A Detailed Introduction of MAP Kinase Signaling Pathway

  • MAPK is an important transmitter of signals 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, cellular stress and cell adhesion. Protein kinase. MAPK is named because it is activated when cells are activated by stimulation with mitogens such as growth factors. All eukaryotic cells express MAPK. The basic composition of the MAPK pathway is a three-stage kinase pattern that is conserved from yeast to humans, including MAPK kinase (MKKK), MAPK kinase (MKK) and MAPK. It is activated in turn to regulate various important cell physiology/pathological processes such as cell growth, differentiation, stress adaptation to the environment, and inflammatory response.

     

     

    Mitogen-activated protein kinases (MAP kinases, MAPK) chains are one of the important pathways in eukaryotic signaling networks and play a key role in gene expression regulation and cytoplasmic function. The MAPK chain consists of a class 3 protein kinase MAP3K-MAP2K-MAPK, which transmits an upstream signal to a downstream response molecule by sequential phosphorylation. MAPK belongs to the CMGC (CDK/MAPK/GSK3/CLK) kinase group. The closest proteins to MAPKs are cyclin-dependent kinases (CDKs).

     

    MAPK signaling pathway member

     

    MAPK is an important transmitter of signals from the cell surface to the interior of the nucleus. Fourteen MKKK, seven MKKs and twelve MAPKs have been identified in mammalian cells. Analysis shows that these kinases belong to different subfamilies.

     

    MKKK

    The four subfamilies of MKKK have been identified, and the Raf subfamily has the most thorough research, including B-Raf, A-Raf, and Raf1. The MEKK subfamily consists of four MEKKs (MEKK1~MEKK4). ASK1 and Tpl2 form the third subfamily of MKKK. The fourth subfamily is quite different from the above three, including MST (mammalian sterile 20-like), SPRK, MUK (MAPK upstream kinase), TAK1, and the least correlated MOS (molony sarcoma oncoprotein).

     

    MKK

    For MKK, MEK1 is closely related to MEK2, while MKK3 is closely related to MKK6.

     

    MAPK

    MAPK can be divided into 4 subfamilies: ERK, p38, JNK and ERK5. These pathways are named after them, for example, the MAPK pathway using JNK is called the JNK pathway.

     

    Find

    The first mitogen-activated protein kinase found in mammals is ERK1 (MAPK3). Since ERK1 and its close relative ERK2 (MAPK1) are involved in growth factor signaling, the family was named "mitogen activated". With the discovery of other MAPK members, it is increasingly clear that the name is a misnomer because most MAPKs are actually involved 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 regulator of cell proliferation is not general, but a highly specialized function.

     

    Types
    Most MAPKs share many common features, such as activation of two phosphorylation events, three-layer pathway structures, and similar substrate recognition sites. These are the "classic" MAPKs. However, there are also some ancient "outlier" kinases that do not have dual phosphorylation sites, form only two 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 an independent population as opposed to classical MAPKs.

     

     

    MAPK structure


    Primary structure
    MKK activates MAPK by simultaneous phosphorylation of the two sites, threonine (T) and tyrosine (Y). The two phosphorylation sites are separated by an amino acid to form the tripeptide TXY. Different MAPK subfamily members have different X residues between their diphosphorylation sites, but each subfamily has a standard 12 conserved subregions, which are markers that distinguish eukaryotic protein kinase superfamily. one. There is high homology between members of the MAPK family. For example, p38β, p38γ, and p38δ have 75%, 62%, and 64% homology to p38α, respectively, and about 40% to 50% homology to other MAPK family members. The tripeptide group is located in the Loop12 loop structure between the VII and VIII subregions of the protein kinase, which is located on the surface of the molecule and adjacent to the active site, some of which form a lip-like structure called phosphorylation lip or Activation lip. This region is considered to be the key structure for determining the activity of various protein kinases, including MAPK.

     

    Secondary and super secondary structure
    Similar to other protein kinases, ERK2, p38 and JNK1 both have a smaller amino acid domain and a larger carboxy-terminal domain, both
    They are connected together by an intersection. The amino acid domain is mainly composed of β-sheet, while the carboxyl-terminal domain is mainly α-helix, and the two structures form a fissure with the junction, which is the ATP binding site.

     

    Spatial structure
    General structure:
    P38 has approximately 40% sequence homology with ERK2. When the two domains of p38 and ERK2 are simultaneously overlapped, the root mean square (RMS) deviation is 0.17 nm. The homology of JNK with ERK2 and p38 is 40% and 51%, respectively, and its overall structure is also very similar to ERK2 and p38. The carboxy-terminal domain of ERK2 and p38 was overlapped with the carboxy-terminal domain of JNK, which were rotated by 2.5° and 4°, respectively, compared to the carboxy-terminal domain of JNK3. When the amino acid and carboxy terminal domains of ERK2 were overlapped with the corresponding domains of JNK3, the RMS deviations were 0.115 nm and 0.158 nm.

     

    Structural features of the substrate binding pocket:

    In all MAPKs, the amino acid residues that form the substrate binding pocket are fairly conserved. When unstimulated, the substrate binding pocket of ERK2 is occupied by Arg192; when ERK2 is phosphorylated, Arg192 is turned away from its original position, thereby exposing the substrate binding pocket for substrate binding. The mechanism of activation of this site in p38 is unclear.

     

     

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