Current Medicinal ChemistryCurrent Medicinal ChemistryCurrent Medicinal Chemistry0929-86731875-533XBentham Science64511210.2174/0929867331666230818110812Anti-Infectives and Infectious DiseasesResearch ArticleAssociation of Neurokinin-1 Receptor Signaling Pathways with CancerRodriguezFranciscoinfo@benthamscience.netCovenasRafaelinfo@benthamscience.netDepartment of Biochemistry and Molecular Biology, Faculty of Chemical Sciences, University of SalamancaBMD (Bases Moleculares del Desarrollo), University of Salamanca2010202431396460648607012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://edgccjournal.org/0929-8673/article/view/645112

Background:Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and epigenetic changes, modified intracellular signaling, and failure of control mechanisms caused by intrinsic and extrinsic factors alone or combined. No unique biochemical events are responsible; entangled molecular reactions conduct the resident cells in a tissue to display uncontrolled growth and abnormal migration. Copious experimental research supports the etiological responsibility of NK-1R (neurokinin-1 receptor) activation, alone or cooperating with other mechanisms, in cancer appearance in different tissues. Consequently, a profound study of this receptor system in the context of malignant processes is essential to design new treatments targeting NK-1R-deviated activity.

Methods:This study reviews and discusses recent literature that analyzes the main signaling pathways influenced by the activation of neurokinin 1 full and truncated receptor variants. Also, the involvement of NK-1R in cancer development is discussed.

Conclusion:NK-1R can signal through numerous pathways and cross-talk with other receptor systems. The participation of override or malfunctioning NK-1R in malignant processes needs a more precise definition in different types of cancers to apply satisfactory and effective treatments. A long way has already been traveled: the current disposal of selective and effective NK-1R antagonists and the capacity to develop new drugs with biased agonistic properties based on the receptor's structural states with functional significance opens immediate research action and clinical application.

Neurokinin-1 receptortruncated NK-1Rsignaling pathwaysG-protein-coupled receptorsNK-1R antagonistscancer treatment.Kroemer, G.; Pouyssegur, J. Tumor cell metabolism: Cancer’s Achilles’ heel. Cancer Cell, 2008, 13(6), 472-482. doi: 10.1016/j.ccr.2008.05.005 PMID: 18538731Revathidevi, S.; Munirajan, A.K. Akt in cancer: Mediator and more. Semin. Cancer Biol., 2019, 59, 80-91. doi: 10.1016/j.semcancer.2019.06.002 PMID: 31173856Nirmaladevi, R.; Paital, B.; Jayachandran, P.; Padma, P.R.; Nirmaladevi, R. Epigenetic alterations in cancer. Front. Biosci., 2020, 25(6), 1058-1109. doi: 10.2741/4847 PMID: 32114424GPCR. Database., 2022. Available from: https://gpcrdb.org/protein/nk1r_human (Accessed on: 22 December 2022).Venkatakrishnan, A.J.; Flock, T.; Prado, D.E.; Oates, M.E.; Gough, J.; Madan Babu, M. Structured and disordered facets of the GPCR fold. Curr. Opin. Struct. Biol., 2014, 27, 129-137. doi: 10.1016/j.sbi.2014.08.002 PMID: 25198166Wootten, D.; Christopoulos, A.; Sexton, P.M. Emerging paradigms in GPCR allostery: Implications for drug discovery. Nat. Rev. Drug Discov., 2013, 12(8), 630-644. doi: 10.1038/nrd4052 PMID: 23903222Jiang, H.; Galtes, D.; Wang, J.; Rockman, H.A. G protein-coupled receptor signaling: Transducers and effectors. Am. J. Physiol. Cell Physiol., 2022, 323(3), C731-C748. doi: 10.1152/ajpcell.00210.2022 PMID: 35816644Engelman, D.M.; Xiao Zhou, F.; Cocco, M.J.; Russ, W.P.; Brunger, A.T. Interhelical hydrogen bonding drives strong interactions in membrane proteins. Nat. Struct. Biol., 2000, 7(2), 154-160. doi: 10.1038/72430 PMID: 10655619DeWire, S.M.; Ahn, S.; Lefkowitz, R.J.; Shenoy, S.K. Beta-arrestins and cell signaling. Annu. Rev. Physiol., 2007, 69(1), 483-510. doi: 10.1146/annurev.physiol.69.022405.154749 PMID: 17305471Rajagopal, S.; Rajagopal, K.; Lefkowitz, R.J. Teaching old receptors new tricks: Biasing seven-transmembrane receptors. Nat. Rev. Drug Discov., 2010, 9(5), 373-386. doi: 10.1038/nrd3024 PMID: 20431569Weis, W.I.; Kobilka, B.K. The molecular basis of G protein-coupled receptor activation. Annu. Rev. Biochem., 2018, 87(1), 897-919. doi: 10.1146/annurev-biochem-060614-033910 PMID: 29925258Smith, J.S.; Pack, T.F.; Inoue, A.; Lee, C.; Zheng, K.; Choi, I.; Eiger, D.S.; Warman, A.; Xiong, X.; Ma, Z.; Viswanathan, G.; Levitan, I.M.; Rochelle, L.K.; Staus, D.P.; Snyder, J.C.; Kahsai, A.W.; Caron, M.G.; Rajagopal, S. Noncanonical scaffolding of G αi and β-arrestin by G protein–coupled receptors. Science., 2021, 371(6534), eaay1833. doi: 10.1126/science.aay1833 PMID: 33479120DeVree, B.T.; Mahoney, J.P.; Vélez-Ruiz, G.A.; Rasmussen, S.G.F.; Kuszak, A.J.; Edwald, E.; Fung, J.J.; Manglik, A.; Masureel, M.; Du, Y.; Matt, R.A.; Pardon, E.; Steyaert, J.; Kobilka, B.K.; Sunahara, R.K. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature, 2016, 535(7610), 182-186. doi: 10.1038/nature18324 PMID: 27362234Liu, Y.; An, S.; Ward, R.; Yang, Y.; Guo, X.X.; Li, W.; Xu, T.R. G protein-coupled receptors as promising cancer targets. Cancer Lett., 2016, 376(2), 226-239. doi: 10.1016/j.canlet.2016.03.031 PMID: 27000991Chaudhary, P.K.; Kim, S. An insight into GPCR and G-proteins as cancer drivers. Cells, 2021, 10(12), 3288. doi: 10.3390/cells10123288 PMID: 34943797Luo, J.; Yu, F.X. GPCR-hippo signaling in cancer. Cells, 2019, 8(5), 426. doi: 10.3390/cells8050426 PMID: 31072060Kage, R.; Leeman, S.E.; Boyd, N.D. Biochemical characterization of two different forms of the substance P receptor in rat submaxillary gland. J. Neurochem., 1993, 60(1), 347-351. doi: 10.1111/j.1471-4159.1993.tb05857.x PMID: 8380195Holst, B.; Nygaard, R.; Valentin-Hansen, L.; Bach, A.; Engelstoft, M.S.; Petersen, P.S.; Frimurer, T.M.; Schwartz, T.W. A conserved aromatic lock for the tryptophan rotameric switch in TM-VI of seven-transmembrane receptors. J. Biol. Chem., 2010, 285(6), 3973-3985. doi: 10.1074/jbc.M109.064725 PMID: 19920139UniProt Database. 2022. Available from: https://www.uniprot.org/uniprot/P25103 (Accessed on: 22 December 2022).Gayen, A.; Goswami, S.K.; Mukhopadhyay, C. NMR evidence of GM1-induced conformational change of Substance P using isotropic bicelles. Biochim. Biophys. Acta Biomembr., 2011, 1808(1), 127-139. doi: 10.1016/j.bbamem.2010.09.023 PMID: 20937248V Euler, U.S.; Gaddum, J.H. An unidentified depressor substance in certain tissue extracts. J. Physiol., 1931, 72(1), 74-87. doi: 10.1113/jphysiol.1931.sp002763 PMID: 16994201Severini, C.; Improta, G.; Falconieri-Erspamer, G.; Salvadori, S.; Erspamer, V. The tachykinin peptide family. Pharmacol. Rev., 2002, 54(2), 285-322. doi: 10.1124/pr.54.2.285 PMID: 12037144Almeida, T.A.; Rojo, J.; Nieto, P.M.; Pinto, F.M.; Hernandez, M.; Martín, J.D.; Candenas, M.L. Tachykinins and tachykinin receptors: Structure and activity relationships. Curr. Med. Chem., 2004, 11(15), 2045-2081. doi: 10.2174/0929867043364748 PMID: 15279567Zhang, Y.; Lu, L.; Furlonger, C.; Wu, G.E.; Paige, C.J. Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis. Nat. Immunol., 2000, 1(5), 392-397. doi: 10.1038/80826 PMID: 11062498Borbély, É.; Helyes, Z. Role of hemokinin-1 in health and disease. Neuropeptides, 2017, 64, 9-17. doi: 10.1016/j.npep.2016.12.003 PMID: 27993375Mussap, C.J.; Geraghty, D.P.; Burcher, E. Tachykinin receptors: A radioligand binding perspective. J. Neurochem., 1993, 60(6), 1987-2009. doi: 10.1111/j.1471-4159.1993.tb03484.x PMID: 8388031Pennefather, J.N.; Lecci, A.; Candenas, M.L.; Patak, E.; Pinto, F.M.; Maggi, C.A. Tachykinins and tachykinin receptors: A growing family. Life Sci., 2004, 74(12), 1445-1463. doi: 10.1016/j.lfs.2003.09.039 PMID: 14729395Preininger, A.M.; Meiler, J.; Hamm, H.E. Conformational flexibility and structural dynamics in GPCR-mediated G protein activation: A perspective. J. Mol. Biol., 2013, 425(13), 2288-2298. doi: 10.1016/j.jmb.2013.04.011 PMID: 23602809Pándy-Szekeres, G.; Esguerra, M.; Hauser, A.S.; Caroli, J.; Munk, C.; Pilger, S.; Keserű, G.M.; Kooistra, A.J.; Gloriam, D.E. The G protein database, GproteinDb. Nucleic Acids Res., 2022, 50(D1), D518-D525. doi: 10.1093/nar/gkab852 PMID: 34570219Deng, X.T.; Tang, S.M.; Wu, P.Y.; Li, Q.P.; Ge, X.X.; Xu, B.M.; Wang, H.S.; Miao, L. SP/NK-1R promotes gallbladder cancer cell proliferation and migration. J. Cell. Mol. Med., 2019, 23(12), 7961-7973. doi: 10.1111/jcmm.14230 PMID: 30903649Muñoz, M.; Rosso, M.; Coveñas, R. Neurokinin-1 receptor antagonists against hepatoblastoma. Cancers., 2019, 11(9), 1258. doi: 10.3390/cancers11091258 PMID: 31466222Muñoz, M.; Coveñas, R. Coveñas, R. The neurokinin-1 receptor antagonist aprepitant: An intelligent bullet against cancer? Cancers., 2020, 12(9), 2682. doi: 10.3390/cancers12092682 PMID: 32962202Isorna, I.; Esteban, F.; Solanellas, J.; Coveñas, R.; Muñoz, M. The substance P and neurokinin-1 receptor system in human thyroid cancer: An immunohistochemical study. Eur. J. Histochem., 2020, 64(2), 3117. doi: 10.4081/ejh.2020.3117 PMID: 32363847Esteban, F.; Ramos-García, P.; Muñoz, M.; González-Moles, M.Á. Substance P and neurokinin 1 receptor in chronic inflammation and cancer of the head and neck: A Review of the literature. Int. J. Environ. Res. Public Health, 2021, 19(1), 375. doi: 10.3390/ijerph19010375 PMID: 35010633Coveñas, R.; Muñoz, M. Involvement of the substance P/neurokinin-1 receptor system in cancer. Cancers., 2022, 14(14), 3539. doi: 10.3390/cancers14143539 PMID: 35884599García-Aranda, M.; Téllez, T.; McKenna, L.; Redondo, M. Neurokinin-1 receptor (NK-1R) antagonists as a new strategy to overcome cancer resistance. Cancers., 2022, 14(9), 2255. doi: 10.3390/cancers14092255 PMID: 35565383Ji, T.; Ma, K.; Wu, H.; Cao, T.; Substance, P. (SP)/neurokinin-1 receptor axis promotes perineural invasion of pancreatic cancer and is affected by lncRNA LOC389641. J. Immunol. Res., 2022, 2022, 1-17. doi: 10.1155/2022/5582811 PMID: 35600049Muñoz, M.; Rosso, M.; Coveñas, R. Triple negative breast cancer: How neurokinin-1 receptor antagonists could be used as a new therapeutic approach. Mini Rev. Med. Chem., 2020, 20(5), 408-417. doi: 10.2174/1389557519666191112152642 PMID: 31721701Ebrahimi, S.; Mirzavi, F.; Aghaee-Bakhtiari, S.H.; Hashemy, S.I. SP/NK1R system regulates carcinogenesis in prostate cancer: Shedding light on the antitumoral function of aprepitant. Biochim. Biophys. Acta Mol. Cell Res., 2022, 1869(5), 119221. doi: 10.1016/j.bbamcr.2022.119221 PMID: 35134443Rodriguez, E.; Pei, G.; Zhao, Z.; Kim, S.; German, A.; Robinson, P. Substance P antagonism as a novel therapeutic option to enhance efficacy of cisplatin in triple negative breast cancer and protect PC12 cells against cisplatin-induced oxidative stress and apoptosis. Cancers., 2021, 13(15), 3871. doi: 10.3390/cancers13153871 PMID: 34359773Zhang, X.W.; Li, L.; Hu, W.Q.; Hu, M.N.; Tao, Y.; Hu, H.; Miao, X.K.; Yang, W.L.; Zhu, Q.; Mou, L.Y. Neurokinin-1 receptor promotes non-small cell lung cancer progression through transactivation of EGFR. Cell Death Dis., 2022, 13(1), 41. doi: 10.1038/s41419-021-04485-y PMID: 35013118DeFea, K.A.; Vaughn, Z.D.; O’Bryan, E.M.; Nishijima, D.; Déry, O.; Bunnett, N.W. The proliferative and antiapoptotic effects of substance P are facilitated by formation of a β-arrestin-dependent scaffolding complex. Proc. Natl. Acad. Sci., 2000, 97(20), 11086-11091. doi: 10.1073/pnas.190276697 PMID: 10995467Pal, K.; Mathur, M.; Kumar, P.; DeFea, K. Divergent β-arrestin-dependent signaling events are dependent upon sequences within G-protein-coupled receptor C termini. J. Biol. Chem., 2013, 288(5), 3265-3274. doi: 10.1074/jbc.M112.400234 PMID: 23235155Guo, S.; Zhao, T.; Yun, Y.; Xie, X. Recent progress in assays for GPCR drug discovery. Am. J. Physiol. Cell Physiol., 2022, 323(2), C583-C594. doi: 10.1152/ajpcell.00464.2021 PMID: 35816640Stamm, S.; Gruber, S.B.; Rabchevsky, A.G.; Emeson, R.B. The activity of the serotonin receptor 2C is regulated by alternative splicing. Hum. Genet., 2017, 136(9), 1079-1091. doi: 10.1007/s00439-017-1826-3 PMID: 28664341Valentin-Hansen, L.; Frimurer, T.M.; Mokrosinski, J.; Holliday, N.D.; Schwartz, T.W. Biased Gs versus Gq proteins and β-arrestin signaling in the NK1 receptor determined by interactions in the water hydrogen bond network. J. Biol. Chem., 2015, 290(40), 24495-24508. doi: 10.1074/jbc.M115.641944 PMID: 26269596Smith, J.S.; Lefkowitz, R.J.; Rajagopal, S. Biased signalling: From simple switches to allosteric microprocessors. Nat. Rev. Drug Discov., 2018, 17(4), 243-260. doi: 10.1038/nrd.2017.229 PMID: 29302067Wootten, D.; Christopoulos, A.; Marti-Solano, M.; Babu, M.M.; Sexton, P.M. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat. Rev. Mol. Cell Biol., 2018, 19(10), 638-653. doi: 10.1038/s41580-018-0049-3 PMID: 30104700Alvarez-Curto, E.; Inoue, A.; Jenkins, L.; Raihan, S.Z.; Prihandoko, R.; Tobin, A.B.; Milligan, G. Targeted elimination of G proteins and arrestins defines their specific contributions to both intensity and duration of G protein-coupled receptor signaling. J. Biol. Chem., 2016, 291(53), 27147-27159. doi: 10.1074/jbc.M116.754887 PMID: 27852822Liggett, S.B. Phosphorylation barcoding as a mechanism of directing GPCR signaling. Sci. Signal., 2011, 4(185), pe36. doi: 10.1126/scisignal.2002331 PMID: 21868354Steinhoff, M.S.; von Mentzer, B.; Geppetti, P.; Pothoulakis, C.; Bunnett, N.W. Tachykinins and their receptors: Contributions to physiological control and the mechanisms of disease. Physiol. Rev., 2014, 94(1), 265-301. doi: 10.1152/physrev.00031.2013 PMID: 24382888Valentin-Hansen, L.; Park, M.; Huber, T.; Grunbeck, A.; Naganathan, S.; Schwartz, T.W.; Sakmar, T.P. Mapping substance P binding sites on the neurokinin-1 receptor using genetic incorporation of a photoreactive amino acid. J. Biol. Chem., 2014, 289(26), 18045-18054. doi: 10.1074/jbc.M113.527085 PMID: 24831006Garcia-Recio, S.; Gascón, P. Biological and pharmacological aspects of the NK1-receptor. BioMed Res. Int., 2015, 2015, 1-14. doi: 10.1155/2015/495704 PMID: 26421291Spitsin, S.; Pappa, V.; Douglas, S.D. Truncation