STAT protein
Encyclopedia
The STAT protein regulates many aspects of growth, survival and differentiation in cells. The transcription factor
s of this family are activated by Janus kinase
(JAK) and dysregulation of this pathway is frequently observed in primary tumours and leads to increased angiogenesis
, enhanced survival of tumours 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 tumour surveillance.
, 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 ISG (Interferon Stimulated Genes). 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.
for nuclear retention. The unphosphorylated STAT proteins shuttles between cytosol and the nucleus waiting for its activation signal. Once the activated transcription factors reaches the nucleus it binds to consensus DNA-recognition motif called gamma activated sites (GAS) in the promoter region of cytokine
inducible genes and activates transcription of these genes.
s induces activation of the intracellular Janus kinase
that phosphorylates a specific tyrosine residue in the STAT protein which promotes the dimerization
of STAT monomers via their SH2 domain
. The phosphorylated dimer is then actively transported in the nucleus via importin a/b
and RanGDP complex. Once inside the nucleus the active STAT dimer binds to cytokine inducible promoter regions of genes containing gamma activated site (GAS) motif and activate transcription
of these genes. The STAT protein can be dephosphorylated by nuclear phosphatases which leads to inactivation of STAT and the transcription factor becomes transported out of the nucleus by exportin crm1/RanGTP.
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s of this family are activated by Janus kinase
Janus kinase
Janus kinase is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 , but were ultimately published as "Janus kinase"...
(JAK) and dysregulation of this pathway is frequently observed in primary tumours and leads to increased angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, enhanced survival of tumours and immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
. Gene knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
studies have provided evidence that STAT proteins are involved in the development and function of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
and play a role in maintaining immune tolerance
Immune tolerance
Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
and tumour surveillance.
STAT family
The first two STAT proteins were identified in the interferon system. There are seven mammalian STAT family members which have been identified: STAT1STAT1
STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons...
, STAT2
STAT2
Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene.-Interactions:STAT2 has been shown to interact with MED14, CREB-binding protein, SMARCA4, STAT1, IFNAR2, IFNAR1 and ISGF3G.-Further reading:...
, STAT3
STAT3
Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
, STAT4
STAT4
STAT4 is a human gene. The protein encoded by this gene is a member of the STAT protein family of transcription factors....
, STAT5
STAT5
STAT5 refers to two highly related proteins, STAT5A and STAT5B, which are encoded by separate genes, but are 90% identical at the amino acid level....
(STAT5A
STAT5A
Signal transducer and activator of transcription 5A is a protein that in humans is encoded by the STAT5A gene. STAT5A orthologs have been identified in several placentals for which complete genome data are available.-Interactions:...
and STAT5B
STAT5B
Signal transducer and activator of transcription 5B is a protein that in humans is encoded by the STAT5B gene. STAT5B orthologs have been identified in most placentals for which complete genome data are available.-Interactions:...
), and STAT6
STAT6
STAT6 is a human gene. The protein encoded by this gene is a member of the STAT family of transcription factors.In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell...
.
STAT1 homodimers are involved in type II interferon signalling, and bind to the GAS (Interferon-Gamma Activated Sequence) promoter to induce expression of ISG (Interferon Stimulated Genes). 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.
Function
STAT proteins were originally described as latent cytoplasmic transcription factors that require phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
for nuclear retention. The unphosphorylated STAT proteins shuttles between cytosol and the nucleus waiting for its activation signal. Once the activated transcription factors reaches the nucleus it binds to consensus DNA-recognition motif called gamma activated sites (GAS) in the promoter region of cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
inducible genes and activates transcription of these genes.
Activation
Extracellular binding of cytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s induces activation of the intracellular Janus kinase
Janus kinase
Janus kinase is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 , but were ultimately published as "Janus kinase"...
that phosphorylates a specific tyrosine residue in the STAT protein which promotes the dimerization
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
of STAT monomers via their SH2 domain
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
. The phosphorylated dimer is then actively transported in the nucleus via importin a/b
Importin
Importin is a type of protein that moves other protein molecules into the nucleus by binding to a specific recognition sequence, called the nuclear localization signal . Importin is classified as a karyopherin....
and RanGDP complex. Once inside the nucleus the active STAT dimer binds to cytokine inducible promoter regions of genes containing gamma activated site (GAS) motif and activate transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of these genes. The STAT protein can be dephosphorylated by nuclear phosphatases which leads to inactivation of STAT and the transcription factor becomes transported out of the nucleus by exportin crm1/RanGTP.