STATs interferon

PC3 Prostate Invasive (EMT) phenotype developed STAT/interferon, P13-kinase, AKT, and integrin signaling PI3-kinase inhibitors blocked invasive cell growth more effectively in 3-D (30)... 

Cytokine receptors are a group of structurally related receptors, which couple to the JAK-STAT pathway. Cytokine receptors function as homodimers or heterooligomers. They are divided into two main subclasses, class I, which contains receptors for a variety of hematopoietic growth factors and interleukins and class II, which contains receptors for interferons and interleukins 10, 20/24 and 22. 

In mammalia, seven different members encoded by distinct genes have been identified, all of which are activated by a distinct set of cytokines. Diversity in signaling is provided by variants of STAT proteins derived from either alternative splicing of RNA transcripts or proteolytic processing (e.g., STATs 1,3,4, and 5) and the ability of certain STATs to form both homodimers and heterodimers with each other. In response to inteiferon-y monomeric STAT1 dimerizes, while upon interferon-a stimulation a heterotrimeric complex consisting of STAT 1 and STAT2 with associated... 

Originally discovered as DNA-binding proteins that mediate interferon signaling, recent data demonstrated that STAT1 can also exert constitutive functions in the nucleus, which do not require STAT activation with tyrosine phosphorylation. Cells lacking STAT1 are... 

Cytokine receptors that couple to the JAK-STAT Pathway decode the signaling though hematopoietic cytokines (erythropoietin, thrombopoietin, colony-stimulating factors), prolactin, growth hormone, the a-, (3- and y- interferons, and a number of immunomodulatory interleukins [3], They form homodimetic or heterodimeric receptor complexes, which after ligandbinding recruit and activate isotypes of Janus kinases (JAKs). Activated JAKs in turn... 

Chang YE et al. Microarray analysis identifies interferon-inducible genes and Stat-1 as major transcriptional targets of human papillomavims type 31. J Virol 2000 74 4174-4182. 

The intracellular events triggered upon binding of type I or II interferons to their respective receptors are quite similar. The sequence of events, known as the JAK-STAT pathway, has been elucidated over the last few years. It has quickly become apparent that this pathway plays a prominent role in mediating signal transduction, not only for interferon, but also of many cytokines. 

Not surprisingly different ligands activate different members of the STAT family (Table 8.6). Some, such as STATs 1 and 3, are activated by many ligands, whereas others respond to far fewer ligands, e.g. STAT2 appears to be activated only by type I interferons. 

The molecular basis by which interferons promote their characteristic effects, in particular antiviral activity, is understood at least in part. Interferon stimulation of the JAK-STAT pathway induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral replication. These antiviral gene products are generally enzymes, the most important of which are 2 -5 oligoadenylate synthetase (2,5-A synthetase) and the eIF-2a protein kinase. 

Lau, F. and Horvath, C. 2002. Mechanisms of type I interferon cell signalling and STAT-mediated transcriptional responses. Mount Sinai Journal of Medicine 69(3), 156-168. 

Binding of type I interferons to the IFN-a/ S (type I) receptor results in the phosphorylation and hence activation of two members of the JAK family Tyk2 and JAK 1. These kinases then phosphorylate STAT la (also called STAT 91), STAT (STAT 84) and STAT 2 (STAT 113). 

The three activated STATs disengage from the receptor and bind to the cytoplasmic protein, p48. This entire complex translocates to the nucleus, where it interacts directly with upstream regulatory regions of IFN-sensitive genes. These nucleotide sequences are termed interferon-stimulated response elements (ISREs). This induces/augments expression of specific genes, as discussed later. 

A. Oseltamivir inhibits neuraminidase, an enzyme that cleaves neuraminic acid from oligosaccharides. Neuraminidase activity aids the movement of viral particles through neuraminic acid-rich respiratory secretions and is required for the release of progeny virions. Inhibition of viral DNA polymerase is the mechanism of action of nucleoside analogue antiviral drugs. Interferons do stimulate the JAK-STAT signaling pathway but do not stimulate proliferation of immune cells. Ribavirin inhibits GTP synthesis, and the antiretroviral protease inhibitors (e.g., ritonavir) inhibit HIV protease. 

The receptors for cytokines and interferons are the starting point for signal transduction chains that bring about an activation of transcription factors. The signaling pathway involves the Janus protein kinase and Stat transcription factors (see 11.1.4). Phosphoty-rosine-SH2 interactions are also involved in several steps of signal transduction here. 

Starting from the activated Jak kinases, a signaling pathway leads directly to transcription factors that are phosphorylated by the Jak kinases on tyrosine residues and activated for stimulation of transcription (review Horvath and Darnell, 1997). These transcription factors belong to a class of proteins known as Stat proteins (Stat = signal transducer and activator of transcription). At least seven different Stat proteins are known (Statl-4, StatSa, StatSb, Stat6). The first Stat proteins, Statl and Stat2, were foimd in association with signal transduction via interferon y. 

The Jak-Stat pathway for the interferons a, P and y has been well investigated. The interferon y pathway uses Statl protein, which binds as a homodimer to the correspon-... 

Fig. 11.8. Scheme of signal transduction via interferon a. The receptor for interferon a (IFNa) binds and activates the Jak kinases Jakl and Tykl. These phosphorylate the Stat factors Statl and Stat2, leading to formation of Statl-Stat2 heterodimers. The heterodimers are transported into the nucleus and bind to a corresponding DNA element known as ISRE (interferon stimulated response element). Another protein, p48, is also involved in transcription activation of the interferon regulated gene. 

Ulloa, L., Doody, J. and Massague, J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway (1999) Nature 397, 710-713... 

David, M., E. Petricoin, 3rd, C. Benjamin, R. Pine, M.J. Weber, and A.C. Lamer, Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science, 1995. 269(5231) 1721-3. 

The leptin signal is transduced by a mechanism also used by receptors for interferon and growth factors, the JAIC-STAT system (Fig. 23-34 see Fig. 12-9). The leptin receptor, which has a single transmembrane segment, dimerizes when leptin binds to the extracellular domain of two monomers. Both monomers are phos-phorylated on a Tyr residue of the intracellular domain by a Janus kinase (JAK). The -Tyr residues become docking sites for three proteins that are signal transducers and activators of transcription (STATs 3, 5, and 6, sometimes called fat-STATS). The docked STATs are then phosphorylated on Tyr residues by the... 

Ransohoff RM. 1998. Cellular responses to interferons and other cytokines The JAK-STAT paradigm. NEJM. 338 616-168. 

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