Members of the signal transducer and activator of transcription ( STAT) protein family are intracellular transcription factors that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation. They are primarily activated by membrane receptor-associated (JAK). Dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis which enhances the survival of and immunosuppression. Gene knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.
STAT family
The first two STAT proteins were identified in the
interferon system. There are seven mammalian STAT family members that have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6.
STAT1 homodimers are involved in type II interferon signalling, and bind to the
GAS (Interferon-
Gamma
Activated
Sequence) promoter to induce expression of interferon stimulated genes (ISG). In type I interferon signaling, STAT1-STAT2 heterodimer combines with
IRF9 (
Interferon
Response
Factor) to form
ISGF3 (
Interferon
Stimulated
Gene
Factor), which binds to the
ISRE (
Interferon-
Stimulated
Response
Element) promoter to induce ISG expression.
Structure
All seven STAT proteins share a common structural motif consisting of an
N-terminal domain followed by a
coiled-coil, DNA-binding domain, linker, Src homology 2 (SH2), and a
C-terminal transactivation. Much research has focused on elucidating the roles each of these domains play in regulating different STAT isoforms. Both the N-terminal and SH2 domains mediate homo or heterodimer formation, while the coiled-coil domain functions partially as a nuclear localization signal (NLS). Transcriptional activity and DNA association are determined by the transactivation and DNA-binding domains, respectively.
Activation
Extracellular binding of
or
induce activation of receptor-associated
, which phosphorylate a specific tyrosine residue within the STAT protein promoting
protein dimer via their SH2 domains. The phosphorylated dimer is then actively transported to the nucleus via an
importin ternary complex. Originally, STAT proteins were described as
latent cytoplasmic transcription factors as phosphorylation was thought to be required for nuclear retention. However, unphosphorylated STAT proteins also shuttle between the cytosol and nucleus, and play a role in gene expression. Once STAT reaches the nucleus, it binds to a consensus DNA-recognition motif called gamma-activated sites (GAS) in the promoter region of
cytokine-
and activates transcription. The STAT protein can be dephosphorylated by nuclear
phosphatases, which leads to inactivation of STAT and subsequent transport out of the nucleus by an
exportin-RanGTP complex.
See also
==Additional images==
External links
