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, 2 (4), e27080

STATs Get Their Move On


STATs Get Their Move On

Nancy C Reich. JAKSTAT.


Understanding the mechanisms that regulate dynamic localization of a protein within a cell can provide critical insight to its functional molecular interactions. Signal transducers and activators of transcription (STATs) play essential roles in development, proliferation, and immune defense. However the consequences of STAT hyperactivity can predispose to diseases including autoimmunity and cancer. To function as transcription factors STATs must gain access to the nucleus, and knowledge of the mechanisms that regulate STAT nuclear trafficking can provide a means to control STAT action. This review presents a synopsis of some of the studies that address the nuclear dynamics of the STAT proteins. Evidence suggests that not all STATs are the same. Nuclear import of STAT1 and STAT4 appears linked to their tyrosine phosphorylation and the formation of parallel dimers via reciprocal phosphotyrosine and Src homology 2 domain interactions. This dimer arrangement generates a conformational nuclear localization signal. STAT2 is imported continually to the nucleus in an unphosphorylated state due to its association with IRF9, but the dominant nuclear export signal of STAT2 shuttles the complex back to the cytoplasm. Following STAT2 tyrosine phosphorylation, it can form dimers with STAT1 to affect nuclear import as the trimeric complex (ISGF3). Distinctly, STAT3, STAT5, and STAT6 are continually imported to the nucleus independent of tyrosine phosphorylation. Mutational studies indicate the nuclear localization signals in these STATs require the conformational structure of their coiled-coil domains. Increases in STAT nuclear accumulation following cytokine stimulation appear coordinate with their ability to bind DNA.

Keywords: STAT; export; import; nuclear traffic; tyrosine phosphorylation.


Figure 1. Nuclear trafficking of STAT1 linked to tyrosine phosphorylation and DNA binding. Top: Linear diagram of STAT1 domains: coiled-coil (CC) domain, DNA-binding domain (DBD), Src homology domain 2 (SH2), and tyrosine 701 phosphorylated by Janus kinases (JAK) (pY). Bottom: U-STAT1 exists primarily as an anti-parallel dimer (bottom left). Blue image represents STAT1 with circle at N-terminus. Following tyrosine phosphorylation by Janus kinases (JAK), reciprocal pY and SH2 domain interactions between monomers generate parallel dimers (top left). STAT1 parallel dimers are recognized by importin-α5:importin-β1 and are imported to the nucleus. In the nucleus Ran-GTP binds importin-β1 and the complex releases STAT1 cargo (top right). STAT1 phosphorylated dimers bind DNA targets in responsive genes. Protein tyrosine phosphatases (PTPase) and PIAS proteins contribute to STAT1 dissociation from DNA, and the NES in the STAT1 DBD is recognized by the Crm1 exportin to effect nuclear export.
Figure 2. Nucleocytoplasmic transport of STAT2. Green image represents STAT2 with circle at N-terminus. U-STAT2 is bound to the IRF9 transcription factor and the complex is continually imported to the nucleus due to the constitutive NLS of IRF9 that is recognized by importin-α:importin-β1 (top left). In the nucleus, the Crm1-mediated NES in the carboxyl terminus of STAT2 effects dominant nuclear export of the complex (right). Following tyrosine phosphorylation by Janus kinases (JAK) in the cytoplasm, STAT2 dimerizes with tyrosine phosphorylated STAT1 to form the trimeric interferon stimulated gene factor 3 (ISGF3) that is imported to the nucleus and binds DNA (bottom left).
Figure 3. STAT5 nuclear import independent of tyrosine phosphorylation. Orange image represents STAT5 with circle at N-terminus. U-STAT5 forms an anti-parallel dimer (bottom left) and is recognized by importin-α3:importin-β1 for continuous import to the nucleus. The coiled-coil domain functions as an unconventional NLS both before and following tyrosine phosphorylation of STAT5 by Janus kinases (JAK) (top left). Nuclear export of STAT5 is mediated by both Crm1-dependent and Crm1-independent NESs (right).

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