STAT5

STAT5 was originally discovered in mammary gland cells. Hence its first name: "mammary gland factor" (MGF).

STATs (Signal Transducers and Activators of Transcription) are key components of the JAK/STAT pathway. Of the seven STATs, STAT5A and STAT5B are of central importance due to their important roles in cellular differentiation, adipogenesis, oncogenesis and immune function. Evidence suggests that STAT5A is clustered in breast tissue. In contrast, STAT5B expression is stronger in muscle and liver (Bachmann J et al. 2011).

STAT5 refers to two proteins: STAT5A and STAT5B, which share 94% structural homology but are transcribed by separate genes. STAT5A and STAT5B have molecular weights of 94 and 92 kD, respectively. The most significant difference between STAT5A and STAT5B is 20 amino acids in the transactivation domain (TAD) of STAT5A. Both STAT5A and STAT5B are activated by phosphorylation at Tyr694 and Tyr699, respectively, by JAK2, which in turn is activated by the binding of numerous cytokines and hormones such as growth hormone (GH), erythropoietin (EPO), prolactin (PRL), and various interleukins (ILs) to their receptors (Hennighausen L et al. 2008). JAK2 and STAT5 are important for IL-3 and GM-CSF (granulocyte macrophage colony-stimulating factor)-regulated macrophage function .

STATs STAT5A and STA5B have both redundant and non-redundant functions that include modulation of cell differentiation, lipid mobilization, lymphocyte development, and oncogenesis. The diverse spectrum of STAT5 functions is consistent with the cell-specific functions of STAT5 proteins.

STATs are the primary substrates for JAKs (Janus kinases). There are seven STAT proteins: STAT 1, 2, 3, 4, 5A, 5B and 6. They all consist of a helical N-terminal domain (ND), a coiled-coil domain (CC), a DNA-binding domain (DBD), a helical linker (LK), a Src homology 2 domain (SH2) and a transactivation domain (TAD) located in the C-terminal region (Szelag M et al. 2016). The SH2 domain is essential for the recruitment of STAT proteins to the hormone/cytokine receptor.

The pathway consists of receptor-associated Janus kinases (JAKs), signal transducers and activators of transcription (STATs), and a cytokine or hormone receptor that binds the respective ligand (Mullen M et al. 2016). The JAK-STAT pathway transduces extracellular signals into the nucleus and regulates a variety of cellular activities including apoptosis, differentiation, proliferation and immunological responses.

STAT5A and STAT5B interact with cytokine/hormone receptors, nuclear receptors, transcriptional regulators, proto-oncogenes, kinases and phosphatases. Among these STAT5-interacting proteins, some serve as coactivators others as corepressors to regulate STAT5 transcriptional activity (Rawlings JS et al 2004).

Activators include signal transducing adaptor molecules (STAMs) and proteins containing SH2 domains ((Rawlings JS et al. 2004). Inhibitors include suppressors of cytokine signaling (SOCS) and tyrosine phosphatases (Greenhalgh CJ et al (2001).

Under basal conditions, STATs are inactive in the cytosol. Once recruited to the activated JAK/receptor complex and tyrosine phosphorylated within the SH2 domain by JAKs, they form dimers and/or tetramers, translocate to the nucleus and associate with promoter regions such as gamma activated sequence (GAS) elements. The binding affinity of individual STATs to specific sites varies (Szelag M et al. 2016). The interaction of STATs with gene promoters can inhibit or enhance the expression of their target genes.

STAT5 properties and functions: In mammals, STAT5 proteins have been associated with many functions, including cell differentiation, lipid mobilization, and lymphocyte development (Kaltenecker D et al. 2017; Heltemes-Harris LM et al. 2012). Furthermore, STAT5A plays an important role in adipocyte development.

STAT5 regulates the expression of β-casein, a milk protein. Hormones that activate STAT5 mediate their biological effects via receptors that associate with STAT5 proteins. These include prolactin receptor (PRL), growth hormone receptor (GHR), IL-3R (interleukin-3 receptor), and EPOR (erythropoietin receptor).

STAT5 interacts with activating proteins involved in the general transcription factor machinery. These include CBP (CREB-binding protein) and p300, both nuclear coactivators that exhibit histone acetyltransferase activity (Pfitzner E et al (1998). Furthermore, STAT5 interacts with SRC-1 (steroid receptor coactivator 1), a nuclear coactivator and NcoA-1.

Proteins that repress the transcriptional activity of STAT5 include SMRT (silencing mediator for retinoic acid receptor and thyroid hormone receptor), a corepressor for several members of the nuclear receptor family. SMRT interacts with both STAT5A and STAT5B (Nakajima H et al. (2001). Furthermore, SHD1 (Sac3 domain-containing protein), a protein (Sefat-E-Khuda et al. 2004) that binds to either the SH2 domain or the coiled-coil domainof STAT5 (Sefat-E-Khuda et al. 2004). SOCS proteins can bind directly to tyrosine kinases to deactivate them, but can also block cytokine receptor docking sites to inhibit activation of STATs in the JAK/STAT pathway (Banks AS et al. 2005).

Association of STAT5 with members of the nuclear receptor family:

PR (progesterone receptor) is a nuclear receptor that plays a critical role in mammary gland growth and differentiation. PR physically interacts with STAT5A in the nucleus of HeLa cells, C4 HI tumors and T47D cells.

GR (glucocorticoid receptor) is a steroid receptor found in all cell types that mediates the effects of cortisol and other glucocorticoids and has cell-specific functions. After ligand binding, GR dimerizes and translocates to the nucleus. GR has been shown to physically interact with both STAT5A and STAT5B in a variety of cell types including mammary gland cells, hepatocytes, pancreatic acinar cells, hippocampal cells, tumor cells, immune cells, and adipocytes (Engblom D et al. 2007).

EZH2 (enhancer of zeste homolog 2) is a histone lysine N-methyltransferase enzyme involved in DNA methylation and plays an important role in the regulation of transcription . STAT5 was shown to physically interact with EZH2 in HCT116 human colon cancer cells by co-immunoprecipitation experiments .

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