Mitogen Activated Protein (MAP) kinase kinase kinase, MAPKKK (or MAP3K) is a
serine/threonine-specific protein kinase
A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human prot ...
which acts upon
MAP kinase kinase
Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) is a dual-specificity kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).
MAP2K is classified as .
There are seven genes:
* (a.k.a. MEK1)
* (a. ...
. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, 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 ...
. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction.
Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:
*
MAP3K1 (aka MEKK1)
*
MAP3K2 (aka MEKK2)
*
MAP3K3
Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the ''MAP3K3'' gene, which is located on the long arm of chromosome 17 (17q23.3).MAP3K3 in GeneCards – The Human Gene Compendium. https://www.genecards. ...
(aka
MEKK3)
*
MAP3K4
Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the ''MAP3K4'' gene.
The central core of each mitogen-activated protein kinase (MAPK) pathway is a conserved cascade of 3 protein kinases: an activated MAPK ...
(aka MEKK4)
*
MAP3K5
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and ...
(aka
ASK1
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and ...
)
*
MAP3K6 (aka
ASK2
Ask is the active verb for a direct question.
Ask may also refer to:
Places
* Ask, Akershus, a village in Gjerdrum municipality, Viken county, Norway
* Ask, Buskerud, a village in Ringerike municipality, Viken county, Norway
* Ask, Vestland, a ...
)
*
MAP3K7
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the ''MAP3K7'' gene.
Structure
TAK1 is an evolutionarily conserved kinase in the MAP3 K family and clusters with the tyro ...
(aka
MEKK7) (aka
TAK1)
*
MAP3K8 (aka
TPL2
Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the ''MAP3K8'' gene.
Function
The gene was identified by its oncogenic transforming activity in cells. The encoded protein is a member of the serine/thr ...
or
Tpl2
Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the ''MAP3K8'' gene.
Function
The gene was identified by its oncogenic transforming activity in cells. The encoded protein is a member of the serine/thr ...
)
*
MAP3K9
Mitogen-activated protein kinase kinase kinase 9 is an enzyme that in humans is encoded by the ''MAP3K9'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." m ...
*
MAP3K10
Mitogen-activated protein kinase kinase kinase 10 is an enzyme that in humans is encoded by the ''MAP3K10'' gene.
Function
The protein encoded by this gene is a member of the serine/threonine kinase family. This kinase has been shown to activa ...
*
MAP3K11
Mitogen-activated protein kinase kinase kinase 11 is an enzyme that in humans is encoded by the ''MAP3K11'' gene.
Function
The protein encoded by this gene is called MLK3 and it is a member of the serine/threonine kinase family. This kinase co ...
(aka
MEKK11) (aka MLK3)
*
MAP3K12
Mitogen-activated protein kinase 12 is an enzyme that in humans is encoded by the ''MAP3K12'' gene.
Function
The protein encoded by this gene is a member of serine/threonine protein kinase family. This kinase contains a leucine-zipper domain, a ...
(aka MUK)
*
MAP3K13
Mitogen-activated protein kinase kinase kinase 13 is an enzyme that in humans is encoded by the ''MAP3K13'' gene.
Function
The protein encoded by this gene is a member of serine/threonine protein kinase family. This kinase contains a dual leuci ...
(aka
LZK)
*
MAP3K14
Mitogen-activated protein kinase kinase kinase 14 also known as NF-kappa-B-inducing kinase (NIK) is an enzyme that in humans is encoded by the ''MAP3K14'' gene.
Function
This gene encodes mitogen-activated protein kinase kinase kinase 14, NIK, ...
*
MAP3K15
Mitogen-activated protein kinase kinase kinase 15 is a protein that in humans is encoded by the MAP3K15 gene.
Function
The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAPK) family. These family members fun ...
*
MAP3K16 (aka
TAO1 or
TAOK1
Serine/threonine-protein kinase TAO1 is an enzyme that in humans is encoded by the ''TAOK1'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''gene ...
)
*
MAP3K17 (aka
TAO2
''Tao'' or ''Dao'' is the natural order of the universe, whose character one's intuition must discern to realize the potential for individual wisdom, as conceived in the context of East Asian philosophy, East Asian religions, or any other phil ...
or
TAOK2
Serine/threonine-protein kinase TAO2 is an enzyme that in humans is encoded by the ''TAOK2'' gene.
Interactions
TAOK2 has been shown to interact with MAP2K6
Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase ...
)
*MAP3K18 (aka TAO3 or TAOK3)
*
RAF1
RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the ''RAF1'' gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase ( ...
*
BRAF
*
ARAF
Serine/threonine-protein kinase A-Raf or simply A-Raf is an enzyme that in humans is encoded by the ''ARAF'' gene. A-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases.
Compared to the other members of this ...
*
ZAK
Zak may refer to:
People
* Zak (surname), a surname of Russian origin
* Żak, a Polish surname
* Žák, a Czech surname
* Zak (given name)
Fictional characters
* Zak Adama, in the '' Battlestar Galactica'' franchise
* Zak Dingle, in UK TV ''Emme ...
