Trends in Cell Biology
ReviewCycling, stressed-out and nervous: cellular functions of c-Abl
Section snippets
Subcellular location of c-Abl
Early efforts at understanding the role of c-Abl focused on where the protein resided in the cell, with the hope that the location would give important clues about function. The subcellular location of c-Abl was first determined by overexpressing the murine type IV protein in fibroblasts and was unexpectedly found to be largely nuclear, but with a significant fraction in the cytoplasm that is associated mostly with filamentous actin and the plasma membrane3. This general pattern of localization
Insights from Abl-deficient mice
The mouse c-abl gene was one of the first genes targeted by homologous recombination, which generated a true null allele12 and one encoding a truncated Abl protein with intact kinase activity13. Interestingly, both knockout alleles resulted in the same phenotype: abl−/− mice are born runted, have shortened survival and exhibit abnormal eyes, frequent rectal prolapse and defective spermatogenesis14. Some animals also have splenic and thymic atrophy, with a 10–30-fold decrease in the number of
Regulation of c-Abl kinase activity
Like c-Src, wild-type c-Abl protein does not transform fibroblasts or haematopoietic cells, even when overexpressed3, suggesting that Abl kinase activity is regulated tightly in cells. However, biochemical and mutational studies suggest that the mechanism of regulation of Abl kinase activity is different from that of Src-family kinases. c-Src is regulated negatively by phosphorylation of the C-terminal Tyr527 by Csk and other cellular kinases and assumes an inactive state where the
Nuclear functions of c-Abl
Several lines of evidence suggest a role for nuclear c-Abl in regulation of the cell cycle26. A portion of the nuclear pool of c-Abl in cells in G1 phase of the cell cycle is complexed with the retinoblastoma protein, Rb. In this complex, the C-terminal pocket of Rb binds to the ATP-binding lobe of the Abl kinase domain, resulting in inhibition of Abl kinase activity. Phosphorylation of Rb by cyclin-D–cdk4/6 kinases at the G1–S boundary results in release of c-Abl and activation of Abl kinase
Cytoplasmic functions of c-Abl
Compared with its nuclear functions, less is known about the function of c-Abl in the cytoplasm. A large proportion of cytoplasmic Abl is associated with the F-actin cytoskeleton through the C-terminal actin-binding domain. This domain has distinct binding activity for both filamentous (F) and monomeric (G) actin in vitro9, and together the two domains can mediate bundling of F-actin filaments. In vivo, the low concentration of c-Abl makes it unlikely that Abl is a major modifier of the
Conclusions and future prospects
Very rapid progress has been made in the past several years in understanding the complex and multifaceted biology of c-Abl. Roles for c-Abl in cell-cycle regulation, stress responses, integrin signalling and neural development are likely. Despite this progress, a single comprehensive model of Abl function is not possible at this time. In the near future, we can expect advances on several fronts. A crystal structure of mammalian c-Abl, perhaps both in an active form and complexed with an
Acknowledgements
I thank Li-Huei Tsai, Christopher A. Walsh, Bruce Mayer and Tony Koleske for helpful discussions, and Peter Jackson and David Van Vactor for their critical review of the manuscript. This work was supported by NIH grants CA74625 and CA77691. R. A. V. is a Scholar of the Leukemia Society of America and the Carl and Margaret Walter Scholar in Blood Research at Harvard Medical School.
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