Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase.
The ubiquitously expressed nonreceptor tyrosine kinase c-Abl contains three nuclear localization signals, however, it is found in both the nucleus and the cytoplasm of proliferating fibroblasts. A rapid and transient loss of c-Abl from the nucleus is observed upon the initial adhesion of fibroblasts onto a fibronectin matrix, suggesting the possibility of nuclear export [Lewis, J., Baskaran, R. , Taagepera, S., Schwartz, M. & Wang, J. (1996) Proc. Natl. Acad. Sci. USA 93, 15174-15179]. Here we show that the C terminus of c-Abl does indeed contain a functional nuclear export signal (NES) with the characteristic leucine-rich motif. The c-Abl NES can functionally complement an NES-defective HIV Rev protein (RevDelta3NI) and can mediate the nuclear export of glutathione-S-transferase. The c-Abl NES function is sensitive to the nuclear export inhibitor leptomycin B. Mutation of a single leucine (L1064A) in the c-Abl NES abrogates export function. The NES-mutated c-Abl, termed c-Abl NES(-), is localized exclusively to the nucleus. Treatment of cells with leptomycin B also leads to the nuclear accumulation of wild-type c-Abl protein. The c-Abl NES(-) is not lost from the nucleus when detached fibroblasts are replated onto fibronectin matrix. Taken together, these results demonstrate that c-Abl shuttles continuously between the nucleus and the cytoplasm and that the rate of nuclear import and export can be modulated by the adherence status of fibroblastic cells.
Taagepera
S
S
Department of Biology, Center for Molecular Genetics and the Cancer Center, University of California at San Diego, La Jolla CA 92093-0322, USA.
McDonald
D
D
Loeb
J E
JE
Whitaker
L L
LL
McElroy
A K
AK
Wang
J Y
JY
Hope
T J
TJ
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D015694:Gene Products, rev / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*
D000199:Actins; D015694:Gene Products, rev; D011500:Protein Synthesis Inhibitors; D003513:Cycloheximide; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl