ABL tyrosine kinases: evolution of function, regulation, and specificity.
ABL-family proteins comprise one of the best conserved branches of the tyrosine kinases. Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2-tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases. This cassette is coupled to an actin-binding and -bundling domain, which makes ABL proteins capable of connecting phosphoregulation with actin-filament reorganization. Two vertebrate paralogs, ABL1 and ABL2, have evolved to perform specialized functions. ABL1 includes nuclear localization signals and a DNA binding domain through which it mediates DNA damage-repair functions, whereas ABL2 has additional binding capacity for actin and for microtubules to enhance its cytoskeletal remodeling functions. Several types of posttranslational modifications control ABL catalytic activity, subcellular localization, and stability, with consequences for both cytoplasmic and nuclear ABL functions. Binding partners provide additional regulation of ABL catalytic activity, substrate specificity, and downstream signaling. Information on ABL regulatory mechanisms is being mined to provide new therapeutic strategies against hematopoietic malignancies caused by BCR-ABL1 and related leukemogenic proteins.
Colicelli
John
J
Department of Biological Chemistry, Molecular Biology Institute and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. colicelli@mednet.ucla.edu
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D019143:Evolution, Molecular; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D006801:Humans; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains
D000199:Actins; D019913:Nuclear Localization Signals; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl