Nucleocytoplasmic Shuttling of STATs. A Target for Intervention?

Abstract

Signal transducer and activator of transcription (STAT) proteins are transcription factors that in the latent state are located predominantly in the cytoplasm. Activation of STATs through phosphorylation of a single tyrosine residue results in nuclear translocation. The requirement of tyrosine phosphorylation for nuclear accumulation is shared by all STAT family members but mechanisms of nuclear translocation vary between different STATs. These differences offer opportunities for specific intervention. To achieve this, the molecular mechanisms of nucleocytoplasmic shuttling of STATs need to be understood in more detail. In this review we will give an overview on the various aspects of nucleocytoplasmic shuttling of latent and activated STATs with a special focus on STAT3 and STAT5. Potential targets for cancer treatment will be identified and discussed.

Keywords: STAT3; STAT5; cancer; nuclear pore complex; nuclear transport receptors; nucleocytoplasmic shuttling; targeting.

Figure 1

Structures of STAT proteins with putative nuclear localization signals (NLS) and nuclear export signals (NES) highlighted as listed in Table 1. In this context, “putative” means that the corresponding sequences do not fulfill classical NLS or NES functions but are required for nuclear transport or interaction with nuclear transport receptors. (a) General scheme of structural domains of STAT proteins (NTD, N-terminal domain; CCD coiled-coil domain; DBD, DNA-binding domain; LD, linker domain; SD, SH2 domain; TAD, transactivation domain). Numbers refer to amino acid positions. (b–d) Structures of individual STAT proteins as ribbon representations (left) or space-filling representations (middle and right). Domains are stained according to the coloring of the scheme in (a), DNA is shown in pink. Putative NLS and NES are marked in red and cyan, respectively. The corresponding references are listed in Table 1. PDB IDs: STAT1, 1BF5; STAT3, 1BG1; STAT5A, 1Y1U. Images of structures were generated with PyMOL.