c-Abl: activation and nuclear targets

Abstract

The c-Abl tyrosine kinase and its transforming variants have been implicated in tumorigenesis and in many important cellular processes. c-Abl is localized in the nucleus and the cytoplasm, where it plays distinct roles. The effects of c-Abl are mediated by multiple protein-protein and protein-DNA interactions and its tyrosine kinase domain. At the biochemical level, the mechanism of c-Abl kinase activation and the identification of its target proteins and cellular machineries have in part been solved. However, the phenotypic outcomes of these molecular events remained in large elusive. c-Abl has been shown to regulate the cell cycle and to induce under certain conditions cell growth arrest and apoptosis. In this respect the interaction of c-Abl with p53 and p73 has attracted particular attention. Recent findings have implicated c-Abl in an ionizing irradiation signaling pathway that elicits apoptosis. In this pathway p73 is an important immediate downstream effector. Here I review the current knowledge about these nuclear processes in which c-Abl is engaged and discuss some of their possible implications on cell physiology. Cell Death and Differentiation (2000) 7, 10 ± 16.

c-Abl tyrosine kinase promotes adipocyte differentiation by targeting PPAR-gamma 2

“…Upon SH3 domain binding to the PxxP motif, c-Abl might undergo modulation (32), however because c-Abl activation precedes PPARγ2 accumulation, there must be an alternative means of c-Abl activation. c-Abl is known to be activated physiologically by DNA damage response elements like ataxia telangiectasia mutant (ATM) protein (33).…”

The NF-κB pathway blockade by the IKK inhibitor PS1145 can overcome Imatinib resistance

“…29,30 It has been demonstrated that c-ABL inhibits IkBa degradation by inducing its accumulation in the nucleous. 31,32 c-ABL is a protein that actively shuttles between the cytoplasm and the nucleus. 33 Interestingly IkBa also actively undergoes nucleus-cytoplasm shuttling.…”

Crk family adaptors–signalling complex formation and biological roles

“…It is also not known, though tempting to speculate, whether a CRKL ± STAT5 heterodimer formed via their SH2 domains would allow the CRKL SH3 domains to bring additional enzymes, for example kinases like c-Abl or HPK1 into the nucleus. c-Abl is well known to have nuclear functions (Shaul, 2000;Wang, 2000) and both HPK1 and c-Abl can phosphorylate c-Jun in vitro (Barila et al, 2000;EK Schmidt and SM Feller, unpublished data). Furthermore, c-Abl and HPK1 were found to bind to each other upon experimentally-induced DNA-damage (Ito et al, 2001).…”