. Reducing the Ena dose by half profoundly suppresses ablM; it is as effective as adding back a wild-type abl transgene. Ena is also a critical target of Abl during embryonic morphogenesis. Although the data suggest that the primary effect of loss of Abl is Ena deregulation, they do not rule out Abl acting on the cytoskeleton by other mechanisms (Grevengoed, 2003).
The mechanism by which Abl regulates Ena has remained mysterious. This study demonstrates that Abl regulates Ena by regulating its intracellular localization. In the absence of Abl, Ena localizes to ectopic sites. Alterations in Ena and actin localization have been observed at the leading edge of migrating epidermal cells in abl mutants during dorsal closure. This suggests that regulation of Ena localization by Abl may be a more general mechanism. It is hypothesized that Abl targets Ena to places where it is needed to modulate actin dynamics, perhaps by excluding it from other sites where Ena activity would be detrimental (Grevengoed, 2003).
There are many ways in which Abl could restrict Ena localization. Abl's kinase activity is essential, and thus Abl phosphorylation of Ena may restrict its localization by preventing Ena binding to partners that localize to particular cortical sites, or by promoting Ena binding to partners that sequester it in the cytoplasm. Phosphorylation of Ena by Abl in vitro inhibits binding of Ena to SH3 domains, whereas Mena/VASP phosphorylation by PKA alters binding to SH3 domains and actin. However, if direct phosphorylation were the only mechanism by which Abl regulated Ena, mutating Ena's phosphorylation sites should create a protein that can no longer be regulated and thus would localize to ectopic sites. Instead, mutation of all of the Abl phosphorylation sites in Ena modestly reduced Ena function, rather than making it ectopically active as is seen in abl mutants (Grevengoed, 2003).
Thus, Abl may regulate Ena by additional mechanisms. Abl may modulate Ena localization and restrict Ena activity by direct binding (this could still require Abl kinase activity, since auto-phosphorylation or phosphorylation of other partners may regulate protein-protein interactions). Abl might sequester Ena in the cytoplasm in an inactive state, or it might recruit Ena to appropriate sites. Alternately, binding of Abl's SH3 domain to the Ena proline-rich region might prevent Ena from binding to other partners, such as profilin, which might in turn modulate both Ena localization and activity. In thinking about these different possible mechanisms, it is interesting to note that Abl localizes to the actin caps and apical pseudocleavage furrows during syncytial stages and the apical portion of the cellularization furrow, the precise places where ectopic actin accumulation occurs in its absence. Thus, it is poised to act at this location. Working out the details of the mechanism by which Abl regulates Ena localization will be one of the next challenges (Grevengoed, 2003).
This work provides an in vivo test of the current model for Ena function, and allows extension of this model. The excess growth of microvilli seen when Ena is ectopically localized in early embryos fits well with work on Ena/VASP function in mammalian fibroblasts, where forced localization of Ena/VASP proteins to the leading edge promotes the formation of long, unbranched filaments. Ena also localizes to the ends of filopodia and microspikes, suggesting that Ena's role in promoting long unbranched actin structures is broadly conserved. Earlier experiments in fibroblasts artificially altered Ena localization. This study demonstrates that Ena localization is a normal regulatory point in vivo, and that Abl is a critical player in this process. Finally, in vitro experiments have suggested that Ena promotes filament elongation by antagonizing capping protein. Mutations in cpb enhance the effects of mutations in abl in the CNS and probably during oogenesis. These data are consistent with Ena and capping protein playing antagonistic roles in vivo, with Abl potentially influencing the outcome of this antagonism. However, Abl and capping protein may also work together independently of Ena in the regulation of actin dynamics (Grevengoed, 2003).
Different actin regulators play fundamentally different biochemical roles. Models often picture all of these regulators modulating actin assembly and disassembly at a single site, but of course individual cells target different actin regulators to distinct sites, creating actin structures with diverse functions. Syncytial embryos provide an excellent example. During interphase, they assemble actin-based microvillar caps above each nucleus. As they enter prophase, caps are disassembled and actin polymerization is redirected to the pseudocleavage furrows. This is likely to require new machinery: both Arp2/3 and the formin Dia are required for pseudocleavage furrow formation, but not for actin caps. Cellularization also requires distinct machinery to polymerize/disassemble apical microvilli and to recruit and modulate actin at the cellularization front. For transitions to occur smoothly, two fundamental changes have to occur: the location at which actin polymerization occurs must change, and a different constellation of actin regulators must be deployed to produce the distinct actin structures observed (Grevengoed, 2003).
