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Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
that in humans is encoded by the ''MAP2K7''
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 ...
. This protein is a member of the
mitogen-activated protein 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. ...
family. The MKK7 protein exists as six different
isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (1 and 2 isoforms). MKK7 is involved in
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
mediating the cell responses to proinflammatory
cytokine 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 autoc ...
s, and environmental stresses. This
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule dona ...
specifically activates
MAPK8 Mitogen-activated protein kinase 8 (also known as JNK1) is a ubiquitous enzyme that in humans is encoded by the ''MAPK8'' gene. Function The protein encoded by this gene is a member of the MAP kinase and JNK family. MAP kinases act as an inte ...
/JNK1 and MAPK9/JNK2, and this kinase itself is
phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
and activated by MAP kinase kinase kinases including MAP3K1/MEKK1,
MAP3K2 Mitogen-Activated Protein Kinase Kinase Kinase 2 also known as MEKK2 (MEK/ERK Kinase 2) is an enzyme that in humans is encoded by the ''MAP3K2'' gene. Function The protein encoded by this gene is a member of serine/threonine protein kinase fami ...
/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.genecard ...
/MEKK5, and
MAP4K2 Mitogen-activated protein kinase kinase kinase kinase 2 is an enzyme that in humans is encoded by the ''MAP4K2'' gene. Function The protein encoded by this gene is a member of the serine/threonine protein kinase family. Although this kinase is ...
/GCK. MKK7 is ubiquitously expressed in all tissue. However, it displays a higher level of expression in skeletal muscle. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found.


Nomenclature

MAP2K7 is also known as: * MKK7 * JNK-activated kinase 2 * MAPK/ERK kinase 7 (MEK7) * Stress-activated protein kinase kinase 4 (SAPK kinase 4, SAPKK4) * c-Jun N-terminal kinase kinase 2 (JNK kinase 2, JNKK2) * Stress-activated / extracellular signal-regulated protein kinase kinase 2 (SEK2)


Isoforms

The murine MKK7 protein is encoded by 14
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
s which can be alternatively
spliced Spliced may refer to: *Spliced, the result of rope splicing Rope splicing in ropework is the forming of a semi-permanent joint between two ropes or two parts of the same rope by partly untwisting and then interweaving their strands. Splices c ...
to yield a group of protein
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule dona ...
s. This results in six
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
s with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (1 and 2 isoforms). The molecular mass of the isoforms spans from 38 to 52
kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at r ...
, with between 345 and 467 amino acids. The physiological relevance of the different MKK7 isoforms is still unclear. Evidence shows that the MKK7α, which lacks an NH2-terminal extension, shows a lower basal activity in binding
JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are res ...
compared to the MKKβ and γ isoforms. The increased basal activity in the β and γ isoforms can be due to the three D-motifs present in the N-terminus of these isoforms.


Structure and function


D-motifs

MKK7 has three conserved D-motifs (MAPK-recruiting
short linear motif In molecular biology short linear motifs (SLiMs), linear motifs or minimotifs are short stretches of protein sequence that mediate protein–protein interaction. The first definition was given by Tim Hunt: "The sequences of many proteins contain s ...
s) on its intrinsically disordered
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
. D-motifs typically consist of a cluster of positively charged
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s followed by alternating hydrophobic amino acids. D-motifs are strictly required for the recruitment of MAPKK substrates, such as JNK. The kinase domains of MAPKs contain certain surface features, such as the so-called common docking (CD) region, alongside the docking (D) groove, that specifically recognize their cognate D-motifs. The D-motifs found in MKK7 are highly specific for JNKs, but have a relatively low binding affinity. It was suggested that the motifs of MKK7 can synergize with each other to provide an efficient substrate phosphorylation It has been shown that all three D-motifs are necessary for correct JNK1:MKK7 complex formations, and for the phosphorylation and activation of JNK1 by MKK7.


DVD region

A special extension to the C-terminal kinase domain core, the so-called "Domain for Versatile Docking" (DVD) is a region found in MKK7 as in most known MAP2Ks,. The DVD region is a stable, mostly helical fold of roughly 20 amino acids, that adds onto the back side of the catalytic core of the MAP2K kinase domains. This domain extension is both required for the specific binding to, and activation of MKK7 by respective upstream MAPKKKs. Other mitogen activated protein kinase kinases also require the DVD region (in addition to various other non-canonical elements of their kinase domains, like the "MKK1/2-loop") to be able to discriminate against the various MAPKKK upstream. These special MAPKK:MAPKKK kinase-domain/kinase-domain interactions facilitate the phosphorylation of MKK7. In addition to the activation of MKK7, binding to the DVD region may also affect the MKK7
activation loop In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA. IDPs rang ...
in such a way that the
Ser Ser or SER may refer to: Places * Ser, a village in Bogdand Commune, Satu Mare County, Romania * Serpens (Ser), an astronomical constellation of the northern hemisphere * Serres, known as Ser in Serbian, a city in Macedonia, Greece Organizations ...
and Thr of the S-K-A-K-T motif become accessible for
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
.


Kinase domain

The MKK7 contains one kinase domain. The direct MKK7:MAPKKK interaction (using the DVD region), facilitates the phosphorylation of MKK7 by MAPKKKs on serine and threonine in a S-K-A-K-T motif in the catalytic domain (kinase domain).


