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Getting the message across, STAT! Design principles of a molecular signaling circuit.

Vinkemeier U - J. Cell Biol. (2004)

Bottom Line: The STAT transcription factors, usually referred to as "latent cytoplasmic proteins," have experienced a fundamental reevaluation of their dynamic properties.This review focuses on recent studies that have identified continuous transport factor-independent nucleocytoplasmic cycling of STAT1, STAT3, and STAT5 as a basic principle of cytokine signaling.In addition, molecular mechanisms that modulate flux rates or cause retention were recognized, and together these findings have provided novel insight into the rules of cellular signal processing.

View Article: PubMed Central - PubMed

Affiliation: Abteilung Zelluläre Signalverarbeitung, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Freie Universität Berlin, 13125 Berlin, Germany. vinkemeier@fmp-berlin.de

ABSTRACT
The STAT transcription factors, usually referred to as "latent cytoplasmic proteins," have experienced a fundamental reevaluation of their dynamic properties. This review focuses on recent studies that have identified continuous transport factor-independent nucleocytoplasmic cycling of STAT1, STAT3, and STAT5 as a basic principle of cytokine signaling. In addition, molecular mechanisms that modulate flux rates or cause retention were recognized, and together these findings have provided novel insight into the rules of cellular signal processing.

Show MeSH
Schematic representation of STAT1 nucleocytoplasmic cycling in resting cells (A) and during interferon stimulation (B). Carrier-independent cycling is depicted with blue arrows, carrier-dependent translocation with yellow arrows. Imperatives for carrier-dependent transport are indicated in red; the red bar represents the export block of phosphorylated STAT dimers. Phosphorylation and dimerization are indicated (+P). The reverse reaction, which is under control of the DNA off-rate, is also indicated (−P). Arrow widths are proportionate to their corresponding flux rates.
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fig2: Schematic representation of STAT1 nucleocytoplasmic cycling in resting cells (A) and during interferon stimulation (B). Carrier-independent cycling is depicted with blue arrows, carrier-dependent translocation with yellow arrows. Imperatives for carrier-dependent transport are indicated in red; the red bar represents the export block of phosphorylated STAT dimers. Phosphorylation and dimerization are indicated (+P). The reverse reaction, which is under control of the DNA off-rate, is also indicated (−P). Arrow widths are proportionate to their corresponding flux rates.

Mentions: The recognition that cytoplasmic and nuclear pools of STAT proteins exchange rapidly and quantitatively even before their activation is in stark contrast to conventional textbook knowledge, where unphosphorylated STATs usually are described as exclusively cytoplasmic proteins. It has become clear, though, that only the unphosphorylated STAT molecule is endowed with both nuclear import and export capability (Fig. 2 A, blue arrows; Marg et al., 2004). Although unphosphorylated STATs were reported in the cell nucleus before stimulation (Chatterjee-Kishore et al., 2000; Meyer et al., 2002b), the highly dynamic behavior of STATs in resting cells was uncovered only recently. The intracellular precipitation of STAT1 after the microinjection of specific antibodies in conjunction with the microinjection of recombinant STATs was used to assess the flux rates in living cells. These experiments were complemented by permeabilized cell assays and together these approaches lead to the discovery that unphosphorylated STAT1, STAT3, and STAT5 are constantly shuttling between the cytosol and the nucleus via a mechanism that does not require metabolic energy or transport factors (Meyer et al., 2002a; Marg et al., 2004).


Getting the message across, STAT! Design principles of a molecular signaling circuit.

Vinkemeier U - J. Cell Biol. (2004)

Schematic representation of STAT1 nucleocytoplasmic cycling in resting cells (A) and during interferon stimulation (B). Carrier-independent cycling is depicted with blue arrows, carrier-dependent translocation with yellow arrows. Imperatives for carrier-dependent transport are indicated in red; the red bar represents the export block of phosphorylated STAT dimers. Phosphorylation and dimerization are indicated (+P). The reverse reaction, which is under control of the DNA off-rate, is also indicated (−P). Arrow widths are proportionate to their corresponding flux rates.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172545&req=5

fig2: Schematic representation of STAT1 nucleocytoplasmic cycling in resting cells (A) and during interferon stimulation (B). Carrier-independent cycling is depicted with blue arrows, carrier-dependent translocation with yellow arrows. Imperatives for carrier-dependent transport are indicated in red; the red bar represents the export block of phosphorylated STAT dimers. Phosphorylation and dimerization are indicated (+P). The reverse reaction, which is under control of the DNA off-rate, is also indicated (−P). Arrow widths are proportionate to their corresponding flux rates.
Mentions: The recognition that cytoplasmic and nuclear pools of STAT proteins exchange rapidly and quantitatively even before their activation is in stark contrast to conventional textbook knowledge, where unphosphorylated STATs usually are described as exclusively cytoplasmic proteins. It has become clear, though, that only the unphosphorylated STAT molecule is endowed with both nuclear import and export capability (Fig. 2 A, blue arrows; Marg et al., 2004). Although unphosphorylated STATs were reported in the cell nucleus before stimulation (Chatterjee-Kishore et al., 2000; Meyer et al., 2002b), the highly dynamic behavior of STATs in resting cells was uncovered only recently. The intracellular precipitation of STAT1 after the microinjection of specific antibodies in conjunction with the microinjection of recombinant STATs was used to assess the flux rates in living cells. These experiments were complemented by permeabilized cell assays and together these approaches lead to the discovery that unphosphorylated STAT1, STAT3, and STAT5 are constantly shuttling between the cytosol and the nucleus via a mechanism that does not require metabolic energy or transport factors (Meyer et al., 2002a; Marg et al., 2004).

Bottom Line: The STAT transcription factors, usually referred to as "latent cytoplasmic proteins," have experienced a fundamental reevaluation of their dynamic properties.This review focuses on recent studies that have identified continuous transport factor-independent nucleocytoplasmic cycling of STAT1, STAT3, and STAT5 as a basic principle of cytokine signaling.In addition, molecular mechanisms that modulate flux rates or cause retention were recognized, and together these findings have provided novel insight into the rules of cellular signal processing.

View Article: PubMed Central - PubMed

Affiliation: Abteilung Zelluläre Signalverarbeitung, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Freie Universität Berlin, 13125 Berlin, Germany. vinkemeier@fmp-berlin.de

ABSTRACT
The STAT transcription factors, usually referred to as "latent cytoplasmic proteins," have experienced a fundamental reevaluation of their dynamic properties. This review focuses on recent studies that have identified continuous transport factor-independent nucleocytoplasmic cycling of STAT1, STAT3, and STAT5 as a basic principle of cytokine signaling. In addition, molecular mechanisms that modulate flux rates or cause retention were recognized, and together these findings have provided novel insight into the rules of cellular signal processing.

Show MeSH