The data support a hypothesis in which the balance of activity of different actin regulators at distinct sites is tightly regulated, influencing the nature of the actin structures produced. One regulator is Abl. In its absence, Ena localizes ectopically to the cortical region, upsetting the temporal and spatial balance of actin regulators. This leads to a change in both the location and nature of actin polymerization during mitosis. Excess actin is polymerized into microvillar projections that extend from the apical region of the furrows, whereas insufficient actin is directed to the pseudocleavage furrows. Similarly, during cellularization in ablM mutants, actin polymerization continues to be directed to apical microvilli, whereas in a wild-type embryo this ceases early in cellularization (Grevengoed, 2003).
The data also suggest that there is cross-talk between different modulators of actin polymerization, and that the balance of their activities determines the outcome. Although many actin modulators are unaffected in ablM mutants, both the Arp2/3 complex and Dia are recruited to sites of ectopic actin polymerization. However, genetic analysis suggests that although Ena mislocalization plays a critical role in the actin alterations seen in ablM mutants, Dia and Arp2/3 mislocalization may not. In fact, reduction of the dose of Dia enhanced the ablM phenotype. Dia normally promotes actin polymerization lining the furrows. In ablM mutants, the balance of actin polymerization is already shifted to the apical microvilli because of ectopic Ena localization. Reduction in the dose of Dia might further reduce actin polymerization in pseudocleavage furrows, resulting in the observed enhancement of the ablM phenotype. The abnormal recruitment of Dia to the apical regions in ablM mutants may also reduce pseudocleavage furrow formation (Grevengoed, 2003).
It will now be important to investigate how the cell regulates the distinct types of actin polymerization required for distinct cellular and developmental processes. One mechanism of cross-talk may involve direct or indirect recruitment of one type of actin modulator by another. Abl's ability to interact with both Ena and the Arp2/3 regulator WAVE1 is interesting in this regard. However, the recruitment of Arp3 and Dia to ectopic actin structures observed in ablM mutants may have a more simple explanation. Both are thought to have a higher affinity for newly polymerized, ATP-bound actin, which is likely to be increased where ectopic actin polymerization appears to occur (Grevengoed, 2003).
Drosophila Abl also functions in other contexts. It has a role in embryonic morphogenesis, where it also acts, at least in part, via Ena. However, in this context Abl also affects AJ stability. Since Ena is normally highly enriched in AJs, it is hypothesized that Abl helps restrict Ena localization to AJs, and thus helps initiate the proper organization of actin underlying AJs. In Abl's absence, Ena may localize to sites other than AJs, leading to ectopic actin polymerization at those sites and reduction in actin polymerization at AJs (analogous to the divergent effects on apical actin and pseudocleavage/cellularization furrows). Since the cortical actin belt underlying the AJ plays an important role in its stability, this could explain the phenotype of abl mutants. A similar model may help explain the roles of Abl and Ena in axon outgrowth. The network of actin filaments in the growth cone is complex, with different types of actin in filopodia and in the body of the growth cone. By regulating Ena localization, Abl may influence the balance of the different types of actin, thus influencing growth cone motility. Likewise, in fibroblasts, where Ena/VASP proteins regulate motility, the Arp2/3 regulators N-WASP and WAVE localize to sites at the leading edge distinct from those where Mena is found. Whether Abl or Arg regulate the localization of Ena/VASP family proteins in mammals remains to be determined. Likewise, it is possible that deregulation of Ena/VASP proteins underlie some of the alterations in cell behavior in Bcr-Abltransformed lymphocytes. Experiments to test whether Ena/VASP activity is important for either mammalian Abl's normal function or for the pathogenic effects of Bcr-Abl will help answer these questions (Grevengoed, 2003).
In the nervous system, neurons form in different regions, then they migrate and occupy specific positions. RP2/sib, a well-studied neuronal pair in the Drosophila ventral nerve cord (VNC), has a complex migration route. This study shows that the Hem protein, via the WAVE complex, regulates migration of GMC-1 and its progeny RP2 neuron. In Hem or WAVE mutants, RP2 neuron either abnormally migrates, crossing the midline from one hemisegment to the contralateral hemisegment, or does not migrate at all and fails to send out its axon projection. Hem regulates neuronal migration through stabilizing WAVE. Since Hem and WAVE normally form a complex, the data argues that in the absence of Hem, WAVE, which is presumably no longer in a complex, becomes susceptible to degradation. It was also found that Abelson tyrosine kinase affects RP2 migration in a similar manner as Hem and WAVE, and appears to operate via WAVE. However, while Abl negatively regulates the levels of WAVE, it regulates migration via regulating the activity of WAVE. The results also show that during the degradation of WAVE, Hem function is opposite to that of and downstream of Abl (Zhu, 2011).
