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The molecular components which mediate cytokine signaling from the cell membrane to the nucleus were studied. Upon the interaction of cytokines with their receptors, members of the janus kinase (Jak) family of cytoplasmic protein tyrosine kinases and of the signal transducers and activators of transcription (Stat) family of transcription factors are activated through tyrosine phosphorylation. It has been suggested that the Stat proteins are substrates of the Jak protein tyrosine kinases. MGF‐Stat5 is a member of the Stat family which has been found to confer the prolactin response. MGF‐Stat5 can be phosphorylated and activated in its DNA binding activity by Jak2. The activation of MGF‐Stat5 is not restricted to prolactin. Erythropoietin (EPO) and growth hormone (GH) stimulate the DNA binding activity of MGF‐Stat5 in COS cells transfected with vectors encoding EPO receptor and MGF‐Stat5 or vectors encoding GH receptor and MGF‐Stat5. The activation of DNA binding by prolactin, EPO and GH requires the phosphorylation of tyrosine residue 694 of MGF‐Stat5. The transcriptional induction of a beta‐casein promoter luciferase construct in transiently transfected COS cells is specific for the prolactin activation of MGF‐Stat5; it is not observed in EPO‐ and GH‐treated cells. In the UT7 human hematopoietic cell line, EPO and granulocyte‐macrophage colony stimulating factor activate the DNA binding activity of a factor closely related to MGF‐Stat5 with respect to its immunological reactivity, DNA binding specificity and molecular weight. These results suggest that MGF‐Stat5 regulates physiological processes in mammary epithelial cells, as well as in hematopoietic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Since the discovery of their physiological roles in cytokine signalling, the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs) have attracted considerable attention, to the point that the concept of a intracellular signalling pathway, named JAWSTAT, has emerged. As originally defined, this pathway involves ligand-dependent activation of a particular class of receptor-associated tyrosine kinases, the JAK proteins, which phosphorylate themselves and receptor components, creating recruitment sites for STAT transcription factors. The STATs are phosphorylated, they dissociate from the receptor . JAK complex and translocate to the nucleus where they participate in transcriptional gene activation. Although this pathway was found initially to be activated by interferons, it is now known that a large number of cytokines, growth factors and hormonal factors activate JAK and/or STAT proteins. Recent findings have suggested that the interdependence of JAKs and STATs might not be absolute as originally thought.Keywords: Janus kinase; signal transducer and activator of transcription; cytokine ; receptor; signaling ; protein-tyrosine kinase; transcription factor.In the last three years, several reviews have been published on the JAWSTAT pathway [I-101. Here, we will summarise recent functional and structural analyses of these proteins, recapitulate our present fragmentary understanding of their roles in signalling, and anticipate the key questions of the near future. In doing so, we will discuss the JAK and STAT families separately, since, as suggested by recent findings, their interdependence might not be as absolute as originally thought. The JAK family of protein tyrosine kinasesThe JAK proteins are highly related intracellular protein tyrosine kinases of 120-140 kDa, characterised by an amino-terminal portion of approximately 600 amino acids and two kinase domains, each of about 250 residues, separated by a short hinge region (Fig. 1). A canonical tyrosine kinase domain [JAK homology region 1 (JHl)] domain at the carboxyl end of the protein is flanked by a central kinase-like domain (also referred to as pseudokinase or JH2 domain) unique to the family. A nonconserved amino terminus of approximately 30-50 amino acids