Introduction

Signal transducer and activator of transcription 5B is a protein that belongs to the STAT family. A Gene duplication event of STAT5 gave rise to the highly related members STAT5A and STAT5B.

Members of the STAT family each have 5 domains:

The N-terminal domain which aids in the protein’s dimerization after activation by phosphorylation.
The “Coiled-Coil” domain acts as a dimerization tag and a nuclear localisation sequence (NLS).
A DNA binding domain.
An SH2 domain, docks STAT to phosphorylated tyrosine residue. Particularly on cytokine receptors in the JAK/STAT pathway.

The C-terminal transactivation domain aids with targeting gene expression. This region varies in the STAT family and activates different transcription factors.

Mechanism

The dimerization of cell-surface receptors is caused by the binding of a variety of ligands, such as cytokines (including interferons and interleukins). The receptor bound JAKs are then activated by transphosphorylation. The activated JAKs then phosphorylate a tyrosine residue on the receptor. This provides a binding site for the STAT5B SH2 domain (Jatiani et al., 2010). After STAT has been recruited onto the receptor, JAKs phosphorylates the STAT at Y699. This allows the STAT protein to separate from the receptor. Each STAT's SH2 domain binds to another phosphorylated tyrosine residue on the SH2 of the STAT5B protein forming a homodimer.

A heterodimer may be formed for other STAT family members. The STAT5B homodimer then translocates to the cell. It then induces transcription of target genes when it enters the nucleus (Schindler, Levy & Decker, 2007).

Associated Co-activators and Regulatory Proteins

Members of the STAT family are transcription factors that upregulate target gene transcription and, like many others, recruit co-activators such as CBP and p300.

These coactivators increase the accessibility of target genes to STAT5B and recruit necessary proteins required for gene transcription. The transactivation domains (TADs) of STATs mediate the relationship between STATs and coactivators (Schindler, Levy & Decker, 2007).

The JAK-STAT signalling pathway is part of the ALK pathway and is curtail for transcription and cytokine signalling so must be tightly regulated. Activated STAT5B protein inhibitors are one of three types of proteins:

1. Protein inhibitors of activated STAT (PIAS)

2. Protein tyrosine phosphatases (PTPs)

3. Suppressors of cytokine signalling (SOCS).

STAT5 in a Physiological Context

The JAK-STAT signalling can be inhibited in two ways by PIAS proteins (Shuai, 2006).

1. STATs can be blocked from phosphorylation and activation by PIAS adding a SUMO (small ubiquitin-like modifier) group marker, keeping STATs
out of the nucleus.

2. STATs can also be prevented from binding to DNA by PIAS.

Experiments in which the deletion of genes were done to determine the functions of the STAT5 gene. The deletion of both STAT5 and 5B resulted in mice that lost development in female fertility. For instance, they would be unable to lactate, and their corpus luteum could not develop. However, in the case where only STAT5B alone was deleted, the mice shared phenotypes similar with those observed in GHR deficient mice. They were observed to have reduced growth and lacked sexually dimorphic characteristics found in normal liver enzymes.

Although reports of mutation in humans are rare, these reports are characterized by growth retardation, IGF-I deficiency, and insensitivity to GH. The first reported case of STAT5B mutation in humans were found in 2003. The homozygous mutation in the 16-year-old female was found as a critical substitution mutation in the SH2 domain, disrupting the anti-parallel β-sheets that provides a pocket for binding against phosphotyrosine residues.

The STAT5 gene is also implicated in the proper functioning of T-cell receptor activation. More specifically, the Lck kinase which phosphorylates the T-cell receptor adaptor proteins/ complex CD3 that is anchored to co-receptors CD4/ CD8.

Deletion of one of the STAT5 genes lead to partial defects in T-cells, while deletion of both genes leads to more substantial T-cell proliferation defects. This suggests that STAT5A/5B play redundant roles in this context.

The modulation of transcription of genes that encode proteins that inhibit or cause cell death, such as the Bcl-2 family members or caspases, is triggered by STAT5.

STAT5B regulates transcription of proteins that are involved in regulation of cell death, for instance Bcl-2 and caspases. STAT5B cooperates with Ras and PI3-Kinase to regulate their transcription. Persistent STAT5(B) activation has been related to several human cancers, including leukaemia, breast and prostate. (Debierre-Grockiego, 2004).

References

Aaronson, D.S. & Horvath, C.M. (2002) A road map for those who don’t know JAK-STAT. Science. 296 (5573), 1653–1655.

Debierre-Grockiego, F. (2004) Anti-apoptotic role of STAT5 in haematopoietic cells and in the pathogenesis of malignancies.

Jatiani, S.S., Baker, S.J., Silverman, L.R. & Premkumar Reddy, E. (2010) JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: Approaches for targeted therapies. Genes and Cancer. [Online]. 1 (10) pp.979–993. Available from: doi:10.1177/1947601910397187.

Schindler, C., Levy, D.E. & Decker, T. (2007) JAK-STAT signaling: From interferons to cytokines. Journal of Biological Chemistry. [Online]. 282 (28) pp.20059–20063. Available from: doi:10.1074/jbc.R700016200.

Shuai, K. (2006) Regulation of cytokine signaling pathways by PIAS proteins. In: Cell Research. [Online]. February 2006 pp. 196–202. Available from: doi:10.1038/sj.cr.7310027.