Several studies have suggested that Hem dynamically regulates polymerization of F-actin. Hem can play a crucial role in linking extracellular signals to the cytoskeleton. On the other hand, Hem is also part of the WAVE complex and it may regulate the activity of the WAVE complex to promote polymerization of F-actin. The result that the migration defect in Hem mutants can be completely rescued by expression of WAVE from a transgene indicates that Hem regulates neuronal migration via WAVE (Zhu, 2011).
How Hem regulates WAVE is controversial. It has been argued that Hem (together with PIP212) inhibits WAVE in the WAVE complex. Upon activation by Rac1 or Nck, the WAVE complex dissociates releasing an active WAVE-HSPC300 to mediate actin nucleation. This conclusion was also supported by the findings that loss-of-function for Hem leads to an excess of F-actin in the cytosol. Moreover, a reduction in the WAVE gene dosage suppressed axon guidance defects in Hem mutant embryos. But, in vitro studies using Drosophila tissue culture cells argue that Hem protects WAVE from proteasome-mediated degradation. The current in vivo results are consistent with these studies and show that WAVE is protected by Hem and the above alternate model may be incorrect (Zhu, 2011).
The WAVE protein was first identified in Dictyostelium discoideum as a suppressor of mutations in the cAMP receptor (SCAR) but it is present in flies to humans. All WAVEs contain a N-terminal WHD/SHD (WAVE/SCAR homologue domain), a central proline-rich region and a C-terminal VCA domain. WAVE protein regulates actin polymerization by mediating the signal of Rac to Arp2/3 in lamellipodia. It is involved in forming branched and cross-linked actin networks. Unlike WASp proteins, which are intrinsically inactive by autoinhibition and activated by directly binding to Cdc42, PIP2 etc., WAVE appears to be intrinsically active, at least in vitro.However, the majority of WAVE is in the 'WAVE complex' with four other proteins: Hem, Sra-1/PIR121/CYFIP, Abi and HSPC300/Brk1 (Zhu, 2011).
In the WAVE-complex, direct association between WAVE, Abi and HSPC300 represents the backbone of the complex. Hem binds to Sra-1 forming a sub-complex, which is able to bind to Rac through Sra-1. The interaction between Abi and Hem is what binds Hem and Sra-1 into the complex. Hem and Sra-1 are sequentially recruited to the WAVE complex. Free subunits and assembly intermediates of the WAVE-complex are usually not detected but supposedly degraded. Also, previous studies suggest that depletion of one component leads to degradation of others. Indeed, the current results, that in Hem mutants, the level of WAVE protein, but not the WAVE gene transcription, is drastically reduced supports this contention. Perhaps in the absence of Hem, WAVE complex is either not formed or partially formed, resulting in the degradation of WAVE and phenotypes such as mis-migration of neurons. When the levels of WAVE are supplemented using a WAVE transgene (UAS-WAVE), the migration defect in Hem mutants is promptly rescued (Zhu, 2011).
While a complete lack of WAVE (or Hem) function causes an arrest in the migration of RP2, a reduction in the levels of WAVE due to a reduction in the levels of Hem causes abnormal migration. For example, the lowest level of WAVE is seen in the Hem allele that has the strongest penetrance. Moreover, since this mis-migration defect is rescued by expressing WAVE from a transgene, it can be concluded that this mis-migration is also due to an effect on WAVE. It has been suggested that the WAVE-complex exists cytoplasmically and in membrane-bound forms. Through an interaction with Rac, WAVE gets recruited to the lamellipodia where actin polymerization required for membrane protrusion is initiated and regulated. The integrity of the complex is critical for its proper localization since removal of either WAVE or Abi prevents its translocation to the leading edge of the lamellipodia. It is possible that a reduction in the levels of WAVE in Hem mutant embryos causes non-translocation of the WAVE complex to the membrane, causing a non/mis-migration of RP2 (Zhu, 2011).