of neurokinin-1 receptor—Negative regulation of substance P signaling. J. Leukoc. Biol., 2018, 103(6), 1043-1051. doi: 10.1002/JLB.3MIR0817-348R PMID: 29345372Javid, H.; Asadi, J.; Zahedi Avval, F.; Afshari, A.R.; Hashemy, S.I. The role of substance P/neurokinin 1 receptor in the pathogenesis of esophageal squamous cell carcinoma through constitutively active PI3K/Akt/NF-κB signal transduction pathways. Mol. Biol. Rep., 2020, 47(3), 2253-2263. doi: 10.1007/s11033-020-05330-9 PMID: 32072401Ebrahimi, S.; Javid, H.; Alaei, A.; Hashemy, S.I. New insight into the role of substance P/neurokinin-1 receptor system in breast cancer progression and its crosstalk with MICRORNAS. Clin. Genet., 2020, 98(4), 322-330. doi: 10.1111/cge.13750 PMID: 32266968Ballesteros, J.A.; Weinstein, H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. J. Neurosci. Methods, 1995, 25, 366-428. doi: 10.1016/S1043-9471(05)80049-7Harris, J.A.; Faust, B.; Gondin, A.B.; Dämgen, M.A.; Suomivuori, C.M.; Veldhuis, N.A.; Cheng, Y.; Dror, R.O.; Thal, D.M.; Manglik, A. Selective G protein signaling driven by substance P–neurokinin receptor dynamics. Nat. Chem. Biol., 2022, 18(1), 109-115. doi: 10.1038/s41589-021-00890-8 PMID: 34711980Rodriguez, F.D; Coveñas, R. The neurokinin-1 receptor: Structure dynamics and signaling. Receptors., 2022, 1(1), 54-71. doi: 10.3390/receptors1010004PDB. Protein Data Bank. 2022. Available from: https://pdb101.rcsb.orgSehnal, D.; Bittrich, S.; Deshpande, M.; Svobodová, R.; Berka, K.; Bazgier, V.; Velankar, S.; Burley, S.K.; Koča, J.; Rose, A.S. Mol* Viewer: Modern web app for 3D visualization and analysis of large biomolecular structures. Nucleic Acids Res., 2021, 49(W1), W431-W437. doi: 10.1093/nar/gkab314 PMID: 33956157Jean-Charles, P.Y.; Kaur, S.; Shenoy, S.K. Protein-coupled receptor signaling through β-Arrestin-dependent mechanisms. J. Cardiovasc. Pharmacol., 2017, 70(3), 142-158. doi: 10.1097/FJC.0000000000000482 PMID: 28328745Shukla, A.K.; Dwivedi-Agnihotri, H. Structure and function of β-arrestins, their emerging role in breast cancer, and potential opportunities for therapeutic manipulation. Adv. Cancer Res., 2020, 145, 139-156. doi: 10.1016/bs.acr.2020.01.001 PMID: 32089163Perry-Hauser, N.A.; Hopkins, J.B.; Zhuo, Y.; Zheng, C.; Perez, I.; Schultz, K.M.; Vishnivetskiy, S.A.; Kaya, A.I.; Sharma, P.; Dalby, K.N.; Chung, K.Y.; Klug, C.S.; Gurevich, V.V.; Iverson, T.M. The two non-visual arrestins engage ERK2 differently. J. Mol. Biol., 2022, 434(7), 167465. doi: 10.1016/j.jmb.2022.167465 PMID: 35077767Xiao, K.; McClatchy, D.B.; Shukla, A.K.; Zhao, Y.; Chen, M.; Shenoy, S.K.; Yates, J.R., III; Lefkowitz, R.J. Functional specialization of β-arrestin interactions revealed by proteomic analysis. Proc. Natl. Acad. Sci., 2007, 104(29), 12011-12016. doi: 10.1073/pnas.0704849104 PMID: 17620599Peterson, Y.K.; Luttrell, L.M. The diverse roles of arrestin scaffolds in G protein-coupled receptor signaling. Pharmacol. Rev., 2017, 69(3), 256-297. doi: 10.1124/pr.116.013367 PMID: 28626043Ghosh, E.; Dwivedi, H.; Baidya, M.; Srivastava, A.; Kumari, P.; Stepniewski, T.; Kim, H.R.; Lee, M.H.; van Gastel, J.; Chaturvedi, M.; Roy, D.; Pandey, S.; Maharana, J.; Guixà-González, R.; Luttrell, L.M.; Chung, K.Y.; Dutta, S.; Selent, J.; Shukla, A.K. Conformational sensors and domain swapping reveal structural and functional differences between β-Arrestin isoforms. Cell Rep., 2019, 28(13), 3287-3299.e6. doi: 10.1016/j.celrep.2019.08.053 PMID: 31553900Wess, J. The two β-arrestins regulate distinct metabolic processes: Studies with novel mutant mouse models. Int. J. Mol. Sci., 2022, 23(1), 495. doi: 10.3390/ijms23010495 PMID: 35008921Han, M.; Gurevich, V.V.; Vishnivetskiy, S.A.; Sigler, P.B.; Schubert, C. Crystal structure of beta-arrestin at 1.9 A: possible mechanism of receptor binding and membrane Translocation. Structure, 2001, 9(9), 869-880. doi: 10.1016/S0969-2126(01)00644-X PMID: 11566136Milano, S.K.; Pace, H.C.; Kim, Y.M.; Brenner, C.; Benovic, J.L. Scaffolding functions of arrestin-2 revealed by crystal structure and mutagenesis. Biochemistry, 2002, 41(10), 3321-3328. doi: 10.1021/bi015905j PMID: 11876640Shenoy, S.K.; Lefkowitz, R.J. Trafficking patterns of beta-arrestin and G protein-coupled receptors determined by the kinetics of beta-arrestin deubiquitination. J. Biol. Chem., 2003, 278(16), 14498-14506. doi: 10.1074/jbc.M209626200 PMID: 12574160Shenoy, S.K.; Lefkowitz, R.J. Receptor-specific ubiquitination of beta-arrestin directs assembly and targeting of seven-transmembrane receptor signalosomes. J. Biol. Chem., 2005, 280(15), 15315-15324. doi: 10.1074/jbc.M412418200 PMID: 15699045Kim, K.; Han, Y.; Duan, L.; Chung, K.Y. Scaffolding of mitogen-activated protein kinase signaling by β-arrestins. Int. J. Mol. Sci., 2022, 23(2), 1000. doi: 10.3390/ijms23021000 PMID: 35055186Cahill, T.J., III; Thomsen, A.R.B.; Tarrasch, J.T.; Plouffe, B.; Nguyen, A.H.; Yang, F.; Huang, L.Y.; Kahsai, A.W.; Bassoni, D.L.; Gavino, B.J.; Lamerdin, J.E.; Triest, S.; Shukla, A.K.; Berger, B.; Little, J., IV; Antar, A.; Blanc, A.; Qu, C.X.; Chen, X.; Kawakami, K.; Inoue, A.; Aoki, J.; Steyaert, J.; Sun, J.P.; Bouvier, M.; Skiniotis, G.; Lefkowitz, R.J. Distinct conformations of GPCR–β-arrestin complexes mediate desensitization, signaling, and endocytosis. Proc. Natl. Acad. Sci., 2017, 114(10), 2562-2567. doi: 10.1073/pnas.1701529114 PMID: 28223524Seckler, J.M.; Robinson, E.N.; Lewis, S.J.; Grossfield, A. Surveying nonvisual arrestins reveals allosteric interactions between functional sites. Proteins, 2023, 91(1), 99-107. doi: 10.1002/prot.26413 PMID: 35988049Yang, Z.; Yang, F.; Zhang, D.; Liu, Z.; Lin, A.; Liu, C.; Xiao, P.; Yu, X.; Sun, J.P. Phosphorylation of G protein-coupled receptors: From the barcode hypothesis to the flute model. Mol. Pharmacol., 2017, 92(3), 201-210. doi: 10.1124/mol.116.107839 PMID: 28246190Jean-Charles, P.Y.; Rajiv, V.; Sarker, S.; Han, S.; Bai, Y.; Masoudi, A.; Shenoy, S.K. A single phenylalanine residue in β-arrestin2 critically regulates its binding to G protein–coupled receptors. J. Biol. Chem., 2022, 298(5), 101837. doi: 10.1016/j.jbc.2022.101837 PMID: 35307348Kawakami, K.; Yanagawa, M.; Hiratsuka, S.; Yoshida, M.; Ono, Y.; Hiroshima, M.; Ueda, M.; Aoki, J.; Sako, Y.; Inoue, A. Heterotrimeric Gq proteins act as a switch for GRK5/6 selectivity underlying β-arrestin transducer bias. Nat. Commun., 2022, 13(1), 487. doi: 10.1038/s41467-022-28056-7 PMID: 35078997Sarma, P.; Saha, S.; Shukla, A.K. Making the switch: The role of Gq in driving GRK selectivity at GPCRs. Sci. Signal., 2022, 15(726), eabo4949. doi: 10.1126/scisignal.abo4949 PMID: 35316098Grundmann, M.; Merten, N.; Malfacini, D.; Inoue, A.; Preis, P.; Simon, K.; Rüttiger, N.; Ziegler, N.; Benkel, T.; Schmitt, N.K.; Ishida, S.; Müller, I.; Reher, R.; Kawakami, K.; Inoue, A.; Rick, U.; Kühl, T.; Imhof, D.; Aoki, J.; König, G.M.; Hoffmann, C.; Gomeza, J.; Wess, J.; Kostenis, E. Lack of beta-arrestin signaling in the absence of active G proteins. Nat. Commun., 2018, 9(1), 341-343. doi: 10.1038/s41467-017-02661-3 PMID: 29362459Zhu, L.; Almaça, J.; Dadi, P.K.; Hong, H.; Sakamoto, W.; Rossi, M.; Lee, R.J.; Vierra, N.C.; Lu, H.; Cui, Y.; McMillin, S.M.; Perry, N.A.; Gurevich, V.V.; Lee, A.; Kuo, B.; Leapman, R.D.; Matschinsky, F.M.; Doliba, N.M.; Urs, N.M.; Caron, M.G.; Jacobson, D.A.; Caicedo, A.; Wess, J. β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions. Nat. Commun., 2017, 8(1), 14295-, 8, 14295. doi: 10.1038/ncomms14295 PMID: 28145434Zhang, Y.X.; Li, X.F.; Yuan, G.Q.; Hu, H.; Song, X.Y.; Li, J.Y.; Miao, X.K.; Zhou, T.X.; Yang, W.L.; Zhang, X.W.; Mou, L.Y.; Wang, R. β-Arrestin 1 has an essential role in neurokinin-1 receptor-mediated glioblastoma cell proliferation and G2/M phase transition. J. Biol. Chem., 2017, 292(21), 8933-8947. doi: 10.1074/jbc.M116.770420 PMID: 28341744Jafri, F.; El-Shewy, H.M.; Lee, M.H.; Kelly, M.; Luttrell, D.K.; Luttrell, L.M. Constitutive ERK1/2 activation by a chimeric neurokinin 1 receptor-beta-arrestin1 fusion protein. Probing the composition and function of the G protein-coupled receptor "signalsome". J. Biol. Chem., 2006, 281(28), 19346-19357. doi: 10.1074/jbc.M512643200 PMID: 16670094Schmidlin, F.; Roosterman, D.; Bunnett, N.W. The third intracellular loop and carboxyl tail of neurokinin 1 and 3 receptors determine interactions with β-arrestins. Am. J. Physiol. Cell Physiol., 2003, 285(4), C945-C958. doi: 10.1152/ajpcell.00541.2002 PMID: 12958028Bagnato, A.; Rosanò, L. Rosanò, L. New routes in GPCR/β-arrestin-driven signaling in cancer progression and metastasis. Front. Pharmacol., 2019, 10, 114. doi: 10.3389/fphar.2019.00114 PMID: 30837880Foord, S.M.; Bonner, T.I.; Neubig, R.R.; Rosser, E.M.; Pin, J.P.; Davenport, A.P.; Spedding, M.; Harmar, A.J. International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol. Rev., 2005, 57(2), 279-288. doi: 10.1124/pr.57.2.5 PMID: 15914470Campbell, A.P.; Smrcka, A.V. Targeting G protein-coupled receptor signalling by blocking G proteins. Nat. Rev. Drug Discov., 2018, 17(11), 789-803. doi: 10.1038/nrd.2018.135 PMID: 30262890Khan, S.M.; Sleno, R.; Gora, S.; Zylbergold, P.; Laverdure, J.P.; Labbé, J.C.; Miller, G.J.; Hébert, T.E. The expanding roles of Gβγ subunits in G protein-coupled receptor signaling and drug action. Pharmacol. Rev., 2013, 65(2), 545-577. doi: 10.1124/pr.111.005603 PMID: 