Signal transducer and activator of transcription 3 (STAT3) is a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
which in humans is encoded by the ''STAT3''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
It is a member of the
STAT protein
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
family.
Function
STAT3 is a member of the
STAT protein
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
family. In response to
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
and
growth factors
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for reg ...
, STAT3 is phosphorylated by receptor-associated
Janus kinase
Janus kinase (JAK) 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 and 2 (since they were just two of many discoveries ...
s (JAK), forms homo- or heterodimers, and translocates to the cell nucleus where it acts as a
transcription activator
A transcriptional activator is a protein (transcription factor) that increases transcription of a gene or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and, ...
. Specifically, STAT3 becomes activated after phosphorylation of tyrosine 705 in response to such ligands as
interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
s,
epidermal growth factor (EGF),
Interleukin (IL-)5 and
IL-6. Additionally, activation of STAT3 may occur via phosphorylation of serine 727 by
Mitogen-activated protein kinases
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses ...
(MAPK) and through
c-src
Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src, or simply c-Src (cellular Src; pronounced "sarc", as it is short for sarcoma), is a non-receptor tyrosine kinase protein that in humans is encoded by the ''SRC'' gene ...
non-receptor tyrosine kinase. 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
Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...
and
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
STAT3-deficient mouse
embryo
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
s 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
embryonic stem cell
Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consi ...
s (ESCs). Indeed,
LIF
Lithium fluoride is an inorganic compound with the chemical formula LiF. It is a colorless solid, that transitions to white with decreasing crystal size. Although odorless, lithium fluoride has a bitter-saline taste. Its structure is analogous to ...
, which is supplied to
murine
The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families ex ...
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
T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg different ...
helper T cells, which have been implicated in a variety of
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s.
During viral infection, mice lacking STAT3 in T-cells display impairment in the ability to generate T-follicular helper (Tfh) cells and fail to maintain antibody based immunity.
STAT3 caused upregulation in E-selectin, a factor in metastasis of cancers.
Hyperactivation of STAT3 occurs in
COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
infection and other viral infections.
[ ][ ]
Clinical significance
Loss-of-function mutations in the STAT3 gene result in
Hyperimmunoglobulin E syndrome
Hyperimmunoglobulinemia E syndrome (HIES), of which the autosomal dominant form is called Job's syndrome or Buckley syndrome, is a heterogeneous group of immune disorders. Job's is also very rare at about 300 cases currently in the literature.
P ...
, 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, while constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.
It has anti-apoptotic as well as proliferative effects.
STAT3 can promote oncogenesis by being constitutively active through various pathways as mentioned elsewhere. A tumor suppressor role of STAT3 has also been reported.
In the report on human
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
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.
Increased activity of STAT3 in cancer cells, leads to changes in the function of protein complexes that control expression of inflammatory genes, with result profound change in the secretome and the cell phenotypes, their activity in the tumor, and their capacity for metastasis.
Interactions
STAT3 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
AR,
* ELP2
Elongator complex protein 2 is a protein that in humans is encoded by the ''ELP2'' gene.
Interactions
ELP2 has been shown to interact with STAT3 and Janus kinase 1
JAK1 is a human tyrosine kinase protein essential for signaling for certain type ...
,
* EP300
Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...
,
* EGFR,
* HIF1A
Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 ( HIF-1) that is encoded by the ''HIF1A'' gene. The Nobel Prize in Physiology or Medicine 2019 was awarde ...
,
* JAK1
JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family (e.g. IL-2R, I ...
,
* JUN
* KHDRBS1
KH domain-containing, RNA-binding, signal transduction-associated protein 1 is a protein that in humans is encoded by the ''KHDRBS1'' gene.
This gene encodes a member of the K homology domain-containing, RNA-binding, signal transduction-associate ...
,
* mTOR
The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MT ...
,
* MYOD1
MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating myogenesis, muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of pr ...
,
* NDUFA13
NADH dehydrogenase biquinone1 alpha subcomplex subunit 13 is an enzyme that in humans is encoded by the ''NDUFA13'' gene. The NDUFA13 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane a ...
,
* NFKB1
Nuclear factor NF-kappa-B p105 subunit is a protein that in humans is encoded by the ''NFKB1'' gene.
This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD prot ...
,[
* NR3C1,]
* NCOA1
The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by ...
,
* PML,
* RAC1,
* RELA
Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the ''RELA'' gene.
RELA, also known as p65, is a REL-associated protein involved in NF-κB heterodimer formation, nuclear tra ...
,
* RET,
* RPA2
RPA may refer to:
Companies
* RPA (Rubin Postaer and Associates), advertising agency, Santa Monica, California, US
* Republic Airways, ICAO code: RPA
Political groups
* Republican Party of Arkansas, the affiliate of the Republican Party in Arka ...
,
* STAT1
Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family.
Function
All STAT molecules are phosphorylated by receptor associ ...
,
* Stathmin
Stathmin, also known as metablastin and oncoprotein 18 is a protein that in humans is encoded by the ''STMN1'' gene.
Stathmin is a highly conserved 17 kDa protein that is crucial for the regulation of the cell cytoskeleton. Changes in the cytoske ...
,
* Src, and
* TRIP10
Cdc42-interacting protein 4 is a protein that in humans is encoded by the ''TRIP10'' gene.
Interactions
TRIP10 has been shown to interact with STAT3, Wiskott-Aldrich syndrome protein, Huntingtin, CDC42, AKAP9 and RHOQ
Rho-related GTP-bindi ...
.
* KPNA4
Importin subunit alpha-3, also known as karyopherin subunit alpha-4, is a protein that in humans is encoded by the ''KPNA4'' gene.
Function
The nuclear import of karyophilic proteins is directed by short amino acid sequences termed nuclear loca ...
.
Niclosamide
Niclosamide, sold under the brand name Niclocide among others, is an anthelmintic medication used to treat tapeworm infestations, including diphyllobothriasis, hymenolepiasis, and taeniasis. It is not effective against other worms such as flukes ...
seems to inhibit the STAT3 signalling pathway.
Nicotinamide
Niacinamide or Nicotinamide (NAM) is a form of vitamin B3 found in food and used as a dietary supplement and medication. As a supplement, it is used by mouth to prevent and treat pellagra (niacin deficiency). While nicotinic acid (niacin) may ...
(a type of Vitamin B3) naturally inhibits STAT3. [ ] However NAC (Acetylcysteine
Acetylcysteine, also known as ''N''-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. It has been used ...
) inhibits STAT3 inhibitors.[ ]
References
Further reading
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External links
*
{{Cytokine receptor modulators
Gene expression
Immune system
Proteins
Transcription factors
Signal transduction
Moonlighting proteins