RAG1: A Potential Drug Target for Cancer (G5896)

Target Name: RAG1

NCBI ID: G5896

RAG1: A Potential Drug Target for Cancer

RAG1 (RAG1_HUMAN), also known as PDGF receptor alpha chain, is a protein that is expressed in various tissues of the human body. It is a member of the PDGF family, which is a group of transmembrane proteins that play a crucial role in cell signaling and development. RAG1 is one of the four PDGF receptors that are known to be involved in cancer progression.

The PDGF family of proteins is characterized by the presence of a tyrosine kinase active domain and an intracellular signaling pathway. This domain can convert growth factors into intracellular signaling molecules, leading to a variety of biological effects. RAG1 is a 700-amino-acid polypeptide whose extracellular domain contains an intracellular signal transduction pathway. This pathway consists of two major components: the SMAD binding domain and the tyrosine kinase active domain. The SMAD binding region is an 伪-helical structure containing 21 amino acids, which is where the SMAD protein binds to the PDGF receptor. The tyrosine kinase active domain is a 12-amino acid alpha-helical structure that is where tyrosine kinase activity occurs.

RAG1 plays an important role in various cancers. It is highly expressed in cancers such as skin cancer, neuroblastoma, leukemia, and breast cancer. The expression level of RAG1 is also closely related to the prognosis of various cancers. Studies have shown that the expression level of RAG1 is positively correlated with the invasion and metastasis ability of breast cancer and negatively correlated with the survival rate of neuroblastoma.

Because RAG1 is highly expressed in a variety of cancers, it is considered a potential drug target. Researchers have discovered a variety of drug molecules related to RAG1, including antibodies, drugs and chemicals. Among them, the most eye-catching are anti-PDGF drugs. These drugs inhibit tumor growth by interfering with the PDGF signaling pathway. For example, the anti-PDGF drug apatinib (Apafangen) has been used to treat a variety of cancers, including breast, lung, and prostate cancers.

In addition to anti-PDGF drugs, the researchers also discovered other drugs related to RAG1.

Protein Name: Recombination Activating 1

Functions: Catalytic component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. V(D)J recombination assembles a diverse repertoire of immunoglobulin and T-cell receptor genes in developing B and T-lymphocytes through rearrangement of different V (variable), in some cases D (diversity), and J (joining) gene segments. In the RAG complex, RAG1 mediates the DNA-binding to the conserved recombination signal sequences (RSS) and catalyzes the DNA cleavage activities by introducing a double-strand break between the RSS and the adjacent coding segment. RAG2 is not a catalytic component but is required for all known catalytic activities. DNA cleavage occurs in 2 steps: a first nick is introduced in the top strand immediately upstream of the heptamer, generating a 3'-hydroxyl group that can attack the phosphodiester bond on the opposite strand in a direct transesterification reaction, thereby creating 4 DNA ends: 2 hairpin coding ends and 2 blunt, 5'-phosphorylated ends. The chromatin structure plays an essential role in the V(D)J recombination reactions and the presence of histone H3 trimethylated at 'Lys-4' (H3K4me3) stimulates both the nicking and haipinning steps. The RAG complex also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. The introduction of DNA breaks by the RAG complex on one immunoglobulin allele induces ATM-dependent repositioning of the other allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. In addition to its endonuclease activity, RAG1 also acts as an E3 ubiquitin-protein ligase that mediates monoubiquitination of histone H3. Histone H3 monoubiquitination is required for the joining step of V(D)J recombination. Mediates polyubiquitination of KPNA1 (By similarity)

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