STAT-signalling through the cytoplasmic compartment: consideration of a new paradigm.
The binding of a large number of cytokines and growth factors to their cognate receptors on the surface of mammalian-cell plasma membrane activates a signalling cascade involving the cytoplasmic STAT-family proteins, which is characterized by the nuclear translocation of a cytokine- or growth factor-specific subset of the cytoplasmic pool of the respective tyrosine- and serine-phosphorylated STAT proteins and the consequent transcriptional activation of specific target genes. In the standard model of cytokine-induced STAT signalling such as that elicited by various interferons and interleukins, it is thought that STAT proteins are recruited to the cytoplasmic side of the cell-surface receptor complex from within a monomeric cytosolic pool, and upon tyrosine-phosphorylation by respective Janus kinase family members, dimerize and translocate to the nucleus. The mechanisms which determine and regulate the recruitment of cytosolic STAT proteins to the plasma membrane-receptor complex, the transit of "activated" STATs through the expanse of the cytoplasmic compartment from the plasma membrane to the nuclear pore region, and the transit of STATs through the nuclear pore complex into the nuclear compartment, remain largely unknown. New data from different laboratories suggests consideration of a model for STAT signalling in which STAT proteins function in the cytoplasm not only as free monomers and dimers but as part of heteromeric complexes ("statosomes"), with accessory proteins which may serve to present specific STATs to the plasma membrane-receptor complex, and to chaperone "activated" STATs through the cytoplasmic compartment toward the nucleus and then into the nuclear compartment.
Sehgal
P B
PB
Departments of Cell Biology & Anatomy, and Department of Medicine, Room 201 Basic Science Building, New York Medical College, Valhalla, NY 10595, USA. pravin_sehgal@nymc.edu
D000818:Animals; D016207:Cytokines / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances; D008954:Models, Biological; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
D016207:Cytokines; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators