July 7, 2022

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MAPK signaling pathway

MAPK signaling pathway



 

MAPK signaling pathway. 

RTKs are not only cell membrane receptors that accept extracellular signals, but also “transfer stations” that transmit signals to cells.

 

In this article , we will open the door of the cell, walk into the cell, learn an important intracellular signal transmission pathway, and sense the signal pathway from outside the cell into the cell, until it enters the nucleus and regulates gene expression and induces specific physiological effects. The magic process.

 

 


01 Preface

The mitogen-activated protein kinases (MAPK) signaling pathway is one of the important pathways in the eukaryotic signal transmission network.

It is cell proliferation, differentiation, apoptosis, and stress under normal and pathological conditions. The key signaling pathway of response.

 

MAPK is a group of evolutionarily conserved serine-threonine kinases, which can be divided into 4 subfamilies: ERK, p38, JNK and BMK1 (also known as ERK5), which represent the four classic MAPK pathways respectively.

 

The MAPK signaling pathway is a cascade of phosphorylation. The core members include: MAP kinase kinase (MAPKKK or MKKK), MAP kinase kinase (MAPKK or MKK), and MAP Kinase (MAPK).

At present, 25, 7, and 13 types of MAPKKK, MAPKK, and MAPK have been identified.

 

Among them, MAPKKK represented by RAF acts on MAPKK represented by MEK to phosphorylate and activate it.

The activated MEK then acts on the MAPK family signal molecule to phosphorylate and activate it. The activated MAPK enters the nucleus for regulation. Transcription regulation.

 

MAPK signaling pathwayFigure 1. The four classic pathways of MAPK

 

 

 

 


02 RAS-Raf-MEK 1/2-ERK 1/2 pathway

 

2.1 Signal transmission process

At present, ERK1/ERK2 kinase is the most widely studied in the MAPK family.

The specific process of this pathway is: extracellular growth factors such as EGF activate tyrosine kinase receptors (such as EGFR), provide a binding site for the adaptor protein GRB2, and recruit SOS protein to the cell membrane.

SOS activates Ras by consuming GTP to form Ras-GTP.

 

MAPK signaling pathwayFigure 2. Downstream proteins of Ras

 

 

As shown in the figure above, Ras can interact with multiple downstream proteins after activation, including: AF6, PI3K, PLCε, RAF, etc.

Among them, Ras-GTP recruits Raf protein to the plasma membrane and makes it phosphorylated by various other kinases (PKA, PAK, SRC) to activate its kinase function.

The Raf protein family includes BRAF, ARAF and CRAF (Raf1). BRAF plays an important role in the formation and development of malignant tumors.

 

The activated Raf kinase further binds to the downstream MEK 1/2 and activates ERK1/2.

Activated ERK1/2 can continue to phosphorylate transcription factors such as ELK1, ETS, FOS, JUN, MYC and SP1, and induce the expression of genes related to cell cycle and cell proliferation;

in addition, activated ERK1/2 can also phosphorylate a variety of cells Inner kinases, such as: RAKs, MSKs, MNKs, these kinases have an effect on cell proliferation and adhesion.

 

2.2 Signal pathways and tumors

The following figure shows mutations related to the RTK/RAS/RAF pathway found in different solid tumors.

This signaling pathway is closely related to the occurrence of multiple cancers. For the key targets on this pathway, multiple drugs have been successfully marketed .

 

MAPK signaling pathwayFigure 3. Mutations related to the Ras-Raf-MEK pathway in solid tumors

 

 

2.2.1 Ras and tumor

Ras is a GTP-binding protein, which mainly includes: H-Ras/K-Ras/N-Ras. The three have 85% amino acid homologous sequences among each other and are important targets for cancer research.

 

Among them, Kras is the most frequently occurring subtype in the Ras family, accounting for 85% of the total number of Ras gene mutations.

Studies have found that Kras has mutations in 90% of pancreatic ductal carcinomas; in addition, in melanomas, Ras mutations are nearly 28%, of which N-Ras is the main mutant (93%).

 

Although Ras is closely related to the occurrence and development of tumors, there are still no targeted drugs that directly target Ras on the market.

