Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B

Abstract

Transcription factors from the family of Signal Transducers and Activators of Transcription (STAT) are activated by numerous cytokines. Two members of this family, STAT5A and STAT5B (collectively called STAT5), have gained prominence in that they are activated by a wide variety of cytokines such as interleukins, erythropoietin, growth hormone, and prolactin. Furthermore, constitutive STAT5 activation is observed in the majority of leukemias and many solid tumors. Inactivation studies in mice as well as human mutations have provided insight into many of STAT5's functions. Disruption of cytokine signaling through STAT5 results in a variety of cell-specific effects, ranging from a defective immune system and impaired erythropoiesis, the complete absence of mammary development during pregnancy, to aberrant liver function. On a molecular level, STAT5 has been linked to cell specification, proliferation, differentiation, and survival. Evidence is growing that the diverse outcomes of STAT5 signaling are not only determined by the expression of specific receptors but also by the interaction of STAT5 with cofactors and the cell-specific activity of members of the SOCS family, which negatively regulate STAT function. In this review, we focus on emerging concepts and challenges in the field of Janus kinase (JAK)-STAT5 signaling. First, we discuss unique functions of STAT5 in three distinct systems: mammary epithelial cells, hepatocytes, and regulatory T cells. Second, we present an example of how STAT5 can achieve cell specificity in hepatocytes through a physical and functional interaction with the glucocorticoid receptor. Third, we focus on the relevance of STAT5 in the development and progression of leukemia. Next, we discuss lessons derived from human mutations and disease. Finally, we address an emerging issue that the interpretation of experiments from STAT5-deficient mice and cells might be compromised as these cells might reroute and reprogram cytokine signals to the "wrong" STATs and thus acquire inappropriate cues. We propose that mice with mutations in various components of the JAK-STAT signaling pathway are living laboratories, which will provide insight into the versatility of signaling hardware and the adaptability of the software.

Figure 1.

Regulation of STAT signaling in mammary epithelial cells. Binding of prolactin (PRL) and placental lactogen (PL) to the PRLR or neuregulin1/neuregulin2 (NRG1/2) to ERBB4 activates the receptor-associated JAK kinase and induces the phosphorylation of STAT5A and STAT5B. Upon phosphorylation, STAT5 dimers translocate to the nucleus, where they bind to GAS elements and induce transcription of the genes encoding ELF5, SOCS1, SOCS2, and milk proteins. SOCS1/2 are recruited to the receptor and attenuate STAT5 signaling. Membrane-associated caveolin-1 modulates STAT5 activation by regulating JAK2 accessibility. The phosphatase SHP-2 regulates STAT5 phosphorylation by binding to the receptor and STAT5. ETS5 is a transcription factor in its own right that activates additional genes required for normal mammary function.

Figure 2.

Interaction of GHR and GR signaling through STAT5 in hepatocytes. STAT5B is activated upon binding of GH to its receptor by the associated JAK2. Tyrosine-phosphorylated STAT5B dimers bind to GAS and induce transcription of the negative regulators SOCS2 and SOCS3. SOCS2 and SOCS3 modulate signaling from the GHR and gp-130 receptors, respectively. Transcription of IFG-1 and metabolic genes is induced through additional signals from the GR and depends on the direct interaction of GR and STAT5B tetramers. (G) Glucocorticoid; (gp) glycoprotein.

Figure 3.

STAT5 signaling in Treg cells. In regulatory T cells, STAT5 is phosphorylated by JAK3 upon binding of IL-2 and IL-15 to their respective receptors. STAT5 induces the expression of the IR-2Rα chain and Foxp3 genes.

Figure 4.

(A) Specificity of cytokine–STAT signaling. Cell-specific cytokine signals result, at least in part, from the receptors that are expressed on a cell and the ligands it encounters. Each ligand binds to its cognate receptor and activates a specific STAT molecule, which then induces a particular set of target genes. Some of the target genes encode SOCS proteins, which exert a negative feedback regulation on the signals from the receptors. (B) Altered STAT signaling networks upon deletion of one family member. If one of the STAT family members is missing, inappropriate activation through binding of other family members to the receptor sites previously occupied by the original member may occur. This will induce a different set of target genes. In addition, reduced expression of SOCS proteins will lead to enhanced activation of signals from other receptors and contribute to a change in the cell’s response. In the case of a loss of STAT5, both GH and PRL are able to activate STAT1 and STAT3, which results in the induction of respective target genes. Loss of STAT5 also results in reduced expression of its prominent target genes Socs2 and Socs3 and, as a consequence, the impaired negative feedback loops will further enhance STAT3 activation.