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 n ucleus and the cytoplasm of proliferating fibroblasts. A rapid and tra nsient loss of c-Abl from the nucleus is observed upon the initial adh esion of fibroblasts onto a fibronectin matrix, suggesting the possibi lity of nuclear export [Lewis, J,, Baskaran, R,, Taagepera, S., Schwar tz, 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 funct ional nuclear export signal (NES) with the characteristic leucine-rich motif. The c-Abl NES can functionally complement an NES-defective HIV Rev protein (Rev Delta 3NI) and can mediate the nuclear export of glu tathione-S-transferase. The c-Abl NES function is sensitive to the nuc lear export inhibitor leptomycin B, Mutation of a single leucine (L106 4A) in the c-Abl NES abrogates export function. The NES-mutated c-Abl, termed c-Abl NES(-), is localized exclusively to the nucleus. Treatme nt of cells with leptomycin B also leads to the nuclear accumulation o f wild-type c-Abl protein. The c-Abl NES(-) is not lost from the nucle us when detached fibroblasts are replated onto fibronectin matrix, Tak en together, these results demonstrate that c-Abl shuttles continuousl y between the nucleus and the cytoplasm and that the rate of nuclear i mport and export can be modulated by the adherence status of fibroblas tic cells.