Disease relevance of Abl1

• Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia [1].
• By constructing recombinants between c- and v-abl retroviruses, we show that a point mutation in c-Abl is sufficient to change the myristoylated form of c-Abl into a protein able to transform fibroblasts, but not capable of transforming bone marrow or inducing Abelson disease [2].
• cAbl tyrosine kinase mediates reactive oxygen species- and caveolin-dependent AT1 receptor signaling in vascular smooth muscle: role in vascular hypertrophy [3].
• The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL) [4].
• The nonreceptor tyrosine kinases Jak1 and Jak3, which bind to the v-Abl oncoprotein, are constitutively activated in cells transformed with the Abelson murine leukemia virus [5].

High impact information on Abl1

• For example, the kinases Src and Abelson (Abl) were originally identified as oncogenes and were later characterized as important proteins for signal transduction in various cell types, including lymphocytes [6].
• The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML [4].
• The c-Abl protein is a non-receptor tyrosine kinase involved in many aspects of mammalian development. c-Abl kinase is widely expressed, but high levels are found in hyaline cartilage in the adult, bone tissue in newborn mice, and osteoblasts and associated neovasculature at sites of endochondrial ossification in the fetus [7].
• Mice homozygous for mutations in the gene encoding c-Abl (AIM) display increased perinatal mortality, reduced fertility, foreshortened crania and defects in the maturation of B cells in bone marrow [7].
• Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation [7].

Chemical compound and disease context of Abl1

• We determined the effects of AMN107 and/or LBH589 in Bcr-Abl-expressing human K562 and LAMA-84 cells, as well as in primary chronic myelogenous leukemia (CML) cells [8].
• WRN is tyrosine phosphorylated either transiently by treatment of HeLa cells with bleomycin or constitutively in cells from chronic myeloid leukemia (CML) patients, and these phosphorylations are prevented by treatment with the Abl kinase inhibitor STI-571 [9].
• SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice [10].
• In our study, we have investigated the effect of Imatinib therapy on murine P190 Bcr/Abl lymphoblastic leukemia cells [11].
• Our data indicate that PD180970 is active against several Bcr-Abl mutations that are resistant to imatinib and support the notion that developing additional Abl kinase inhibitors would be useful as a treatment strategy for chronic myelogenous leukemia [12].

Biological context of Abl1

• This suggests a key role for these factors, and perhaps for c-Abl itself, in the regulated activation of Ig light chain gene rearrangement [13].
• Moreover, MuSK and Abl kinases effected reciprocal tyrosine phosphorylation and formed a complex after agrin engagement [14].
• These results indicate that Abl inhibits cell proliferation by interacting with central elements of the cell cycle control apparatus in the nucleus, and suggest a direct connection between p53 and Rb in this growth-inhibitory pathway [15].
• A clue to its normal function is suggested by overexpression of Abl in fibroblasts, which leads to inhibition of cell growth [15].
• Using a quantitative transfection assay, we show that both c-Abl and transforming Abl proteins inhibit entry into S phase and this effect is absolutely dependent on nuclear localization [15].

Anatomical context of Abl1

• A small molecule Abl kinase inhibitor induces differentiation of Abelson virus-transformed pre-B cell lines [13].
• However, transformation by v-Abl blocks B cell development, resulting in the arrest of these transformants in an early pre-B cell-like state [13].
• In cultured myotubes, Abl kinase activity was required for agrin-induced AChR clustering and enhancement of MuSK tyrosine phosphorylation [14].
• Postsynaptic requirement for Abl kinases in assembly of the neuromuscular junction [14].
• Our data suggest a novel pathway by which c-Abl transduces signals to the actin cytoskeleton through phosphorylating Dok1 Y361 and recruiting Nck [16].

Associations of Abl1 with chemical compounds

• Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib [1].
• v-Abl is an oncogenic form of the c-Abl nonreceptor tyrosine kinase. v-Abl induces transcription of c-myc, and c-Myc function is a necessary but not sufficient component of the v-Abl transformation program [17].
• Nuclear localization of Abl can be directed by a pentalysine nuclear localization signal in the Abl C-terminus [15].
• These data suggest that killing of p53-negative tumor cells by chemotherapy would be enhanced by integrin ligation to activate the alternative c-Abl/p73 pathway [18].
• In this study, we show that c-Abl mediates a second pathway by which adhesion to extracellular matrix regulates cell killing by chemotherapeutic agents 5-arabinofuranosylcytosine, cisplatin, and camptothecin [18].
• Ectopic expression of CrkII, a Rac activator that is inactivated by Abl-mediated tyrosine phosphorylation, antagonizes Abl-mediated dorsal membrane localization of RacV12 [19].

