ROLES OF JAKS IN ACTIVATION OF STATS AND STIMULATION OF C-FOS GENE-EXPRESSION BY EPIDERMAL GROWTH-FACTOR

The tyrosine kinase JAK1 and the transcription factors STAT1 and STAT3 are phosphorylated in response to epidermal growth factor (EGF) and o ther growth factors. We have used EGF receptor-transfected cell lines defective in individual JAKs to assess the roles of these kinases in S TAT activation and signal transduction in response to EGF. Although JA K1 is phosphorylated in response to EGF, it is not required for STAT a ctivation or for induction of the c-fos gene. STAT activation in JAK2- and TYK2-defective cells is also normal, and the tyrosine phosphoryla tion of these two kinases does not increase upon EGF stimulation in wi ld-type or JAK1-negative cells. In cells transfected with a kinase-neg ative mutant EGF receptor, there is no STAT activation in response to EGF and c-fos is not induced, showing that the kinase activity of the receptor is required, directly or indirectly, for these two responses. The data do not support a role for any of the three JAK family member s tested in STAT activation and are consistent with a JAK-independent pathway in which the intrinsic kinase domain of the EGF receptor is cr ucial. Furthermore, data from transient transfection experiments in He La cells, using c-fos promoters lacking the STAT regulatory element c- sis-inducible element, indicate that this element may play only a mino r role in the induction of c-fos by EGF in these cells.