(aka
MLTK)
Classes of MAPKKK and their functions
Several classes of MAPKKK exist, and all of them are
upstream
Upstream may refer to:
* Upstream (bioprocess)
* ''Upstream'' (film), a 1927 film by John Ford
* Upstream (networking)
* ''Upstream'' (newspaper), a newspaper covering the oil and gas industry
* Upstream (petroleum industry)
* Upstream (software ...
of MAP kinases. There are three main classes of MAP Kinases and are regulated by their respective MAPKKKs. These MAP kinases include the extracellular regulated kinases (ERKs), the c-Jun N-terminal Kinases (JNKs), and the p38 MAP kinase. The ERKs are regulated by the Raf family of MAPKKKs and are responsible for cell growth, differentiation, and meiosis. Perhaps the best characterized MAP3K are the members of the oncogenic RAF family (RAF1, BRAF, ARAF), which are effectors of mitogenic ras signaling and which activate the
ERK1/2 (MAPK3/MAPK1) pathway, through activation of MEK1(MAP2K1) and MEK2(MAP2K2). The JNKs are regulated by the MEKK 1/4, MLK 2/3, and ASK 1 MAPKKKs. The p38 MAPK is regulated by MEKK 1-4 and TAO 1/2 families of MAPKKKs and is responsible for inflammation, apoptosis, cell differentiation, and cell cycle regulation. The determination for what cascade is followed is based upon the type of signal, the strength of binding, and the length of binding.
MEKK1 activates
MAPK8/JNK by phosphorylation of its activator SEK1(
MAP2K4).
MAP3K3
Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the ''MAP3K3'' gene, which is located on the long arm of chromosome 17 (17q23.3).MAP3K3 in GeneCards – The Human Gene Compendium. https://www.genecards. ...
directly regulates the
MAPK8/JNK and
extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively; it does not regulate the
p38 pathway.
MAP3K7
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the ''MAP3K7'' gene.
Structure
TAK1 is an evolutionarily conserved kinase in the MAP3 K family and clusters with the tyro ...
(TAK1) participates in regulation of transcription by transforming growth factor-beta (
TGF-beta
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
).
Activation and deactivation of MAPKKK
The most upstream stimuli that activate MAPKKK is either stress or growth factors. This includes mitogens, inflammatory cytokines, ER stress, oxidative stress, UV radiation, and DNA damage. Most MAPKKKs are activated through
GPCR
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
's where the signal from the stimuli binds to the GPCR and the GTPase activity of the g-protein activates the downstream MAPKKK. Other mechanisms for MAPKKK do exist. For instance, the MAPKKK ASK-1 is activated by a
receptor-tyrosine kinase specific for a tumor necrosis factor. Since MAPKKK are activated through the addition of a phosphates group on a serine/threonine residue, they are deactivated by a phosphatase. A common phosphatase used in ASK-1 regulation is PP5. MAPKKKs contain a docking domain which is different from their active site that allows them to contact another substrate. Additionally, several scaffolds are used in the MAPKKK cascade in order to ensure that a specific cascade is used. These scaffolds have a binding site for the MAPKKK, MAPKK, and MAPK, ensuring that the signal occurs rapidly.
Clinical significance
Because MAPKKKs are involved in a wide range of cell responses occurring both in the cytoplasm and the nucleus, a mutation in these genes can cause several diseases. Over-expression of the MAPKKK upstream of the ERK 1/2 MAPK and an increase in
epidermal growth factor receptor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor recept ...
(EGFR) can lead to tumor formation, such as triple negative breast cancer. A mutation in the JNK or p38 family of MAPK or their MAPKKK upstream precursors can result in
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
. This is also seen when there is too much oxidative stress in the brain, causing these MAPKs to undergo more apoptosis and destroy brain cells. MLK, a type of MAPKKK, are associated with
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
and inhibitors to the MLK proteins have been shown to treat Parkinson's disease. The MAPKKK pathways and specifically the over-expression of cascades of JNK and p38 are also involved in
Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
and
polycystic kidney disease
Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cy ...
. Inhibitors of these pathways help in treating the symptoms of the diseases.
Images
File:MAPKpathway.jpg , MAPK pathway. Many of the MAP3K's here are labelled by their alternative names.
See also
*
MAP kinase
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 ...
*
MAP kinase kinase
Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) is a dual-specificity kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).
MAP2K is classified as .
There are seven genes:
* (a.k.a. MEK1)
* (a. ...
*
MAP kinase kinase kinase kinase Mitogen-activated protein kinase kinase kinase kinase (MAP4K) is a family of proteins involved in cellular signal transduction.
* MAP4K1 (aka HPK1)
* MAP4K2 (aka GCK)
* MAP4K3 (aka GLK)
* MAP4K4 (aka HGK)
* MAP4K5 (aka KHS)
* MAP4K6 (aka MINK)
...
*
List of unusual biological names
The trouble with unusual names has not been lost on scientists when needing to explain genetic diseases to lay-people. This has particularly been noted in patients with a defect in the sonic hedgehog gene pathway and the disease formerly named DiGe ...
References
External links
*
*
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Protein kinases
EC 2.7.11