The v-src oncogene encodes a nonreceptor tyrosine kinase. When this gene was expressed in the myeloblastic cell line 32Dcl3, it was found to abrogate interleukin-3 (IL-3) dependence of this cell line and to block its ability to terminally differentiate into granulocytes in response to granulocyte colony-stimulating factor (GCSF). In contrast, a highly related tyrosine kinase gene, v-fgr, fails to render this cell line IL-3 independent for growth or to block its ability to undergo terminal differentiation in the presence of GCSF. The active structural domains of v-src that are responsible for the abrogation of IL-3 dependence of myeloid cells and the mechanisms by which v-src transforms these cells are at present unclear. To identify the domains in v-src which are responsible for this activity, we constructed several chimeric recombinants between the v-src and the related It is becoming increasingly clear that hematopoietic cell growth and differentiation are mediated by a group of soluble factors known as cytokines (14,17,35). These molecules bind to their cognate receptors and mediate intracellular signal transduction events which result in the modulation of gene expression (13). During the past few years, new evidence has emerged to indicate that most cytokines transmit their signals via a new family of tyrosine kinases termed JAK kinases (7,31,35,38). To date, this family consists of four members, i.e., JAK-1, JAK-2, JAK-3, and TYK-2. These kinases, either alone or in conjunction with each other, appear to be responsible for effects mediated by several cytokines and neurokines (2,12,17,22,30,31,35). Current models suggest that interaction of cytokines with their receptors induces receptor dimerization, which increases the affinity of the cytoplasmic domain of the receptor for JAK kinases, resulting in a ligand-dependent increase of a complex that contains the receptors and JAK kinases. This results in activation of the JAK kinases through an event associated with tyrosine phosphorylation. The activated kinases appear to subsequently phosphorylate the receptors as well as cellular substrates, the most important of which are the STATs (signal transducers and activators of transcription). These transcription factors were originally described by Darnell et al. (7) as transcription factors associated with an interferon-mediated signaling mechanism. To date, six different STATs have been discovered, all of which seem to participate in cytokine-or growth hormone-mediated signal transduction (13,23).It is now well-established that several of the oncogenic tyrosine kinases belonging to the Src family have a profound effect on the cytokine dependence of hematopoietic cell lines (1, 26). Most notably, it has been demonstrated that constitutive expression of v-src and v-abl oncogenes in interleukin-3 (IL-3)-dependent myeloid cell lines renders them cytokine independent for growth (1,26,28,29). This alteration in growth factor dependence had suggested that these oncogenes might interfere with signal transduction pathways ...