The main reason is the featureless, nearly spherical structure of the Ras protein without obvious binding sites, so it has been regarded as a “non-drug target” for a long time.

 

However, in recent years, research on covalent inhibitors and the emergence of targeted degradants have made it possible to target KRAS mutants.

 

MAPK signaling pathwayFigure 4. Development of targeted drugs for each link of the pathway

 

2.2.2 BRAF and tumor

The RAF gene family includes BRAF, ARAF and CRAF. Among them, BRAF plays an important role in the formation and development of malignant tumors.

The most common form of BRAF mutation is the mutation of T to A at nucleotide 1,799 of exon 15, which causes the encoded valine to change to glutamate, which is the BRAF V600E mutation (accounting for 80% of all BRAF mutations) .

 

This mutation continuously activates the BRAF protein, increasing its activity by about 500 times, and can continuously activate the downstream ERK independently of the upstream RAS kinase monomer, and ultimately lead to the immortal proliferation and division of cells.

 

At present, the main drugs for BRAF single-target/multi-target are: dabrafenib, regorafenib, verofenib, sorafenib and so on.

 

2.2.3 MEK and tumor

MEK1/2 is the downstream protein of Ras and Raf, which are easily mutated, so it can also be used as a target.

At present, the approved inhibitors of this target are mainly used for melanoma and lung adenocarcinoma, such as trametinib and selumetinib.

 

2.2.4 ERK and tumor

ERK kinase is the only downstream target of MEK kinase. Studies have shown that inhibitors targeting the ERK target can effectively block the RAS-RAF-MEK-ERK signaling pathway, and can effectively reverse the upstream BRAF and MEK mutations.

Currently, ERK inhibitors in clinical trials are mainly: AZD0364, KO-947, Ulixertinib.

 

It is worth noting that the small molecule inhibitor HH2710, developed by Shanghai Haihe Pharmaceuticals and the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, has also been approved by the US FDA for clinical trials in September 2019.

 

It is intended to be used for the treatment of MAPK signals confirmed by testing Malignant tumors with abnormal pathway genes.

 

 

03 Three other MAPK pathways

 

Figure 5. ERK 1/2 and the other three MAPK pathways

 

In addition to the well-known Ras-Raf-MEK-ERK pathway, according to the different types of MAPK (p38, JNK, ERK5), MAPK also has three classic pathways. Among them, the physiological effects involved in p38 and JNK pathways are mainly related to stress responses such as inflammation and apoptosis.

 

3.1 JNK/SAPK cascade reaction

JNK (JUN N-terminal kinases, JNK) mainly includes JNK1/2/3, also called SAPKs (stress-activated protein kinases).

The JNK/SAPK signaling pathway can be stimulated by stress (such as ultraviolet rays, heat shock, hypertonic stimulation and protein synthesis inhibitors, etc.), cytokines (TNFα, IL-1), growth factors (EGF) and certain G protein couplings The receptor is activated.

 

The stress response signal is transmitted to MAPKKK via the Rho subfamily (Rac, Rho, cdc42), one of the members of the small molecule G protein Ras superfamily, and further activates MEK4/7 and JNK in turn.

 

After phosphorylation of JNK is activated, it can act on a variety of downstream transcription factors (such as JUN, ELK1, ETS2, etc.) and kinases (mainly MNK) to produce various physiological effects such as promoting growth, differentiation, survival, and apoptosis.

 

Figure 6. JNK/SAPK cascade reaction

 

3.2 p38 cascade

There are four main types of P38 kinase: p38 α, β, γ and δ. The main inducements that induce this pathway are: hypoxia, ultraviolet radiation, osmotic shock, inflammation and other stress responses.

P38 MAPK kinase is mainly activated by phosphorylation of ERK3/6, and further promotes cell apoptosis and inhibits cell proliferation by inducing transcription factors and kinases.

In addition, this pathway also promotes cell movement.

 

3.3 BMK1 (ERK5) cascade reaction

ERK5 can be activated by upstream MEK5. Similar to the ERK1/2 pathway, this pathway is also related to cell proliferation.

 

 

 

MAPK signaling pathway

(source:internet, reference only)


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