Review Cytokines and Growth Hormones

in mammalian cells.1-3 STAT5A and STAT5B are expressed from two different genes. These are located in tandem on human chro-mosome 17q11.2, and probably arose from gene duplication. The two proteins have approximately 90 kDa and share 94 % amino acid sequence identity, with STAT5A being seven amino acids longer than STAT5B.4,5 STAT5A and STAT5B regulate erythro-poiesis, lymphopoiesis, and the maintenance of the hematopoi-etic stem cell population.2,6-8 The mechanism of STAT activation has been well elabo-rated. Binding of ligands (cytokines or growth factors) to cog-nate receptors activates the associated Janus kinases, JAK1–3 and TYK2 (Fig. 1A). These phosphorylate tyrosine residues of the cytosolic receptor subunit.3,9 Via their Src homology-2 (SH2) domains cytosolic STAT5 molecules bind to the phospho-tyro-sine residues in the receptors and also become phosphorylated by Janus kinases. Phosphorylation occurs at Y694 (STAT5A) or Y699 (STAT5B) and is crucial for the stable association of STAT5 dimers through their SH2 domains binding phosphorylated tyrosine residues. Activated STAT5 dimers translocate into the nucleus and bind mainly to palindromic interferon gamma acti-vated sequences (GAS) with the consensus TTCNNNGAA.10,11 N-terminal interactions between STAT5 molecules on DNA permit tetramerization,11,12 being critically relevant for cytokine and immune responses.13 Disturbances in the signaling cascades induced through STAT5 are often associated with leukemogen-esis and other cancers.5,14,15 STAT5A and STAT5B have overlapping and redundant func-tions. While both STAT5 isoforms can be activated by the same set of cytokines, some cytokines preferentially activate either STAT5A or STAT5B. For example, prolactin (PRL; stimulates milk production by mammary glands, lactation) predomi-nantly activates STAT5A and growth hormone rather induces STAT5B.16 Moreover, distinct roles of the STAT5 isoforms increasingly become appreciated.1