Human PTN blocking peptide

The human PTN gene is located on chromosome 7q33, contains at least 7 exons, and is greater than 42kb in length. The PTN gene is highly conserved in different species. In addition to humans, homologous sequences have been reported in cattle, chickens, mice, fish, insects, and frogs. It is the most conserved gene among all known growth factors. PTN protein is a secretory growth factor that, together with MK, forms the heparin-binding growth factor family. Its protein molecular structure includes two randomly curled amino acid residue ends (N-terminus and C-terminus) and two β-folded structures. Each β-folded structure maintains its spatial structure through disulfide bonds between the five internal peptide chains, and the two β-folded structures are connected by a flexible linker. Known PTN receptors include N receptor (N-syndecan), receptor-type protein tyrosine phosphatase (RPTPβ/ζ) and anaplastic lymphoma enzyme (ALK). PTN has two forms, 15KDa and 18KDa. The 15KDa PTN is produced by removing 12 amino acids from the C-terminus of the 18KDa PTN protein. These two forms of PTN act on different receptors. The 18KDa PTN binds to the receptor-type protein tyrosine phosphatase RPTPβ/ζ, while the 15KDa PTN binds to the anaplastic lymphoma kinase ALK. The signal transduction mediated by the former is related to cell migration, while the signal transduction mediated by the latter is related to the proliferation signal transduction mediated by map kinase.

Figure 1. Summary of the main biological events regulated by PTN occurring in the metabolic organs. (Sources: Ballesteros-Pla C, et al. 2023)

The pleiotropic protein PTN has multiple biological functions: (1) Promoting mitosis: PTN can promote DNA synthesis in cells transformed by the V-Sis proto-oncogene, and has mitotic effects on epithelial cells, endothelial cells and fibroblasts; (2) Promoting the growth of nerve cell axons and participating in the process of nerve cell damage diseases: PTN can promote the growth of axons of different nerve cells, including cultured embryonic cells, peripheral cortical cells, neuroblastoma cells, etc. PTN is also involved in the differentiation of oligodendrocytes and accelerates the differentiation of oligodendrocyte precursor cells into oligodendrocytes, and may have a potentially important role in Alzheimer's disease. (3) Promoting angiogenesis: PTN can be expressed around new blood vessels in the damaged cortex, and only appears around vascular endothelial cells, activated macrophages and activated astrocytes. PTN can also promote the proliferation and DNA synthesis of cultured endothelial cells, and participates in angiogenesis both in vitro and in vivo. (4) Participate in the development of bones, kidneys, lungs and teeth: During embryonic development, PTN is expressed during epithelial-mesenchymal interactions. Teeth, lungs, kidneys and some typical organs are formed through epithelial-mesenchymal interactions. In vitro, PTN can induce ureteral branching, stimulate the formation of chicken limb bud chondroitin, and induce osteoblast migration; (5) Related to tumors: Studies have found that PTN is highly expressed in tumors such as neuroblastoma, glioma, choriocarcinoma, ovarian cancer, prostate cancer, colon cancer, pancreatic cancer and melanoma. In these tumor tissues, endogenous genes are continuously activated, while PTN expression is difficult to detect in the corresponding non-tumor tissues.

In 1992, Wellstein et al. isolated and purified a protein from the culture supernatant of human breast cancer cells. Sequence analysis confirmed that it was PTN. PTN mRNA can be detected in human breast cancer cells. Experiments have found that human breast cancer cells can secrete PTN and stimulate tumor cell growth and tumor blood vessel formation. Subsequently, PTN was found to be abnormally expressed in a variety of tumors and tumor cells. Some researchers used ELISA to quantitatively detect PTN in the serum of patients with pancreatic cancer, colon cancer, gastric cancer, testicular cancer and other tumors. The results found that the serum PTN content of tumor patients was significantly higher than that of the control group. Some researchers also measured PTN concentrations in the serum of normal controls, pancreatitis and pancreatic cancer patients, and found that PTN increased in a gradient among the three. They believed that abnormal expression of PTN may be an early event in the development of pancreatic cancer, and PTN It can be used as a monitoring indicator for the treatment effect of pancreatic cancer. Researchers have found that PTN is differentially expressed in melanocytic nevi and melanocytomas, and believe that PTN may be one of the important factors promoting the formation of melanocytic tumors. In addition, researchers also found that PTN is highly expressed in breast cancer cells and believe that PTN increases the malignancy of cancer cell phenotypes by activating the PTN/RPTPβ/ζ signaling pathway, thus having a significant impact on the tumor microenvironment. The study found that 100% of gastric cancer and adjacent tissues express PTN mRNA. The expression of PTN protein in cancer tissues is significantly higher than that in adjacent tissues, and the expression of PTN protein in patients with distant metastasis is significantly higher than that in those without metastasis. This shows that PTN protein expression is related to the invasive growth of gastric cancer. High expression of PTN can also accelerate peripheral nerve invasion of prostate cancer, is closely related to prostate cancer TNM stage and lymph node metastasis, and reduces the 3-year postoperative survival rate of prostate cancer patients. Studies have found that PTN levels in the serum of patients with multiple myeloma are significantly elevated and significantly reduced when treatment is effective, suggesting that PTN may be a biomarker for monitoring multiple myeloma disease status and treatment response.

HBGF-8
Heparin-binding growth factor 8
HB-GAM
OSF-1
Pleiotrophin