Physical interactions of Abl1

• DNA microarray analyses enabled us to identify two genes inhibited by v-Abl that encode the Igk 3' enhancer-binding transcription factors Spi-B and IRF-4 [13].
• The results show that the c-Abl SH3 domain binds directly to a proline-rich site (amino acids 567-576) in the Arg C-terminal region [20].
• An Abl mutant which no longer binds p53 does not enhance p53 transcriptional activity and fails to suppress growth [21].
• The catalytic activity of c-Abl tyrosine kinase is reduced in fibroblasts that are detached from the extracellular matrix [22].
• Here we demonstrate that c-Abl interacts constitutively with DNA-PK [23].

Enzymatic interactions of Abl1

• c-Abl phosphorylates Dok1 to promote filopodia during cell spreading [16].
• In vitro evidence indicates that DNA-dependent protein kinase (DNA-PK) can also phosphorylate and thus potentially activate Abl kinase activity in response to IR exposure [24].
• The transcription factor STAT5 is constitutively tyrosine phosphorylated and activated after transformation of hematopoietic cells by p210Bcr/Abl [25].
• We show that Bcr-Abl phosphorylates SHPTP1 on C-terminal Y536 and Y564 sites [26].
• We also found that vinexin alpha but not beta was phosphorylated at tyrosine residue when c-Abl or v-Abl was co-expressed [27].

Regulatory relationships of Abl1

• Filopodia are dynamic F-actin structures that cells use to explore their environment. c-Abl tyrosine kinase promotes filopodia during cell spreading through an unknown mechanism that does not require Cdc42 activity [16].
• These results support a model where c-Abl is inhibited in part through an intramolecular Src homology 3-linker interaction and stimulated to full catalytic activity by sequential phosphorylation at Tyr-412 and Tyr-245 [28].
• We find that a construct encoding the first two Src homology 3 (SH3) domains of the Src homology 2/SH3 adaptor protein Nck can activate c-Abl in human 293T cells [29].
• The c-Abl nonreceptor tyrosine kinase is activated by growth factor signals such as the platelet-derived growth factor (PDGF) and functions downstream of the PDGF-beta receptor (PDGFR) to mediate biological processes such as membrane ruffling, mitogenesis, and chemotaxis [30].
• GTPase analysis with a Ras-GTP-specific precipitation assay showed constitutive elevation of GTP-loaded Ras in cells expressing the leukaemic Abl proteins [31].

Other interactions of Abl1

• Using an unbiased approach, we identified Dok1 as a specific c-Abl substrate in spreading fibroblasts [16].
• Further, we demonstrate that the Abl cytostatic effect requires both the Rb and p53 tumor suppressor gene products [15].
• Here, we show that the related kinase Arg is activated downstream of PDGFRs in a manner dependent on Src family kinases and phospholipase C gamma1 (PLC-gamma1)-mediated phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, as we showed previously for c-Abl [30].
• These data show that, although both kinases are activated and form complexes with proteins in the PDGFR signaling pathway, only c-Abl functions downstream of PLC-gamma1 to mediate chemotaxis [30].
• In contrast, those cells isolated from our previously established CML model mice resist apoptosis in cytokine-free medium without the induction of Bim expression, and these effects are reversed by the Abl-specific kinase inhibitor imatinib mesylate [32].
• Second, the c-Abl effects on insulin signaling are not observed in cells devoid of FAK (FAK(-/-) cells) [33].

Analytical, diagnostic and therapeutic context of Abl1

• Inactivation of cytoplasmic c-Abl by the kinase-inactive Abl-PP-K(-) (AblP242E/P249E/K290M) or by microinjection of Abl neutralizing antibodies inhibited mitogenesis [34].
• Microarray analysis indicated that Early Growth Response-1 (EGR1) gene expression is induced by c-Abl kinase activity, which was confirmed at the message and protein levels [35].
• Cell fractionation shows that both EGF-Rs and cAbl are found basally in Cav1-enriched membrane fractions [3].
• Aph2 was demonstrated to interact with c-Abl by co-immunoprecipitation assays [36].
• Immunofluorescence obtained using antibodies against alphaI SigmaI/++betaI SigmaI spectrin and Abl tyrosine kinase but not against alphaII/betaII spectrin colocalized with the overexpressed green fluorescent protein-SH3-binding protein [37].

References