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Neurotensin Receptor

Neurotensin is a 13-amino acids peptide that is produced from a single precursor, pre-pro-neurotensin, which gives rise to both NTS and the related peptide neuromedin N. Neurotensin (NTS) is a tridecapeptide that acts as neurotransmitter or neuromodulator in the central nervous system (CNS), which has been related to CNS physiology and pathology, such as potent hypothermia, opioid-independent analgesia, Parkinson’s disease and Schizophrenia; In the periphery, NTS as a local hormone, which has a detrimental effect by contributing to fat storage, obesity and metabolic disorders. Among the diverse biological effects of NTS is an ability to promote the growth of tissue, this effect not only indicates a role for NTS in the regulation of normal tissue growth, but also suggests that NTS could contributes to the growth of cancers. Neurotensin exerts its effects primarily through two seven-transmembrane G-protein-coupled receptors (GPCR), namely high-affinity neurotensin receptor1 (NTSR1) and low-affinity neurotensin receptor (NTSR2), as well as through NTSR3 (Sortilin 1), a single transmembrane domain sorting receptor. β-catenin translocates to nucleus and associates with transcription factor T cell factor (Tcf), the β-catenin/Tcf complex activates NTSR1 gene transcription through binding to the functional consensus DNA binding site for Tcf in the NTSR1 promoter, suggesting that the Wnt/APC/β-catenin signaling pathway is responsible for dysregulation of NTSR1 in colon cancer. 
The NTSR2 receptor is a 410-amino acids protein, which shares approximately 64% homology with NTSR1. The NTSR3 (sortilin 1) receptor is unique among the NTSRs that it is a single transmembrane domain receptor of the Type Ι family, which is not specific for NTS and can bind a variety of ligands, such as lipoprotein lipase, receptor associated protein (RAP), pro-neurotrophins and sphingolipid activator protein(SAP). The mechanisms underlying NTSR3-induced cancer progression depend, in part, on soluble NTSR3(sNTSR3), which is released by shedding from the extracellular domain of NTSR3; soluble NTSR3 increases intracellular calcium concentrations and induces focal adhesion kinase (FAK)/Src-dependent activation of the inositol1,4,5-trisphosphate (IP3) kinase pathway in adenocarcinoma epithelial cells. There are many signal transduction pathways that mediate the main effects of NTS and they have been studied in different types of cancer, including non-small cell lung cancers (NSCLC), pancreatic adenocarcinomas, prostate cancers, hepatocellular carcinoma, colon tumors, breast cancers, and gliomas. Neurotensin participates in each step of cancer progression, from survival and growth to metastatic spread, with all these cellular events activated because of the abnormal expression of NTSRs.

References

1.Ouyang Q, et al. Clin Exp Pharmacol Physiol. 2017;44(8):841–846.