These results show that WAVE protein exists as three different molecular weight forms. Treatment of the extract with phosphatase collapses these three forms into a single band, indicating that WAVE protein is phosphorylated, with varying degrees of phosphorylation to yield different molecular weight species. Whether there are any changes in the three different forms with respect to their relative contributions in Hem and Abl mutants was examined. However, no changes were found in their relative contributions and the levels of all the forms were reduced in Hem mutants. Therefore, it may be that the reduction in all the forms, or that the reduction in one or two of the forms is responsible for the migration defect. In Abl mutants, the level of WAVE is modestly increased, which is the opposite to that of the effect of Hem on WAVE. Thus, it seems more likely that the activity of WAVE is affected in Abl mutants. Being a protein kinase, it was possible that Abl phosphorylates WAVE, thus affecting either its activity or level. However, no significant changes in were seen in the relative levels of the different phosphorylated forms of WAVE in Abl mutants. It has been shown in vitro that Abl is recruited to WAVE by Abi following cell stimulation, triggering the translocation of Abl together with the WAVE complex to the leading edge of the membrane. Thus, Abl might affect WAVE activity, either directly or indirectly, via the translocation of the WAVE complex to the membrane of an actively migrating RP2. It is also possible that Abl affects migration in a pathway that does not involve WAVE (Zhu, 2011).
In contrast, the effect of loss-of-function for Abl on WAVE levels is more pronounced in older embryos. These results indicate that Abl directly or indirectly regulates the levels of WAVE. Furthermore, though modest, ectopic expression of Abl does down-regulate WAVE. Interestingly, the results also show that Hem regulation of WAVE levels is downstream of the Abl regulation of WAVE since the Hem; Abl double mutants had the same levels of WAVE as Hem single mutants. It seems likely that in the absence of Hem, WAVE protein gets degraded, resulting in the loss of migration or abnormal migration. Whereas in Abl mutants, the most likely scenario is that the activity of WAVE is affected, resulting in the same migration defect (Zhu, 2011).
Exons - 10
Bases in 3' UTR - 1611
Abelson (Abl) gene consists of 10 exons extending over 26 kilobase pairs of genomic DNA. The DNA sequence encodes a protein of 1,520 amino acids with strong sequence similarity to the human c-abl proto-oncogene beginning in the type lb 5' exon and extending through the region essential for tyrosine kinase activity. When the tyrosine kinase homologous region is expressed in Escherichia coli, phosphorylation of proteins on tyrosine residues is observed. These results show that the abl gene is highly conserved through evolution and encodes a functional tyrosine protein kinase required for Drosophila development (Henkemeyer, 1988). There are five different 3' ends to ABL mRNA sequences, due to multiple polyadenylation sites separated from one another by as much as one kb (Telford, 1985).
The amino-terminal region of Abl tyrosine kinase related proteins shares several common features with Src-family members. These include a myristoylation site, and the arrangement of Src-homology domains in the primary sequence. Characteristic of the Abl-family members, however, is a large C-terminal extention beyond the kinase domain. The C-terminal segments are not well conserved among Abl-family members. For example, Drosophila Abl and the mammalian c-Abl are between 16-32% identical in this region. The divergent C-terminal segments are not interchangeable between Drosophila Abl and c-Abl, while the kinase domains are interchangeable. These results indicate that the C-terminal segments are important in specifying the biological functions of the Abl tyrosine kinases, and suggest that Drosophila Abl and c-Abl may perform different functions. Nevertheless, a C-terminal actin binding domain appears to be conserved. A presumed DNA binding domain and nuclear transport sequence is present in a region in c-Abl that is not conserved in Drosophila Abl (Wang, 1993 and references).
The Drosophila melanogaster abl and the murine v-abl genes encode tyrosine protein kinases (TPKs) whose amino acid sequences are highly conserved. To assess functional conservation between the two gene products, Drosophila abl/v-abl-chimeric Abelson murine leukemia viruses were constructed. In these chimeric Abelson murine leukemia viruses, the TPK and carboxy-terminal regions of v-Abl were replaced with the corresponding regions of Drosophila Abl. The chimeric Abelson murine leukemia viruses are able to mediate morphological and oncogenic transformation of NIH 3T3 cells and are able to abrogate the interleukin-3 dependence of a lymphoid cell line. A virus that contains both TPK and carboxy-terminal Drosophila Abl regions has no in vitro transforming activity for primary bone marrow cells and lacks the ability to induce tumors in susceptible mice. A virus that replaces only a portion of the v-Abl TPK region with that of Drosophila Abl has low activity in in vitro bone marrow transformation and tumorigenesis assays. These results indicate that the transforming functions of Abl TPKs are only partially conserved through evolution. These results also imply that the TPK region of v-Abl is a major determinant of its efficient lymphoid cell-transforming activity (Holland, 1990).
date revised: 15 October 2005
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