Integrative Signaling Through c-Abl A Tyrosine Kinase with Nuclear and Cytoplasmic Functions

The mammalian genome is estimated to encode between 100 and 200 tyrosine kinases ( 1). Protein tyrosine kinases are found in multicellular organisms, but not in unicellular eukaryotes such as yeast (1,2). Thus, tyrosine kinases are likely to be involved in regulatory processes required for the formation and the maintenance of multicellularity. Consistent with this notion, all of the known tyrosine kinases can be linked to the transduction of extracellular signals from hormones, cytokines, peptide growth factors, cell-matrix interactions, and cell-cell interactions. Although most of these tyrosine kinases are associated with receptors at or near the plasma membrane, a few tyrosine kinases are localized to the nucleus as well (3). The first tyrosine kinase shown to be in the nucleus was c-Abl (4). The c-Abl tyrosine kinase was identified as the normal cellular homolog of the Gag-v-Abl oncoprotein of Abelson murine leukemia virus (5). In human and mouse, c-Abl and a related tyrosine kinase, Arg, have been identified (5). Abl-related tyrosine kinases have also been isolated from Drosophila and Caenorhabditis elegans (5). The tyrosine kinase domain of the Abl-family members is highly conserved through evolution. The Abl family members are characterized by a large C-terminal region that is not as well conserved through evolution (5). Whereas the Abl-family of tyrosine kinases contain the Srchomology domains SH3 and SH2, they are distinct from the Src family members. Both c-Abl and Arg are widely expressed in a variety of mammalian cell types (5). The murine and feline c-abl gene has each been transduced by a retrovirus to generate a transforming virus that causes leukemia in mice or sarcoma in cats, respectively (5). The human c-abl gene is at the breakpoint of a chromosomal translocation, known as the Philadelphia (PhI) chromosome, which is the cytogenetic hallmark of chronic myeloid leukemia (CML) (6). The juxtaposition of another human gene (Ber) and cabl in the PhI-chromosome leads to the formation of a hybrid Bcr-Abl protein with transforming activity (6,7). Because the transforming proteins Bcr-Abl and Gag-v-Abl contain additional functional domains, and because c-Abl does not transform cells, the