MAPK is an important transmitter of signals from the cell surface to the interior of the nucleus. Mitogen-activated protein kinases (MAPKs) are a group of serine-threonine protein kinases, which can be activated by different extracellular stimuli, such as cytokines, neurotransmitters, hormones, cellular stress and cell adhesion. MAPK was named because it was identified when cultured cells were activated in response to mitogen stimulation such as growth factors. All eukaryotic cells can express MAPK. The basic component of the MAPK pathway is a pattern of tertiary kinases conserved from yeast to humans, including MAP kinase kinase kinase (MKKK), MAP kinase kinase (MKK) and MAPK, which are activated sequentially, together, they regulate cell growth, differentiation, adaptation to environmental stress, inflammatory response and other important physiological/pathological processes. The MAPK chain is one of the important pathways in eukaryotic signal transmission network, which plays a key role in the regulation of gene expression and cytoplasmic function. MAPK belongs to the CMGC (CDK/MAPK/GSK3/CLK) kinase group. The closest related proteins to MAPKs are cyclin-dependent kinases (CDKs).



MAPK schematic overview




Most MAPKs share many common features, such as dependence on the activation of two phosphorylation events, a three-layer pathway structure, and similar substrate recognition sites. These are the "classical" MAPKs. But there are also ancient "outlier" kinases that do not possess a double phosphorylation site, form only a two-layer pathway, and lack the substrate-binding features required for other MAPKs. These are often referred to as "atypical" MAPKs. It is not clear whether these atypical MAPKs form independent populations as opposed to classical MAPKs.


Primary Structure


MKK activates MAPK through simultaneous phosphorylation of threonine (T) and tyrosine (Y) at both sites. These two phosphorylation sites are separated by an amino acid, forming the tripeptidyl TXY. Different MAPK subfamily members have different X residues between their dephosphorylation sites, but each subfamily of MAPK has 12 conserved subregions, which are one of the marks to distinguish the protein kinase superfamily of eukaryotic cells. There is high homology among MAPK family members. For example, p38β, p38γ, and p38δ share 75%, 62%, and 64% identity with p38α, respectively, but about 40% to 50% identity with other MAPK family members. The tripeptidyl group is located in a Loop12 loop between subregions VII and VIII of the protein kinase, which is located on the surface of the molecule and adjacent to the active site. Some of these residues form a lip-like structure known as a phosphorylated lip or activation lip. This region is thought to be a key structure that determines the activity of several protein kinases, including MAPK.



Phosphated distarch phosphate


Secondary and Supersecondary Structures


Similar to other protein kinases, ERK2, P38, and JNK1 all have a small amino acid domain and a large carboxyl-terminal domain, which are linked together by a crossover region. The amino acid domain is mainly composed of β fold, while the carboxyl-terminal domain is mainly α helix. The two structures form a crack at the junction, which is the ATP binding site.


Space Structure


P38 shares about 40% of sequence identity with ERK2. When the two domains of P38 and ERK2 were overlapped together, the deviation of root mean square (RMS) was 0.17nm. JNK shares 40% and 51% homology with ERK2 and p38, respectively, and its overall structure is very similar to that of ERK2 and p38. The carboxyl-terminal domain of ERK2 and P38 was superimposed with that of JNK, which were rotated by 2.5° and 4°, respectively, compared with that of JNK3. When the amino acid and carboxyl-terminal domains of ERK2 were overlapped with the corresponding domain of JNK3, the RMS deviation was 0.115nm and 0.158nm, respectively.


MAPK Pathway


The MAPK pathway is one of the common intersection pathways of signal transduction pathways such as stress, inflammation, cell proliferation, differentiation, functional synchronization, transformation, apoptosis and so on. The extracellular signals are transmitted into cells through signaling networks such as receptors, G/G proteins, protein kinases, and transcription factors, and are involved in cell proliferation, differentiation, carcinogenesis, metastasis, and apoptosis. Different cells have different growth stimuli and stress stimuli. Various effects can be produced by different signaling pathways restricted by different cytoskeletons. The activation of MAPK is tcytoskeletons final step in the intracellular phosphorylation cascade. The classical MAPK cascade includes MAPKKKK(Ras, Rho), MAPKK kinase (MAPKKK), MAPKK serine/threonine phosphorylation, and activated MAPKK, MAPK threonine/tyrosine double phosphorylation.  Enhancers present in the MAPK signal transduction pathway bind to MAPKKKs, MAPKKs, and MAPKs to increase their activation ability by upstream kinases.


MAPK Pathway Pattern and Function


Many stimuli, such as growth factors, cytokines, radiation, osmotic pressure, and shear stress caused by fluid flow across the cell surface, can activate MAPK signal transduction pathway.


The activation of MAPK cascade is the center of various signaling pathways. It is an important class of molecules that receive the signals transferred and transmitted by membrane receptors and carry them into the nucleus. It plays a key role in many signaling pathways related to cell proliferation. In unstimulated cells, MAPK is quiescent. When cells are stimulated by growth factors or other factors, MAPK receives activation signals of MKK and MKKK and is activated, which shows stepwise phosphorylation. In mammals, ERK is widely found in various tissues and participates in the regulation of cell proliferation and differentiation. A variety of growth factor receptors, nutrient-related factor receptors and so on need ERK activation to complete the signal transduction process. JNK family is a key molecule in cell signal transduction induced by various stressors, and is involved in cell response to radiation, osmotic pressure, temperature changes and other stress. P38 mediates inflammation and apoptosis, so it has become a target for the development of anti-inflammatory drugs.

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