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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
Domain structure of STAT1. The residue count is given below the diagram. Dimerization can occur via SH2 domain interactions after phosphorylation of Tyr701. TAD, transcription activation domain.
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fig1: Domain structure of STAT1. The residue count is given below the diagram. Dimerization can occur via SH2 domain interactions after phosphorylation of Tyr701. TAD, transcription activation domain.

Mentions: The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, first identified in the interferon systems, are responsive to a wide range of cytokines and growth factors (Levy and Darnell, 2002). The STAT proteins receive cytokine signals at intracellular receptor chains in the cytoplasm and carry them into the nucleus, where they then act as transcription factors (Levy and Darnell, 2002). Thus, these proteins need to cross the nuclear envelope to functionally link the cell membrane with the promoters of cytokine-responsive genes. Movement of STATs in either compartment is diffusion-controlled and not directed along permanent structures (Lillemeier et al., 2001). Yet, passage through the nuclear gateways, named nuclear pore complexes (NPCs), provides a formidable diffusion barrier to proteins the size of STATs (>85 kD for the monomer; Fig. 1), as only ions and small molecules not exceeding 40 kD can freely enter the cell nucleus (Suntharalingam and Wente, 2003). The analysis of their nucleocytoplasmic translocation has to consider that the STAT proteins exist in two different states in terms of signaling: before the stimulation of cells with cytokines the STAT molecule exists in a nontyrosine phosphorylated state, the oligomerization status of which is still debated (Sehgal, 2000). Stimulation with cytokines increases the activity of receptor-associated JAK kinases and leads to the formation of tyrosine-phosphorylated STATs, which instantly assemble into homo- or heterodimers via canonical phosphotyrosine-SH2 domain interactions (Shuai et al., 1994; Greenlund et al., 1995). Tyrosine phosphorylation is often described as STAT activation since only the dimer is a high affinity DNA-binding protein required for the induction of cytokine-responsive genes (Shuai et al., 1994). This is achieved by directly targeting cognate recognition elements named gamma activated sites (GAS) (Horvath et al., 1995).


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

Vinkemeier U - J. Cell Biol. (2004)

Domain structure of STAT1. The residue count is given below the diagram. Dimerization can occur via SH2 domain interactions after phosphorylation of Tyr701. TAD, transcription activation domain.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Domain structure of STAT1. The residue count is given below the diagram. Dimerization can occur via SH2 domain interactions after phosphorylation of Tyr701. TAD, transcription activation domain.
Mentions: The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, first identified in the interferon systems, are responsive to a wide range of cytokines and growth factors (Levy and Darnell, 2002). The STAT proteins receive cytokine signals at intracellular receptor chains in the cytoplasm and carry them into the nucleus, where they then act as transcription factors (Levy and Darnell, 2002). Thus, these proteins need to cross the nuclear envelope to functionally link the cell membrane with the promoters of cytokine-responsive genes. Movement of STATs in either compartment is diffusion-controlled and not directed along permanent structures (Lillemeier et al., 2001). Yet, passage through the nuclear gateways, named nuclear pore complexes (NPCs), provides a formidable diffusion barrier to proteins the size of STATs (>85 kD for the monomer; Fig. 1), as only ions and small molecules not exceeding 40 kD can freely enter the cell nucleus (Suntharalingam and Wente, 2003). The analysis of their nucleocytoplasmic translocation has to consider that the STAT proteins exist in two different states in terms of signaling: before the stimulation of cells with cytokines the STAT molecule exists in a nontyrosine phosphorylated state, the oligomerization status of which is still debated (Sehgal, 2000). Stimulation with cytokines increases the activity of receptor-associated JAK kinases and leads to the formation of tyrosine-phosphorylated STATs, which instantly assemble into homo- or heterodimers via canonical phosphotyrosine-SH2 domain interactions (Shuai et al., 1994; Greenlund et al., 1995). Tyrosine phosphorylation is often described as STAT activation since only the dimer is a high affinity DNA-binding protein required for the induction of cytokine-responsive genes (Shuai et al., 1994). This is achieved by directly targeting cognate recognition elements named gamma activated sites (GAS) (Horvath et al., 1995).

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