![MKPs role in ERK regulation](https://upload.wikimedia.org/wikipedia/commons/6/60/MKPs_role_in_ERK_regulation.jpg)
MAPK phosphatases (MKPs) are the largest class of
phosphatase
In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
s involved in down-regulating
Mitogen-activated protein 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 to ...
s (MAPK) signaling. MAPK
signalling pathways
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately re ...
regulate multiple features of
development
Development or developing may refer to:
Arts
*Development hell, when a project is stuck in development
*Filmmaking, development phase, including finance and budgeting
*Development (music), the process thematic material is reshaped
*Photographi ...
and
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
. This can involve gene regulation, cell proliferation, programmed cell death and stress responses.
MAPK phosphatases are therefore important regulator components of these pathways.
Function
![The inactivation of MAPKs by MKPs](https://upload.wikimedia.org/wikipedia/commons/1/1a/The_inactivation_of_MAPKs_by_MKPs.jpg)
MAPK phosphatases are only found in
eukaryotes
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
and negatively regulate
MAP 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 to ...
to act as negative feedback.
MKPs are also known as
dual-specificity phosphatases (DUSPs) because they deactivate MAPK by
dephosphorylating the
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 −COOâ ...
and the
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 ...
residues residing in MAPKs activation site. MKPs have a
catalytic region at their
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
and a
regulatory region
A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and vir ...
at their
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 ...
. The position where the MAPK binds to MKP is found near the N-terminus of MKP. The binding is due to the
electrostatic interactions
Electrostatics is a branch of physics that studies electric charges at rest (static electricity).
Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word for amber ...
of the positively charged residues on the MKP binding portion with the negatively charged residues on the MAPK binding site.
Classification
There are 10 main MKPs that can be further broken down into three sub-classes which are representative of either their
genomic structure or the type of
substrate (MAPK) they bind to. These include DUSP1, DUSP2, DUSP4 and DUSP5 that belong to subgroup 1. DUSP6, DUSP7, DUSP9 and DUSP10 belong to subgroup 2. DUSP8 and DUSP16 belong to subgroup 3, these subgroups are based on the genomic structure of the MKPs. The newest MKP-8 brings the total MKPs to 11, MKP-8 plays a role in inhibiting p38 kinase.
Dual specificity phosphatases (DUSPs) also belong to the family of
protein thyrosine phosphatases. MKPs are grouped into type I, II and III; in which type I MKPs are located in the
nuclear region, type II are located in the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
ic region and type III are located in both the nuclear and cytoplasmic region. The different locations of these three types of MKPs allow for them to cause different types of signaling. For example, MKP-1 (a type I MKP) controls gene expression by inactivating the subcellular group of MAPKs. Note that without the LXXLL motif (GFP-MKP-1
47-367) the MKP-1 cannot localize inside the nucleus and it comes before the CH2A domain. The newest MKP, MKP-8, belongs to group I because it is located in the nuclear region of the cell A recent study shows that histone deacetylase isoforms (HDAC1, -2, and -3)
deacetylate
:
In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...
MKP-1 and that this
post-translational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...
increases MAPK signaling and
innate immune signaling.
Although the N-terminal region is the quite distinct between each MKP, they all normally contain
CH2 domains. In MKP-1, MAPK binds to the active site that is between the CH2A and CHB domains located in the N-terminal.
An example of a type II MKP is
MKP-3 which, regulates the activity of
ERK2
Mitogen-activated protein kinase 1, (MAPK 1), also known as ERK2, is an enzyme that in humans is encoded by the ''MAPK1'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extrace ...
by
deposphorylating it and holding it in the cytoplasmic region. MKP-3 also binds to ERK2 regardless of whether it is phosphorylated or not. MKP-4 is another MKP that belongs to Type I and, is distinct from other MKPs in this subgroup because it is only found in placenta, kidney and embryonic liver cells.
MKP-5 is a type III MKP that binds specifically to
p38 and SPK/
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 ar ...
and is found both in the cytoplasmic and nuclear regions of a cell. MKP-5 is only located in the heart, lung, liver, kidney and skeletal muscle cells.
There are also MKPs that belong to a group called Atypical MKPs. For example, Vaccina H1-related (VHR) is an atypical MKP because it only has the DUSP region. VHR is only found in
lymphoid
The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...
and
hematopoietic cell
A blood cell, also called a hematopoietic cell, hemocyte, or hematocyte, is a cell produced through hematopoiesis and found mainly in the blood. Major types of blood cells include red blood cells (erythrocytes), white blood cells (leukocytes), a ...
s, and it inactivates the
ERK1
Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene.
Function
The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) fami ...
/
2 and
JNKs in
T-cell receptor
The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding b ...
s. VHR also induces
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
arrest.
References
{{MAP kinase activation
Cell signaling
Enzymes
Protein kinases