23406670Tennakoon, M.; Senarath, K.; Kankanamge, D.; Ratnayake, K.; Wijayaratna, D.; Olupothage, K.; Ubeysinghe, S.; Martins-Cannavino, K.; Hébert, T.E.; Karunarathne, A. Subtype-dependent regulation of Gβγ signalling. Cell. Signal., 2021, 82, 109947. doi: 10.1016/j.cellsig.2021.109947 PMID: 33582184Harris, G.C.; Aston-Jones, G. Involvement of D2 dopamine receptors in the nucleus accumbens in the opiate withdrawal syndrome. Nature, 1994, 371(6493), 155-157. doi: 10.1038/371155a0 PMID: 7915401Thom, C.; Ehrenmann, J.; Vacca, S.; Waltenspühl, Y.; Schöppe, J.; Medalia, O.; Plückthun, A. Structures of neurokinin 1 receptor in complex with G q and G s proteins reveal substance P binding mode and unique activation features. Sci. Adv., 2021, 7(50), eabk2872. doi: 10.1126/sciadv.abk2872 PMID: 34878828Inoue, A.; Raimondi, F.; Kadji, F.M.N.; Singh, G.; Kishi, T.; Uwamizu, A.; Ono, Y.; Shinjo, Y.; Ishida, S.; Arang, N.; Kawakami, K.; Gutkind, J.S.; Aoki, J.; Russell, R.B. Illuminating G-protein-coupling selectivity of GPCRs. Cell, 2019, 177(7), 1933-1947.e25. doi: 10.1016/j.cell.2019.04.044 PMID: 31160049Senarath, K.; Kankanamge, D.; Samaradivakara, S.; Ratnayake, K.; Tennakoon, M.; Karunarathne, A. regulation of G protein βγ signaling. Int. Rev. Cell Mol. Biol., 2018, 339, 133-191. doi: 10.1016/bs.ircmb.2018.02.008 PMID: 29776603Khan, S.M.; Sung, J.Y.; Hébert, T.E. Gβγ subunits-different spaces, different faces. Pharmacol. Res., 2016, 111, 434-441. doi: 10.1016/j.phrs.2016.06.026 PMID: 27378564Khater, M.; Bryant, C.N.; Wu, G. Gβγ translocation to the Golgi apparatus activates ARF1 to spatiotemporally regulate G protein–coupled receptor signaling to MAPK. J. Biol. Chem., 2021, 296, 100805. doi: 10.1016/j.jbc.2021.100805 PMID: 34022220Smrcka, A.V. G protein βγ subunits: Central mediators of G protein-coupled receptor signaling. Cell. Mol. Life Sci., 2008, 65(14), 2191-2214. doi: 10.1007/s00018-008-8006-5 PMID: 18488142Klayman, L.M.; Wedegaertner, P.B. Wedegaertner, P. B. Inducible inhibition of Gβγ reveals localization-dependent functions at the plasma membrane and Golgi. J. Biol. Chem., 2017, 292(5), 1773-1784. doi: 10.1074/jbc.M116.750430 PMID: 27994056Rajanala, K.; Klayman, L.M.; Wedegaertner, P.B. Gβγ regulates mitotic Golgi fragmentation and G2/M cell cycle progression. Mol. Biol. Cell, 2021, 32(20), br2. doi: 10.1091/mbc.E21-04-0175 PMID: 34260268Madukwe, J.C.; Garland-Kuntz, E.E.; Lyon, A.M.; Smrcka, A.V. G protein βγ subunits directly interact with and activate phospholipase CΕ. J. Biol. Chem., 2018, 293(17), 6387-6397. doi: 10.1074/jbc.RA118.002354 PMID: 29535186Gont, A.; Daneshmand, M.; Woulfe, J.; Lavictoire, S.J.; Lorimer, I.A.J. PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion. Oncotarget, 2017, 8(5), 8559-8573. doi: 10.18632/oncotarget.14348 PMID: 28051998Pfeil, E.M.; Brands, J.; Merten, N.; Vögtle, T.; Vescovo, M.; Rick, U.; Albrecht, I.M.; Heycke, N.; Kawakami, K.; Ono, Y.; Ngako Kadji, F.M.; Hiratsuka, S.; Aoki, J.; Häberlein, F.; Matthey, M.; Garg, J.; Hennen, S.; Jobin, M.L.; Seier, K.; Calebiro, D.; Pfeifer, A.; Heinemann, A.; Wenzel, D.; König, G.M.; Nieswandt, B.; Fleischmann, B.K.; Inoue, A.; Simon, K.; Kostenis, E. Heterotrimeric G protein subunit Gαq is a master switch for Gβγ-mediated calcium mobilization by Gi-coupled GPCRs. Mol. Cell, 2020, 80(6), 940-954.e6. doi: 10.1016/j.molcel.2020.10.027 PMID: 33202251Birnbaumer, L. Expansion of signal transduction by G proteins. Biochim. Biophys. Acta Biomembr., 2007, 1768(4), 772-793. doi: 10.1016/j.bbamem.2006.12.002 PMID: 17258171Davis, T.L.; Bonacci, T.M.; Sprang, S.R.; Smrcka, A.V. Structural and molecular characterization of a preferred protein interaction surface on G protein beta gamma subunits. Biochemistry, 2005, 44(31), 10593-10604. doi: 10.1021/bi050655i PMID: 16060668Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer, 2003, 3(1), 11-22. doi: 10.1038/nrc969 PMID: 12509763Zhang, W.; Liu, H.T. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res., 2002, 12(1), 9-18. doi: 10.1038/sj.cr.7290105 PMID: 11942415Barbosa, R.; Acevedo, L.A.; Marmorstein, R. The MEK/ERK network as a therapeutic target in human cancer. Mol. Cancer Res., 2021, 19(3), 361-374. doi: 10.1158/1541-7786.MCR-20-0687 PMID: 33139506Chen, Q.; Kong, L.; Xu, Z.; Cao, N.; Tang, X.; Gao, R.; Zhang, J.; Deng, S.; Tan, C.; Zhang, M.; Wang, Y.; Zhang, L.; Ma, K.; Li, L.; Si, J. The role of TMEM16A/ERK/NK-1 signaling in dorsal root ganglia neurons in the development of neuropathic pain induced by spared nerve injury (SNI). Mol. Neurobiol., 2021, 58(11), 5772-5789. doi: 10.1007/s12035-021-02520-9 PMID: 34406600Mazein, A.; Rougny, A.; Karr, J.R.; Saez-Rodriguez, J.; Ostaszewski, M.; Schneider, R. Reusability and composability in process description maps: RAS–RAF–MEK–ERK signalling. Brief. Bioinform., 2021, 22(5), bbab103. doi: 10.1093/bib/bbab103 PMID: 33834185Roberts, P.J.; Der, C.J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 2007, 26(22), 3291-3310. doi: 10.1038/sj.onc.1210422 PMID: 17496923Avery, T.Y.; Köhler, N.; Zeiser, R.; Brummer, T.; Ruess, D.A. Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation. Front. Oncol., 2022, 12, 931774. doi: 10.3389/fonc.2022.931774 PMID: 35965494Wan, W.; Xiao, W.; Pan, W.; Chen, L.; Liu, Z.; Xu, J. Isoprenylcysteine carboxyl methyltransferase is critical for glioblastoma growth and survival by activating Ras/Raf/Mek/Erk. Cancer Chemother. Pharmacol., 2022, 89(3), 401-411. doi: 10.1007/s00280-022-04401-x PMID: 35171349Gao, Z.; Chen, J.F.; Li, X.G.; Shi, Y.H.; Tang, Z.; Liu, W.R.; Zhang, X.; Huang, A.; Luo, X.M.; Gao, Q.; Shi, G.M.; Ke, A.W.; Zhou, J.; Fan, J.; Fu, X.T.; Ding, Z.B. KRAS acting through ERK signaling stabilizes PD-L1 via inhibiting autophagy pathway in intrahepatic cholangiocarcinoma. Cancer Cell Int., 2022, 22(1), 128. doi: 10.1186/s12935-022-02550-w PMID: 35305624Yadav, D.K. Editorial: Kinase inhibitors in cancer therapy. Front. Cell Dev. Biol., 2022, 10, 1020297. doi: 10.3389/fcell.2022.1020297 PMID: 36393866Vendramini, E.; Bomben, R.; Pozzo, F.; Bittolo, T.; Tissino, E.; Gattei, V.; Zucchetto, A. KRAS and RAS-MAPK pathway deregulation in mature B cell lymphoproliferative disorders. Cancers., 2022, 14(3), 666. doi: 10.3390/cancers14030666 PMID: 35158933Atif, M.; Mustaan, M.A.; Falak, S.; Ghaffar, A.; Munir, B. Targeting the effect of sofosbuvir on selective oncogenes expression level of hepatocellular carcinoma Ras/Raf/MEK/ERK pathway in Huh7 cell line. Saudi J. Biol. Sci., 2022, 29(8), 103332. doi: 10.1016/j.sjbs.2022.103332 PMID: 35813116Asati, V.; Mahapatra, D.K.; Bharti, S.K. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur. J. Med. Chem., 2016, 109, 314-341. doi: 10.1016/j.ejmech.2016.01.012 PMID: 26807863Yamaguchi, K.; Richardson, M.D.; Bigner, D.D.; Kwatra, M.M. Signal transduction through substance P receptor in human glioblastoma cells: roles for Src and PKCδ. Cancer Chemother. Pharmacol., 2005, 56(6), 585-593. doi: 10.1007/s00280-005-1030-3 PMID: 16012865Degirmenci, U.; Wang, M.; Hu, J. Targeting aberrant RAS/RAF/MEK/ERK signaling for cancer therapy. Cells, 2020, 9(1), 198. doi: 10.3390/cells9010198 PMID: 31941155Williams, R.; Zou, X.; Hoyle, G.W. Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-κB via a G q -dependent pathway. Am. J. Physiol. Lung Cell. Mol. Physiol., 2007, 292(2), L430-L437. doi: 10.1152/ajplung.00475.2005 PMID: 17041011Asl, E.R.; Amini, M.; Najafi, S.; Mansoori, B.; Mokhtarzadeh, A.; Mohammadi, A.; Lotfinejad, P.; Bagheri, M.; Shirjang, S.; Lotfi, Z.; Rasmi, Y.; Baradaran, B. Interplay between MAPK/ERK signaling pathway and MicroRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression. Life Sci., 2021, 278, 119499. doi: 10.1016/j.lfs.2021.119499 PMID: 33865878Muñoz, M.; González-Ortega, A.; Salinas-Martín, M.V.; Carranza, A.; Garcia-Recio, S.; Almendro, V.; Coveñas, R. The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer. Int. J. Oncol., 2014, 45(4), 1658-1672. doi: 10.3892/ijo.2014.2565 PMID: 25175857Yue, J.; López, J.M. Understanding MAPK signaling pathways in apoptosis. Int. J. Mol. Sci., 2020, 21(7), 2346. doi: 10.3390/ijms21072346 PMID: 32231094Tangchirakhaphan, S.; Innajak, S.; Nilwarangkoon, S.; Tanjapatkul, N.; Mahabusrakum, W.; Watanapokasin, R. Mechanism of apoptosis induction associated with ERK1/2 upregulation via goniothalamin in melanoma cells. Exp. Ther. Med., 2018, 15(3), 3052-3058. doi: 10.3892/etm.2018.5762 PMID: 29456710Golestaneh, M.; Firoozrai, M.; Javid, H.; Hashemy, S.I. The substance P/ neurokinin-1 receptor signaling pathway mediates metastasis in human colorectal SW480 cancer cells. Mol. Biol. Rep., 2022, 49(6), 4893-4900. doi: 10.1007/s11033-022-07348-7 PMID: 35429316Ma, J.; Yuan, S.; Cheng, J.; Kang, S.; Zhao, W.; Zhang, J. Substance P promotes the progression of endometrial adenocarcinoma. Int. J. Gynecol. Cancer, 2016, 26(5), 845-850. doi: 10.1097/IGC.0000000000000683 PMID: 27051050Genersch, E.; Hayeß, K.; Neuenfeld, Y.; Haller, H. Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: involvement of Ras-dependent and-independent pathways. J. Cell Sci., 2000, 113(23), 4319-4330. doi: 10.1242/jcs.113.23.4319 PMID: 11069776Koon, H.W.; Zhao, D.; Na, X.; Moyer, M.P.; Pothoulakis, C. Metalloproteinases and transforming growth factor-alpha mediate substance P-induced mitogen-activated protein kinase activation and proliferation in human colonocytes. J. Biol. Chem., 2004, 279(44), 45519-45527. doi: 10.1074/jbc.M408523200 PMID: 15319441Willert, K.; Nusse, R. Wnt proteins. Cold Spring Harb. Perspect. Biol., 2012, 4(9), a007864. doi: 10.1101/cshperspect.a007864 PMID: 22952392Polakis, P. Wnt signaling and cancer. Genes Dev., 2000, 14(15), 1837-1851. doi: 10.1101/gad.14.15.1837 PMID: 10921899Barker, N.; Clevers, H. Catenins, Wnt signaling and cancer. BioEssays, 2000, 22(11), 961-965. doi: 10.1002/1521-1878(200011)22:113.0.CO;2-T PMID: 11056471Bienz, M. beta-Catenin: a pivot between cell adhesion and Wnt signalling. Curr. Biol., 2005, 15(2), R64-R67. doi: 10.1016/j.cub.2004.12.058 PMID: 15668160DeBruine, Z.J.; Ke, J.; Harikumar, K.G.; Gu, X.; Borowsky, P.; Williams, B.O.; Xu, W.; Miller, L.J.; Xu, H.E.; Melcher, K. Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization. Genes Dev., 2017, 31(9), 916-926. doi: 10.1101/gad.298331.117 PMID: 28546512Voronkov, A.; Krauss, S. Wnt/beta-catenin signaling and small molecule inhibitors. Curr. Pharm. Des., 2013, 19(4), 634-664. doi: 10.2174/138161213804581837 PMID: 23016862Mehta, S.; Hingole, S.; Chaudhary, V. The emerging mechanisms of Wnt secretion and signaling in development. Front. Cell Dev. Biol., 2021, 9, 714746. doi: 10.3389/fcell.2021.714746 PMID: 34485301Corda, G.; Sala, A. Non-canonical WNT/PCP signalling in cancer: Fzd6 takes centre stage. Oncogenesis, 2017, 6(7), e364. doi: 10.1038/oncsis.2017.69 PMID: 28737757Janda, C.Y.; Waghray, D.; Levin, A.M.; Thomas, C.; Garcia, K.C. Structural basis of Wnt recognition by Frizzled. Science, 2012, 337(6090), 59-64. doi: 10.1126/science.1222879 PMID: 22653731Ahn, V.E.; Chu, M.L.H.; Choi, H.J.; Tran, D.; Abo, A.; Weis, W.I. Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6. Dev. Cell, 2011, 21(5), 862-873. doi: 10.1016/j.devcel.2011.09.003 PMID: 22000856Huang, X.; Wang, G.; Wu, Y.; Du, Z. The structure of full-length human CTNNBL1 reveals a distinct member of the armadillo-repeat protein family. Acta Crystallogr. D Biol. Crystallogr., 2013, 69(8), 1598-1608. doi: 10.1107/S0907444913011360 PMID: 23897482Brembeck, F.H.; Schwarz-Romond, T.; Bakkers, J.; Wilhelm, S.; Hammerschmidt, M.; Birchmeier, W. Essential role of BCL9-2 in the switch between β-catenin’s adhesive and transcriptional functions. Genes Dev., 2004, 18(18), 2225-2230. doi: 10.1101/gad.317604 PMID: 15371335Katoh, M.; Katoh, M. WNT signaling and cancer stemness. Essays Biochem., 2022, 66(4), 319-331. doi: 10.1042/EBC20220016 PMID: 35837811Pai, S.G.; Carneiro, B.A.; Mota, J.M.; Costa, R.; Leite, C.A.; Barroso-Sousa, R.; Kaplan, J.B.; Chae, Y.K.; Giles, F.J. Wnt/beta-catenin pathway: Modulating anticancer immune response. J. Hematol. Oncol., 2017, 10(1), 101-106. doi: 10.1186/s13045-017-0471-6 PMID: 28476164Taciak, B.; Pruszynska, I.; Kiraga, L.; Bialasek, M.; Krol, M. Wnt signaling pathway in development and cancer. J. Physiol. Pharmacol., 2018, 69(2) doi: 10.26402/jpp.2018.2.07 PMID: 29980141Sha, Y.L.; Liu, S.; Yan, W.W.; Dong, B. Wnt/β-catenin signaling as a useful therapeutic target in hepatoblastoma. Biosci. Rep., 2019, 39(9), BSR20192466. doi: 10.1042/BSR20192466 PMID: 31511432Krishnamurthy, N.; Kurzrock, R. Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat. Rev., 2018, 62, 50-60. doi: 10.1016/j.ctrv.2017.11.002 PMID: 29169144Javid, H.; Mohammadi, F.; Zahiri, E.; Hashemy, S.I. The emerging role of substance P/neurokinin-1 receptor signaling pathways in growth and development of tumor cells. J. Physiol. Biochem., 2019, 75(4), 415-421. doi: 10.1007/s13105-019-00697-1 PMID: 31372898Hong, H.S.; Lee, J.; Lee, E.; Kwon, Y.S.; Lee, E.; Ahn, W.; Jiang, M.H.; Kim, J.C.; Son, Y. A new role of substance P as an injury-inducible messenger for mobilization of CD29+ stromal-like cells. Nat. Med., 2009, 15(4), 425-435. doi: 10.1038/nm.1909 PMID: 19270709Garnier, A.; Vykoukal, J.; Hubertus, J.; Alt, E.; Von Schweinitz, D.; Kappler, R.; Berger, M.; Ilmer, M. Targeting the neurokinin-1 receptor inhibits growth of human colon cancer cells. Int. J. Oncol., 2015, 47(1), 151-160. doi: 10.3892/ijo.2015.3016 PMID: 25998227Niu, X.L.; Hou, J.F.; Li, J.X. The NK1 receptor antagonist NKP608 inhibits proliferation of human colorectal cancer cells via Wnt signaling pathway. Biol. Res., 2018, 51(1), 14-x. doi: 10.1186/s40659-018-0163-x PMID: 29843798Ilmer, M.; Garnier, A.; Vykoukal, J.; Alt, E.; von Schweinitz, D.; Kappler, R.; Berger, M. Targeting the neurokinin-1 receptor compromises canonical Wnt signaling in hepatoblastoma. Mol. Cancer Ther., 2015, 14(12), 2712-2721. doi: 10.1158/1535-7163.MCT-15-0206 PMID: 26516161Mei, G.; Zou, Z.; Fu, S.; Xia, L.; Zhou, J.; Zhang, Y.; Tuo, Y.; Wang, Z.; Jin, D. Substance P activates the Wnt signal transduction pathway and enhances the differentiation of mouse preosteoblastic MC3T3-E1 cells. Int. J. Mol. Sci., 2014, 15(4), 6224-6240. doi: 10.3390/ijms15046224 PMID: 24733069Zhou, J.; Ling, J.; Song, H.; