Abl

The Abl family of non-receptor linked tyrosine kinases relay signals from diverse stimuli to promote changes in cell morphogenesis, migration, adhesion, proliferation and survival. Two Abl family kinases are found in vertebrates: Abl and the Abl-related gene (Arg, also known as Abl2) and homologs in metazoan organisms including Drosophila- (D-) Abl and ABL-1 in C. elegans. The N-terminus of mammalian Abl and Arg proteins is variable, encoded by alternative 5’-exons. The variable region is followed by Src homology 3 (SH3), SH2 and tyrosine kinase domains that are highly conserved through evolution. The Abl family kinases are distinguished from the Src-family kinases by their large C-terminal extensions that contain multiple functional domains to mediate interactions with the actin and microtubule cytoskeletons and other cellular components. The mammalian Abl protein contains three nuclear localization signals and one nuclear export signal. Abl has been shown to undergo nucleocytoplasmic shuttling in mammalian cells; its subcellular localization can be modulated by cell adhesion. The Arg and D-Abl proteins are primarily cytoplasmic, consistent with a role for these proteins in regulating cytoskeleton structure.

In the inactive state, the SH3 and SH2 domains of Abl family kinases form an inhibitory scaffold that holds the kinase domain in an inactive conformation. Several cellular proteins, including F-actin and retinoblastoma protein in the nucleus, have been reported to inhibit Abl kinase activity, possibly by stabilizing this inactive conformation. The kinases become activated by the disassembly of the SH3 and SH2 domains from their inhibitory lock on the kinase, possibly by association with higher affinity ligands on activated receptor complexes. Full kinase activation also requires phosphorylation at two or more tyrosine residues in the short linker between the SH2 and kinase domains and in the kinase domain activation loop. Tyrosine phosphorylation of Abl can be catalyzed by autophosphorylation or by Src family kinases. Abl family kinases can be activated by growth factor stimulation, adhesion receptor engagement, DNA damage and under conditions of oxidative stress. Both Src family kinases and phospholipase C g1 have been shown to mediate Abl and Arg activation following growth factor stimulation, but it remains largely unclear how most stimuli activate Abl and Arg kinase activity.

Abl family kinases regulate cell morphology and motility by regulating cytoskeleton dynamics. Abl and Arg also act downstream of adhesion receptors to promote filopodial and lamellipodial dynamics and inhibit cell spreading and cell migration in cultured fibroblasts. Upon growth factor stimulation, Abl promotes membrane ruffling and attenuates chemotaxis. Abl family kinases can promote cytoskeletal rearrangements by phosphorylating the Crk and Dok1 adaptor proteins and the RhoA inhibitor p190RhoGAP. Arg can also promote cytoskeletal rearrangement independent of kinase activity by using its F-actin- and microtubule-binding domains to promote F-actin-rich protrusions at the cell periphery. Genetic studies in mice and flies have suggested that Abl family kinases are important regulators of neuronal and epithelial morphogenesis during development.

Although Abl and Arg can both function in the cytoplasm, the mammalian Abl performs a unique role in the nucleus. Nuclear Abl kinase is activated in response to DNA damage via pathways that depend on ATM and DNA-PK. Activation of nuclear Abl kinase contributes to the growth arrest or apoptotic response to DNA damage, and Abl has been linked to the regulation of p53 and p73, which are related transcription factors with anti-proliferative and pro-apoptotic functions.

Mutational activation of Abl kinase activity causes greater than 95% of human chronic myelogenous leukemia (CML) and a small percentage of cases of acute lymphocytic leukemia, acute myeloid leukemia and chronic neutrophilic leukemia. Oncogenic activation results from translocation between chromosomes 9 and 22 that fuses exons of the Bcr gene to exons of Abl, resulting in a hybrid gene encoding a Bcr-Abl fusion oncoprotein. Bcr-Abl has hyperactive kinase activity and upregulates mitogenic and anti-apoptotic pathways. A selective Abl inhibitor, Imatinib (STI571;Gleevec), has proven effective in the treatment of chronic phase CML patients. CML patients in acute phase or blast crisis, however, develop resistance to imatinib at a high rate, thereby rendering the drug ineffective.

The Table below contains accepted modulators and additional information.

Abbreviations

AG 568: (αZ)-5-Amino-4-cyano-α-[(3,4-dihydroxyphenyl)methylene]-1H-pyrazole-3-acetonitrile
CNS: Central nervous system
Crk: Cellular homolog of oncogene from CT10 avian sarcoma virus
CrkL: Crk-like protein
dlar: Drosophila leukocyte antigen-related protein
Dok1: Downstream of tyrosine kinases 1
EGF: Epithelial growth factor
ena: Enabled
fax: Failed axon connections
PD173955: 6-(2,6-Dichlorophenyl)-8-methyl-2-[[3-(methylthio)phenyl]amino]-Pyrido[2,3-d]pyrimidin-7(8H)-one
PD180970: 6-(2,6-Dichlorophenyl)-2-[(4-fl uoro-3-methylphenyl)amino]-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one
p190RhoGAP: 190 kD GTPase activating protein for RhoA
PGDF: Platelet-derived growth factor
Rin1: Ras-interactor 1
Robo: Roundabout