tyrosine-protein kinase ABL1; Abelson murine leukemia viral oncogene homolog 1; proto-oncogene c-Abl; p150 (ABL1, ABL, JTK7)
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Function
- protein kinase that regulates key processes linked to cell growth & survival
- regulates cytoskeleton remodeling during cell differentiation, cell division & cell adhesion
- localizes to dynamic actin structures, & phosphorylates CRK & CRKL, DOK1, & other proteins controlling cytoskeleton dynamics
- regulates DNA repair potentially by activating the proapoptotic pathway when the DNA damage is too severe to be repaired
- phosphorylation by cdc2kinase in vitro & during mitosis in vivo inhibits DNA binding
- DNA damage-induced activation of c-Abl requires the function of ATM & Ser-446 phosphorylation (putative)
- phosphorylates PSMA7 that leads to an inhibition of proteasomal activity & cell cycle transition blocks
- substrate specificity of abl matches the binding preference of its SH2-domain[5]
- stabilized in the inactive form by an association between the SH3 domain & the SH2-TK linker region, interactions of the amino-terminal cap, & contributions from an amino-terminal myristoyl group & phospholipids
- activated by autophosphorylation as well as by SRC-family kinase-mediated phosphorylation
- activated by RIN1 binding to the SH2 domain & SH3 domains
- phosphorylated by PRKDC (putative).
- phosphorylation on Thr-735 is required for binding 14-3-3 proteins for cytoplasmic translocation
- interacts with SORBS1 following insulin stimulation
- found in a trimolecular complex containing CDK5 & CABLES1
- interacts with CABLES1 & PSTPIP1
- interacts with ZDHHC16
- interacts with INPPL1/SHIP2
- interacts with the 14-3-3 proteins, YWHAB, YWHAE, YWHAG, YWHAH, SFN AND YWHAZ; the interaction with 14-3-3 proteins requires phosphorylation on Thr-735 &, sequesters ABL1 into the cytoplasm
- interacts with PSMA7
ATP + protein-L-tyrosine = ADP + protein-L-tyrosine phosphate
Structure
- belongs to the protein kinase superfamily, Tyr protein kinase family, ABL subfamily
- contains 1 protein kinase domain
- contains 1 SH2 domain
- contains 1 SH3 domain
- isoform IB is myristoylated on Gly-2
Compartment
- cytoplasm, cytoskeleton, nucleus
- sequestered into the cytoplasm through interaction with 14-3-3 proteins
- isoform IB: nucleus membrane; lipid-anchor
- the myristoylated c-ABL protein is reported to be nuclear
Alternative splicing
Expression
widely expressed
Pathology
- chromosomal translocation t(9;22)(q34;q11) involving ABL1 with BCR is a cause of chronic myeloid leukemia
- translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) & acute lymphoblastic leukemia (ALL)
- contains recognition motif of viral oncogene protein p120gag-abl, EEKE[Y*]HAE[4]
Pharmacology
- inhibited by imatinib mesylate (Gleevec) which is used for the treatment of chronic myeloid leukemia (CML)
- inhibited by VX-680, an inhibitor that acts also on imanitib-resistant mutants
More general terms
More specific terms
Additional terms
References
- ↑ Hunter T. Cooperation between oncogenes. Cell. 1991 Jan 25;64(2):249-70. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/1988147
- ↑ Kipreos ET, Wang JY. Differential phosphorylation of c-Abl in cell cycle determined by cdc2 kinase and phosphatase activity. Science. 1990 Apr 13;248(4952):217-20. PMID: https://www.ncbi.nlm.nih.gov/pubmed/2183353
- ↑ Kipreos ET, Wang JY. Cell cycle-regulated binding of c-Abl tyrosine kinase to DNA. Science. 1992 Apr 17;256(5055):382-5. PMID: https://www.ncbi.nlm.nih.gov/pubmed/1566087
- ↑ 4.0 4.1 Kemp BE, Pearson RB. Protein kinase recognition sequence motifs. Trends Biochem Sci. 1990 Sep;15(9):342-6. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/2238044
- ↑ 5.0 5.1 Pawson T Protein modules and signalling networks Nature 373:573 1995 (SH2-domain) PMID: https://www.ncbi.nlm.nih.gov/pubmed/7531822
- ↑ UniProt http://www.uniprot.org/uniprot/P00519.html
- ↑ Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/ABL.html
- ↑ CGP resequencing studies http://www.sanger.ac.uk/perl/genetics/CGP/cgp_viewer?action=gene&ln=ABL1
- ↑ NIEHS-SNPs http://egp.gs.washington.edu/data/abl1/
- ↑ Wikipedia; Note: Abl entry http://en.wikipedia.org/wiki/Abl_gene