Signaling and regulation

MKK7 play an important part in the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In collaboration with another mitogen-activated protein kinase kinase
MKK4 Dual-specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the ''MAP2K4'' gene. ''MAP2K4'' encodes a dual-specificity kinase that belongs to the Ser/Thr protein kinase family. MAP2K4 phosphorylates MA ...
, MKK7 work as crucial transducers upstream of JNK signaling. Through joint efforts the two MKKs phosphorylate different JNK
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
s. As a result, MKK7 has a great impact on numerous physiological processes such as proliferation and differentiation, as well as pathological processes such as
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 includ ...
and
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
. MKK7 are activated as a result of cellular stresses. They are activated by a number of MKKKs through
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
at a S-K-A-K-T motif located in the MKK7s kinase domain. The MKKKs relate to MKK7 through its DVD site at the C-terminus and phosphorylate MKK7 at
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
and
threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
residues. Once activated, MKK4 and MKK7 directly phosphorylate specific
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
and
threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
residues located in the conserved T-P-Y motif of the activation loop of the JNK protein. Although MKK7 act through dual specificity it tends to phosphorylate
threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
on JNK protein, leaving MKK4 to phosphorylate tyrosine. Phosphorylated and activated JNKs activate substrates like
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 fun ...
s or pro-apoptotic protein. MKK7 and MKK4 seem to be regulating the expression of each other, thereby affecting the JNK signaling. The mono-phosphorylation of JNK on a threonine residue is adequate for the increase in JNK activity, which argues that MKK7 is an important constituent for JNK activity, while the additional phosphorylation of the tyrosine residue by MKK4 provide for a more favorable activation. Overall, MAP2K7 contains multiple amino acid sites that are phosphorylated and ubiquitinated.


Scaffold proteins

In addition to the direct interactions between JNK, MKK7 and other upstream protein kinases, various
scaffold protein In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them i ...
s function to ensure specificity between the components of the MAPK signaling cascade. Different JNK isoforms, MAPK, and MAPKKs (e.g., MKK7 or MKK4) bind specifically to the scaffold proteins. Several mammalian scaffold proteins have been identified. These include the JNK-interacting protein (JIP) 1 and its closerly-related homolog, JIP2 or the (completely unrelated) JIP3 and JIP4 proteins. Nevertheless, JIP1/2 and JIP3/4 were shown to be capable of direct interaction with each other. Plenty of Src-homology-3 (POSH) has also been shown to be a partner of JIP1/2. All these JNK pathway regulators assemble transport complexes, tied to kinesin-dependent vesicular transport. In this context, JIP1/2 act as cargo adaptors, binding to a motor protein and a cargo protein simultaneously. In addition to their "normal" cargoes (C-termini of transmembrane proteins), they also transport MAP2K and MAP3K enzymes, namely MKK7, DLK and MLK3. Kinases bound to the JIP1/2 scaffold are generally sequestrated and thought to be inactive. Since the cargo-linkage mechanism of this complex is believed to be phosphporylation-dependent, phosphorylation by JNK kinase can release its own upstream activators from the scaffold, thus driving a strong local positive feedback loop.


Interactions

MAP2K7 has been shown to interact with: * CNKSR1 * MAP3K1 *
MAPK8 Mitogen-activated protein kinase 8 (also known as JNK1) is a ubiquitous enzyme that in humans is encoded by the ''MAPK8'' gene. Function The protein encoded by this gene is a member of the MAP kinase and JNK family. MAP kinases act as an inte ...
*
MAPK8IP3 C-jun-amino-terminal kinase-interacting protein 3 is an enzyme that in humans is encoded by the ''MAPK8IP3'' gene. The protein encoded by this gene shares similarity with the product of Drosophila syd gene, required for the functional interaction ...
*
MAPK8IP1 C-jun-amino-terminal kinase-interacting protein 1 is an enzyme that in humans is encoded by the ''MAPK8IP1'' gene. The protein encoded by this gene is a regulator of the pancreatic beta-cell function. It is highly similar to JIP-1, a mouse protein ...
* GADD45B *
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 ...
*
MAP3K2 Mitogen-Activated Protein Kinase Kinase Kinase 2 also known as MEKK2 (MEK/ERK Kinase 2) is an enzyme that in humans is encoded by the ''MAP3K2'' gene. Function The protein encoded by this gene is a member of serine/threonine protein kinase fami ...
*
MAPK8IP2 C-jun-amino-terminal kinase-interacting protein 2 is a protein or the name of the gene that encodes it. The gene is also known as Islet-Brain-2 (IB2). This protein is highly expressed in the brain and is almost always deleted in Phelan-McDermid ...
* DUSP19


Biological relevance

MKK7 is involved in the development of epithelial tissues such as skin and lungs, and also the developing teeth, during early embryogenesis in mice. Experiments also indicate that MKK7 in addition to MKK4 are required for mammalian body plan organization during
embryogenesis 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 sperm c ...
. MKK7 has also been suggested to function as a putative Metastase Suppressor Gene (MSG) by possibly promoting tumor dormancy at the
metastatic Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
site. In small mammals, stress like pressure overload can cause cardiac hypertrophy and failure if MKK7 is knocked out. Conditional deletion of ''Map2k7'' in neural stem cells and postmitotic neurons identified a role for MKK7 in axonal elongation. Neuron-specific deletion of ''Map2k7'' showed a role for MKK7 in age-dependent motor dysfunction. Genetic variations in ''MAP2K7'' have been associated with schizophrenia in humans.


References


Further reading

* {{Portal bar, Biology, border=no Mitogen-activated Protein Kinases EC 2.7.11