Signaling mechanisms leading to regulation of gene transcription by growth hormone (GH) and other molecules that signal via the cytokine receptor family have been elusive. Based upon recent findings that GH and interferons activate JAK family tyrosine kinases, we have identified a novel signaling pathway leading from the GH receptor to the nucleus. We report that in 3T3-F442A fibroblasts, GH stimulates tyrosyl phosphorylation of a protein recognized by antibody to p91, a component of DNA-binding complexes that are activated by tyrosyl phosphorylation in response to interferons alpha and gamma. In addition, a GH-inducible DNA binding factor (GHIF) is identified that binds to the c-sis-inducible element of the c-fos promoter. GHIF contains a protein antigenically related to p91 and is tyrosyl-phosphorylated. These findings indicate that in signaling between their receptors and the nucleus, GH and interferons utilize related or identical components, including JAK family tyrosine kinases and proteins in the p91 family. When combined with recent findings that many members of the cytokine receptor family activate JAK kinases, including some cytokines that activate p91-related proteins, these findings suggest that signaling pathways involving JAK kinases and p91 family members may be broadly distributed.