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Interpretation of Cytokine Signaling Through the Transcription Factors STAT5A and STAT5B

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Interpretation of Cytokine Signaling Through the Transcription Factors STAT5A and STAT5B Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B Lothar Hennighausen1 and Gertraud W. Robinson Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA Transcription factors from the family of Signal Trans- the “wrong” STATs and thus acquire inappropriate cues. ducers and Activators of Transcription (STAT) are acti- We propose that mice with mutations in various com- vated by numerous cytokines. Two members of this fam- ponents of the JAK–STAT signaling pathway are living ily, STAT5A and STAT5B (collectively called STAT5), laboratories, which will provide insight into the versa- have gained prominence in that they are activated by a tility of signaling hardware and the adaptability of the wide variety of cytokines such as interleukins, erythro- software. poietin, growth hormone, and prolactin. Furthermore, constitutive STAT5 activation is observed in the major- ity of leukemias and many solid tumors. Inactivation Historical perspective studies in mice as well as human mutations have pro- In 1994, Bernd Groner and colleagues (Wakao et al. vided insight into many of STAT5’s functions. Disrup- 1994), then at the Friedrich Miescher Institute in Basel, tion of cytokine signaling through STAT5 results in a cloned a cDNA from lactating ovine mammary tissue variety of cell-specific effects, ranging from a defective that encoded a transcription factor promoting prolactin- immune system and impaired erythropoiesis, the com- induced transcription of milk protein genes in mammary plete absence of mammary development during preg- epithelium. The respective protein had been coined nancy, to aberrant liver function. On a molecular level, Mammary Gland Factor (MGF), implying specificity to STAT5 has been linked to cell specification, prolifera- the physiology of mammary tissue. However, based on tion, differentiation, and survival. Evidence is growing its similarity to the family of Signal Transducers and that the diverse outcomes of STAT5 signaling are not Activators of Transcription (STAT), it was renamed ap- only determined by the expression of specific receptors propriately STAT5. In 1995, three groups independently but also by the interaction of STAT5 with cofactors and cloned the mouse homolog, now named STAT5A, and a the cell-specific activity of members of the SOCS family, closely related protein, called STAT5B (Azam et al. 1995; which negatively regulate STAT function. In this re- Liu et al. 1995; Mui et al. 1995). It turned out that both view, we focus on emerging concepts and challenges in STAT5A and STAT5B are widely expressed and acti- the field of Janus kinase (JAK)–STAT5 signaling. First, vated by a plethora of cytokines, including prolactin we discuss unique functions of STAT5 in three distinct (PRL), growth hormone (GH), erythropoietin, thrombo- systems: mammary epithelial cells, hepatocytes, and poietin, and several interleukins (ILs). Since the first regulatory T cells. Second, we present an example of how publication in 1997 in these pages of mice that carried STAT5 can achieve cell specificity in hepatocytes either an inactivated Stat5a (Liu et al. 1997) or Stat5b through a physical and functional interaction with the (Udy et al. 1997) gene, we have witnessed great advances glucocorticoid receptor. Third, we focus on the relevance in our understanding of how cytokines transmit their of STAT5 in the development and progression of leuke- message and control physiology and pathophysiology. mia. Next, we discuss lessons derived from human mu- However, we are still far from understanding how a lim- tations and disease. Finally, we address an emerging is- ited set of generic components can trigger specific events sue that the interpretation of experiments from STAT5- ranging from lactation to leukemia. deficient mice and cells might be compromised as these cells might reroute and reprogram cytokine signals to Background STAT5A and STAT5B are two closely related members [Keywords: Mammary epithelium; hepatocytes; immunoregulation; of the family of STAT proteins. STAT5A and STAT5B body growth; cytokine] are 96% conserved at the protein level. The two proteins 1Corresponding author. E-MAIL [email protected]; FAX (301) 480-7312. contain 793 and 786 amino acids, respectively, and the Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1643908. highest degree of divergence is found in the C-terminal GENES & DEVELOPMENT 22:711–721 © 2008 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/08; www.genesdev.org 711 Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Hennighausen and Robinson transactivation domain. STAT5A and STAT5B are en- diately downstream from the Stat5a gene. Although the coded by two genes located on chromosome 11 (in Stat5a and Stat5b gene promoters might share certain mouse) and chromosome 17 (in humans) in a locus that regulatory elements, cell-preferential transcriptional also contains the Stat3 gene. patterns have emerged (Liu et al. 1995). While STAT5A STATs are the mediators of signals that emanate from is the prevalent STAT5 protein in mammary tissue, cytokine receptors. Considered latent transcription fac- STAT5B is more abundant in muscle and liver. Other tors, they are activated upon binding of a ligand to the tissues, such as heart and salivary gland, have an equiva- receptor by phosphorylation of a critical tyrosine residue lent distribution of STAT5A and STAT5B. In 1997, mice through Janus kinases (JAK). Activated STATs bind to with disabling mutations in the genes encoding STAT5A specific DNA sequences, named GAS (␥-interferon-acti- (Liu et al. 1997) and STAT5B (Udy et al. 1997) were re- vated sequences), and initiate transcription of target ported. Mice lacking the individual genes were viable genes. In the cytokine signaling pathway there are a large and displayed distinct defects. Loss of STAT5A resulted number of ligands and receptors that funnel into a lim- in impaired mammary development and differentiation ited number of transcription factors. STAT5 is impli- during pregnancy. The absence of STAT5B led to stunted cated in a wide variety of signaling events foremost in body growth. These gene-specific defects either reflect the immune system, mammary epithelial cells, and he- the tissue distribution of STAT5A and STAT5B or tis- patocytes. sue-specific functions of the two proteins. In 1998, Te- glund and colleagues (Teglund et al. 1998) introduced mutations in both genes in mice revealing redundant and Molecular structure of STAT molecules nonredundant roles of both isoforms. However, immu- nological defects were not as severe as had been antici- All members of the STAT family share a highly con- pated from mutations in receptors that signal through served molecular structure. Structural studies of STAT1, the JAK–STAT5 pathway. As it turned out, the gene tar- the best understood member of the family, have revealed geting mutations resulted in translation of hypomorphic an N-terminal domain, followed by an ␣-helical coiled- N-terminally truncated STAT5A and STAT5B proteins coil and DNA-binding domain and a linker that connects ⌬ (referred to as STAT5 N) that were able to form dimers to the C terminus. The C terminus contains the src ho- but not tetramers. To overcome this potential problem, mology 2 (SH2) domain, followed by a short region con- mice were generated that carried the 110-kb Stat5a/b taining a tyrosine residue, which is critical for the acti- locus flanked by loxP sites (Cui et al. 2004). This per- vation by phosphorylation through JAKs and a transac- mitted Cre-recombinase-based complete deletion of both tivation domain, which is the most divergent part within genes. These mice have been used extensively to explore the STAT family. The molecule contains two flexible cytokine–STAT5 signaling in specific cell types. loops, one between the N terminus and the core frag- ment and a second loop connecting the C terminus to the core. These loops are thought to allow conforma- tional changes in the transition from the inactive to the Mammary epithelium activated state. The three-dimensional structure of an The importance of STAT5A in the mammary gland is unphosphorylated STAT5A core fragment (residues 129– reflected in its original assignment as MGF, a transcrip- 712) lacking 129 amino acids from the N terminus and tion factor that stimulates prolactin-induced expression the C-terminal transactivation domain revealed overall of mammary-specific milk protein genes (Fig. 1). How- similarity to other STAT molecules (Neculai et al. 2005). ever, gene deletion revealed a much more profound role The N-terminal coil-coil domain forms a four-helix in mammary epithelial cells. Deletion of STAT5A (Liu bundle followed by a ␤-barrel domain that connects to et al. 1997) caused an attenuation of mammary alveolar the ␣-helical linker and SH2 domain. The unphosphory- development and milk secretion, while absence of lated STAT5A forms anti-parallel dimers in the cyto- STAT5B (Udy et al. 1997) did not affect mammary de- plasm through hydrophobic interactions of the four-he- velopment. The introduction of mutations into both lix bundle and ␤-barrel domains. Activation of STAT5A STAT5 genes had a much stronger effect, demonstrating by tyrosine phosphorylation induces
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