MAPK is an important transmitter of signal transmission from the cell surface to the interior of the nucleus. Mitogen-activated protein kinase (MAPK) is a group of serine-threonine that can be activated by different extracellular stimuli such as cytokines, neurotransmitters, hormones, cell stress and cell adhesion. Protein kinase. MAPK is named because cultured cells are identified when activated by mitogens such as growth factors. All eukaryotic cells can express MAPK. The basic composition of the MAPK pathway is a three-level kinase model that is conserved from yeast to humans, including MAPK kinase kinase (MKKK), MAP kinase kinase (MKK), and MAPK. These three kinases can Activation in turn regulates many important cell physiological/pathological processes such as cell growth, differentiation, environmental stress adaptation, and inflammatory response. The mitogen-activated protein kinases (MAP kinases, MAPK) chain is one of the important pathways in eukaryotic signaling networks, and plays a key role in gene expression regulation and cytoplasmic functional activities. The MAPK chain consists of three types of protein kinases, MAP3K-MAP2K-MAPK, and transmits upstream signals to downstream response molecules through sequential phosphorylation. MAPK belongs to the CMGC (CDK/MAPK/GSK3/CLK) kinase group. The closest proteins related to MAPKs are cyclin-dependent kinases (CDKs).
Figure 1. Protein structure of MAPK.
Discovery
The first mitogen-activated protein kinase found in mammals was ERK1 (MAPK3). Because ERK1 and its close relative ERK2 (MAPK1) are involved in growth factor signaling, the family was named "mitogen activated". As other MAPK members discovered, it became clear that the name was a misnomer because most MAPKs actually participate in potentially harmful abiotic stress stimuli (high osmotic pressure, oxidative stress, DNA damage, low osmotic pressure) Reaction. The role of mammalian ERK1/2 kinase as a cell proliferation regulator is not general, but a highly specialized function.
Types
Most MAPKs share many common features, such as reliance on the activation of two phosphorylation events, a three-layer pathway structure, and similar substrate recognition sites. These are "classic" MAPKs. However, there are some ancient "outlier" kinases that do not have double phosphorylation sites, form only two-layer pathways, and lack the substrate-binding characteristics required for other MAPKs. These are often referred to as "atypical" MAPKs. It is unclear whether these atypical MAPKs form independent groups contrary to classic MAPKs.
MAPK structure
Primary structure
MKK activates MAPK through simultaneous phosphorylation of two sites, threonine (T) and tyrosine (Y). The two phosphorylation sites are separated by an amino acid in the middle to form the tripeptidyl TXY. Different members of the MAPK subfamily have different X residues between their double phosphorylation sites, but each subfamily has standard 12 conserved subregions, which are the markers that distinguish the eukaryotic protein kinase superfamily. one. MAPK family members have high homology. For example, p38β, p38γ, and p38δ have 75%, 62%, and 64% homology with p38α, respectively, and about 40% to 50% homology with other members of the MAPK family. The tripeptidyl group is located in the Loop12 loop structure between the VII and VIII subregions of the protein kinase. This loop is located on the surface of the molecule and close to the active site. Some of the residues form a lip structure, called a phosphorylated lip or Activation lip. This region is thought to be a key structure determining the activity of a variety of protein kinases, including MAPK.
Secondary and super secondary structure
Similar to other protein kinases, ERK2, p38, and JNK1 have a smaller amino acid domain and a larger carboxy-terminal domain, which are connected by a cross region. The amino acid domain is mainly composed of β-sheet, while the carboxy-terminal domain is mainly α-helix. The two structures form a gap with the junction, which is the ATP binding site.
Activation of MAPK
In the case of classic MAP kinase, the activation loop contains a characteristic TxY (threonine-x-tyrosine) motif (TEY in mammals ERK1 and ERK2, TDY in ERK5, TPY in JNK, p38 kinase TGY), in order to lock the kinase domain to a catalytically active conformation, phosphorylation is required on both threonine and tyrosine residues. In vivo and in vitro, phosphorylation of tyrosine often precedes phosphorylation of threonine, although phosphorylation of either residue can occur without another residue. Phosphorylation of this tandem activation loop is performed by a member of the Ste7 protein kinase family, also known as MAP2 kinase. MAP2 kinase is in turn phosphorylated and activated by many different upstream serine threonine kinases (MAP3 kinases). Because MAP2 kinases show very little activity on substrates other than their homologous MAPKs, the classical MAPK pathway forms a multi-level, but relatively linear signaling pathway. These signaling pathways can effectively pass stimulation from the cell membrane (where many MAP3Ks are activated) to the nucleus (only MAPK can enter the nucleus) or many other subcellular targets.
Inactive of MAPK
Inactivation of MAPKs is performed by various phosphatases. A very conservative family of specialized phosphatases is the so-called MAP kinase phosphatase (MKP), which is a subgroup of bispecific phosphatases (DUSP). As the name suggests, these enzymes are capable of hydrolyzing phosphate groups from phosphotyrosine and phosphothreonine residues. Since the removal of either phosphate group will greatly reduce MAPK activity and substantially eliminate the signal, some tyrosine phosphatases are also involved in inactivating MAP kinases.
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