Abl1 | GeneID:311860 | Rattus norvegicus
[ ] NCBI Entrez Gene
|Gene ID||311860||Official Symbol||Abl1|
|Full Name||c-abl oncogene 1, receptor tyrosine kinase|
|Description||c-abl oncogene 1, receptor tyrosine kinase|
|Also Known As||Abelson murine leukemia viral (v-abl) oncogene homolog 1; v-abl Abelson murine leukemia viral oncogene 1; v-abl Abelson murine leukemia viral oncogene homolog 1|
Orthologs and Paralogs
|GeneID:491292||ABL1||XP_548413.2||Canis lupus familiaris|
[ ] Monoclonal and Polyclonal Antibodies
|1||abcam||ab63530||c Abl antibody (ab63530); Rabbit polyclonal to c Abl|
|2||abcam||ab62189||c Abl (phospho Y245) antibody (ab62189); Rabbit polyclonal to c Abl (phospho Y245)|
|3||abcam||ab61757||c Abl (phospho Y204) antibody (ab61757); Rabbit polyclonal to c Abl (phospho Y204)|
|4||abcam||ab55284||c Abl (phospho Y412) antibody (ab55284); Rabbit polyclonal to c Abl (phospho Y412)|
|5||abcam||ab32080||c Abl antibody [Y421] (ab32080); Rabbit monoclonal [Y421] to c Abl|
|6||abcam||ab10528||c Abl antibody [ABL-148] (ab10528); Mouse monoclonal [ABL-148] to c Abl|
|7||sigma||A5844||Monoclonal Anti-c-Abl antibody produced in mouse ;|
|GO:0000287||Function||magnesium ion binding|
|GO:0030145||Function||manganese ion binding|
|GO:0004715||Function||non-membrane spanning protein tyrosine kinase activity|
|GO:0008022||Function||protein C-terminus binding|
|GO:0019904||Function||protein domain specific binding|
|GO:0004672||Function||protein kinase activity|
|GO:0030036||Process||actin cytoskeleton organization|
|GO:0043065||Process||positive regulation of apoptosis|
|GO:0051353||Process||positive regulation of oxidoreductase activity|
|GO:0006468||Process||protein amino acid phosphorylation|
|GO:0051726||Process||regulation of cell cycle|
MicroRNA and Targets
[ ] MicroRNA Sequences and Transcript Targets from miRBase at Sanger
|RNA Target||miRNA #||mat miRNA||Mature miRNA Sequence|
- [ ] Anfinogenova Y, et al. (2007) "Abl silencing inhibits CAS-mediated process and constriction in resistance arteries." Circ Res. 101(4):420-428. PMID:17615370
- [ ] Mitsushima M, et al. (2006) "Abl kinase interacts with and phosphorylates vinexin." FEBS Lett. 580(17):4288-4295. PMID:16831423
- [ ] Ushio-Fukai M, et al. (2005) "cAbl tyrosine kinase mediates reactive oxygen species- and caveolin-dependent AT1 receptor signaling in vascular smooth muscle: role in vascular hypertrophy." Circ Res. 97(8):829-836. PMID:16151024
- [ ] Alvarez AR, et al. (2004) "Activation of the neuronal c-Abl tyrosine kinase by amyloid-beta-peptide and reactive oxygen species." Neurobiol Dis. 17(2):326-336. PMID:15474370
- [ ] Woodring PJ, et al. (2002) "Modulation of the F-actin cytoskeleton by c-Abl tyrosine kinase in cell spreading and neurite extension." J Cell Biol. 156(5):879-892. PMID:11864995
- [ ] Welch PJ, et al. (1995) "Abrogation of retinoblastoma protein function by c-Abl through tyrosine kinase-dependent and -independent mechanisms." Mol Cell Biol. 15(10):5542-5551. PMID:7565706
- [ ] Mihara K, et al. (1988) "Detection of hypermethylation of the c-abl genomic locus in the spleen of juvenile LE rats." Biochem Biophys Res Commun. 154(3):1061-1066. PMID:2841925
- [ ] Takahashi R, et al. (1986) "Secondary activation of c-abl may be related to translocation to the nucleolar organizer region in an in vitro cultured rat leukemia cell line (K3D)." Proc Natl Acad Sci U S A. 83(4):1079-1083. PMID:3456563
The tyrosine phosphorylated protein Crk-associated substrate (CAS) has previously been shown to participate in the cellular processes regulating dynamic changes in the actin architecture and arterial constriction. In the present study, treatment of rat mesenteric arteries with phenylephrine (PE) led to the increase in CAS tyrosine phosphorylation and the association of CAS with the adapter protein CrkII. CAS phosphorylation was catalyzed by Abl in an in vitro study. To determine the role of Abl tyrosine kinase in arterial vessels, plasmids encoding Abl short hairpin RNA (shRNA) were transduced into mesenteric arteries by chemical loading plus liposomes. Abl silencing diminished increases in CAS phosphorylation on PE stimulation. Previous studies have shown that assembly of the multiprotein compound containing CrkII, neuronal Wiskott-Aldrich Syndrome Protein (N-WASP) and the Arp2/3 (Actin Related Protein) complex triggers actin polymerization in smooth muscle as well as in nonmuscle cells. In this study, Abl silencing attenuated the assembly of the multiprotein compound in resistance arteries on contractile stimulation. Furthermore, the increase in F/G-actin ratios (an index of actin assembly) and constriction on contractile stimulation were reduced in Abl-deficient arterial segments compared with control arteries. However, myosin regulatory light chain phosphorylation (MRLCP) elicited by contractile activation was not inhibited in Abl-deficient arteries. These results suggest that Abl may play a pivotal role in mediating CAS phosphorylation, the assembly of the multiprotein complex, actin assembly, and constriction in resistance arteries. Abl does not participate in the regulation of myosin activation in arterial vessels during contractile stimulation.
Non-receptor tyrosine kinase Abl is a well known regulator of the actin-cytoskeleton, including the formation of stress fibers and membrane ruffles. Vinexin is an adapter protein consisting of three SH3 domains, and involved in signal transduction and the reorganization of actin cytoskeleton. In this study, we found that vinexin alpha as well as beta interacts with c-Abl mainly through the third SH3 domain, and that vinexin and c-Abl were colocalized at membrane ruffles in rat astrocytes. This interaction was reduced by latrunculin B, suggesting an F-actin-mediated regulatory mechanism. We also found that vinexin alpha but not beta was phosphorylated at tyrosine residue when c-Abl or v-Abl was co-expressed. A mutational analysis identified tyrosine 127 on vinexin alpha as a major site of phosphorylation by c- or v-Abl. These results suggest that vinexin alpha is a novel substrate for Abl.
Important output signals of the angiotensin subtype 1 receptor (AT1R) in vascular smooth muscle cells (VSMCs) are mediated by angiotensin II (Ang II)-stimulated transactivation of the epidermal growth factor receptor (EGF-R), which is critical for vascular hypertrophy. Ang II-induced EGF-R transactivation is mediated through cSrc, a proximal target of reactive oxygen species (ROS) derived from NAD(P)H oxidase (NOX) and is dependent on AT(1)R trafficking through caveolin1 (Cav1)-enriched lipid rafts. Underlying molecular mechanisms are incompletely understood. The nonreceptor tyrosine kinase, proto-oncogene cAbl is a substrate of Src and is a major mediator for ROS-dependent tyrosine phosphorylation of Cav1. We thus hypothesized that cAbl is important for ROS-, cSrc-, and Cav1-dependent growth-related AT1R signal transduction. Here we show that Ang II induces tyrosine phosphorylation of cAbl in rat VSMCs and mouse aorta, and that Ang II promotes association of cAbl with AT(1)R, both of which are Src-dependent. Pretreatment of rat VSMCs with the NOX inhibitor diphenylene iodonium or the antioxidants N-acetylcysteine or ebselen significantly inhibited Ang II-induced cAbl phosphorylation. Cell fractionation shows that both EGF-Rs and cAbl are found basally in Cav1-enriched membrane fractions. Knockdown of cAbl protein using small interference RNA inhibits Ang II-stimulated: (1) trafficking of AT1R into, and EGF-R out of, Cav1-enriched lipid rafts; (2) EGF-R transactivation; (3) appearance of the transactivated EGF-R and phospho-Cav1 at focal adhesions; and (4) vascular hypertrophy. These studies provide a novel role of cAbl in the spatial and temporal organization of growth-related AT1R signaling in VSMCs and suggest that cAbl may be generally important in signaling of G-protein coupled receptors.
The deposition and accumulation of amyloid-beta-peptide (Abeta) in the brain are considered a sine qua non for Alzheimer's disease. The experimental delivery of fibrilized Abeta serves as a cellular model for several facets of the disease including the induction of synaptic dysfunction and apoptosis. c-Abl kinase is involved in the regulation of apoptosis and its pro-apoptotic function is in part mediated by its interaction with p73, a p53 homologue. We found that c-Abl activation is involved in cell signals that regulate neuronal death response to Abeta fibrils. Abeta peptide fibrils induced an increase of the c-Abl activity in rat hippocampal neurons as well as an increase in nuclear p73 protein levels and the p73-c-Abl complex. The neuronal cell death induced by Abeta fibrils was prevented by the inhibition of c-Abl with imatinib mesylate (Gleevec or STI571) and by the inhibition c-Abl expression by RNAi. These results directly point to a therapeutic strategy for the treatment of Alzheimer's disease.
The nonreceptor tyrosine kinase encoded by the c-Abl gene has the unique feature of an F-actin binding domain (FABD). Purified c-Abl tyrosine kinase is inhibited by F-actin, and this inhibition can be relieved through mutation of its FABD. The c-Abl kinase is activated by physiological signals that also regulate the actin cytoskeleton. We show here that c-Abl stimulated the formation of actin microspikes in fibroblasts spreading on fibronectin. This function of c-Abl is dependent on kinase activity and is not shared by c-Src tyrosine kinase. The Abl-dependent F-actin microspikes occurred under conditions where the Rho-family GTPases were inhibited. The FABD-mutated c-Abl, which is active in detached fibroblasts, stimulated F-actin microspikes independent of cell attachment. Moreover, FABD-mutated c-Abl stimulated the formation of F-actin branches in neurites of rat embryonic cortical neurons. The reciprocal regulation between F-actin and the c-Abl tyrosine kinase may provide a self-limiting mechanism in the control of actin cytoskeleton dynamics.
The decision to enter the cell division cycle is governed by the interplay between growth activators and growth inhibitors. The retinoblastoma protein (RB) is an example of a growth inhibitor whose main function appears to be the binding and inactivation of key cell cycle activators. One target of RB is a proto-oncoprotein, the c-Abl tyrosine kinase. RB binds to the ATP-binding lobe in the kinase domain and inhibits the nuclear pool of c-Abl in quiescent and G1 cells. Phosphorylation of RB at G1/S releases c-Abl, leading to the activation of this nuclear tyrosine kinase. In this report, we describe the construction of a mutant Abl, replacing the ATP-binding lobe of c-Abl with that of c-Src. The mutant protein AS2 is active as a tyrosine kinase and can phosphorylate Abl substrates, such as the C-terminal repeated domain of RNA polymerase II. AS2, however, does not bind to RB, and its activity is not inhibited by RB. As a result, the nuclear pool of AS2 is no longer cell cycle regulated. Excess AS2, but not its kinase-defective counterpart, can overcome RB-induced growth arrest in Saos-2 cells. Interestingly, wild-type c-Abl, in both its kinase-active and -inactive forms, can also overcome RB. Furthermore, overexpression of a kinase-defective c-Abl in rodent fibroblasts accelerates the transition from quiescence to S phase and cooperates with c-Myc to induce transformation. These effects, however, do not occur with the kinase-defective form of AS2. Thus, the growth-stimulating function of the kinase-defective c-Abl is dependent on the binding and the abrogation of RB function. That RB function can be abolished by the overproduction of one of its binding proteins is consistent with the hypothesis that RB induces cell cycle arrest by acting as a "molecular matchmaker" to assemble protein complexes. Exclusive engagement of RB by one of its many targets is incompatible with the biological function of this growth suppressor protein.
Tumor induction by treatment with polycylic hydrocarbons depends on age and the strains of rats used. Juvenile LE rats are very sensitive to the induction of leukemia and chromosomal breaks by intravenous DMBA injection. We have previously demonstrated a chromosomal translocation in chromosome 3 and 12 in a DMBA induced LE rat leukemia cell K3D. In our present communication we have examined the c-abl expression in the leukemic cell line as well as in the LE rats at different ages. We found that in the leukemic cell K3D the c-abl expression is elevated both at the level of mRNA and protein. In the preleukemic stage, highly elevated expression of c-abl mRNA was detected exclusively in the spleen of the juvenile LE rats. Furthermore this high expression of the c-abl gene correlates well with hypermethylation of possible cytosine residue in the c-abl genomic locus.
Localization of cellular oncogenes (c-onc) near the break points of translocations in tumor cells has indicated involvement of these genes in neoplastic growth. Enhanced transcription of the cellular homolog (c-abl) of the transforming sequence of Abelson murine leukemia virus was observed in K3D, which was one of the cloned cell lines of 7,12-dimethylbenz[a]anthracene-induced rat erythroblastic leukemia. Since the c-abl activation was not observed in the parent cell line (K2D) from which K3D was derived and the latter was different from the former in the presence of a new marker chromosome, t(3;12), this marker may play a role in the expression of c-abl in K3D cells. In contrast to the human c-onc assignments, few rat c-onc assignments have been reported. In situ molecular hybridization studies assigned c-abl to the 3q12 site of the normal chromosome 3 and to the break point of the translocation t(3;12) in K3D cells. Another break point in this translocation chromosome 12p11 involves the nucleolar region, and the 3;12 translocation may involve c-abl and nucleolar cistrons. These results provide evidence of secondary c-onc activation during karyotypic evolution of cloned malignant cells.