STAT3

Signal transducer and activator of transcription 3, also known as STAT3, is a is_associated_with::transcription factor which in humans is encoded by the STAT3 is_associated_with::gene.

Function
The protein encoded by this gene is a member of the is_associated_with::STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by receptor-associated kinases and then form homo- or heterodimers that translocate to the cell nucleus, where they act as is_associated_with::transcription activators. This protein is activated through phosphorylation of tyrosine 705, in response to various cytokines and growth factors including is_associated_with::interferons, is_associated_with::epidermal growth factor (EGF), Interleukin (IL-)5, IL-6, is_associated_with::hepatocyte growth factor (HGF), is_associated_with::leukemia inhibitory factor (LIF), is_associated_with::bone morphogenetic protein 2 (BMP-2), IL-10, and also the hormone is_associated_with::leptin. STAT3 mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. is_associated_with::PIAS3 protein is a specific inhibitor of this protein. Three alternatively spliced transcript variants encoding distinct isoforms have been described.

The binding of is_associated_with::Interleukin 6—family is_associated_with::cytokines (including IL-6, is_associated_with::oncostatin M and is_associated_with::leukemia inhibitory factor) to the gp130 receptor triggers STAT3 phosphorylation by is_associated_with::JAK2. is_associated_with::Epidermal growth factor receptor and certain other is_associated_with::receptor tyrosine kinases, such as is_associated_with::c-MET, phosphorylate STAT3 in response to their ligands. STAT3 is also a target of the c-src non-receptor tyrosine kinase. 12/15-Lipoxygenase derived is_associated_with::reactive oxygen species (ROS), have been shown to mediate the signal transduction between the is_associated_with::platelet-derived growth factor receptor (PDGF-R) and STAT3 activation in vascular smooth muscle cells.

STAT3-deficient mouse is_associated_with::embryos cannot develop beyond embryonic day 7, when gastrulation begins. It appears that at these early stages of development, STAT3 activation is required for self-renewal of is_associated_with::embryonic stem cells (ESCs). Indeed, LIF, which is supplied to murine ESC cultures to maintain their undifferentiated state, can be omitted if STAT3 is activated through some other means.

STAT3 is essential for the differentiation of the TH17 helper T cells, which have been implicated in a variety of is_associated_with::autoimmune diseases.

Clinical significance
Loss-of-function mutations in the STAT3 gene result in is_associated_with::Hyperimmunoglobulin E syndrome, associated with recurrent infections as well as disordered bone and tooth development.

Gain-of-function mutations in the STAT3 gene have been reported to cause multi-organ early onset auto-immune diseases; such as thyroid disease, diabetes, intestinal inflammation, and low blood counts.

Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. It has anti-apoptotic as well as proliferative effects.

Dual role in cancer
STAT3 can promote oncogenesis by being constitutively active through various pathways as mentioned elsewhere. Very recently a tumor suppressor role of STAT3 has also been reported. In the report on human glioblastoma tumor, or brain cancer, STAT3 was shown to have an oncogenic or a tumor suppressor role depending upon the mutational background of the tumor. A direct connection between the PTEN-Akt-FOXO axis (suppressive) and the leukemia inhibitory factor receptor beta (LIFRbeta)-STAT3 signaling pathway (oncogenic) was shown. In addition, two recent studies performed in APC mutant mice showed that STAT3 has an inhibiting role in colon carcinogenesis depending on tumor stage.

Interactions
STAT3 has been shown to interact with:


 * AR,
 * is_associated_with::ELP2,
 * is_associated_with::EP300,
 * EGFR,
 * is_associated_with::HIF1A,
 * JAK1,
 * JUN
 * is_associated_with::KHDRBS1,
 * MTOR,
 * MYOD1,
 * is_associated_with::NDUFA13,
 * is_associated_with::NFKB1,
 * NR3C1,
 * NCOA1,
 * PML,
 * is_associated_with::RAC1,
 * is_associated_with::RELA,
 * RET,
 * is_associated_with::RPA2,
 * is_associated_with::STAT1,
 * Src, and
 * is_associated_with::TRIP10.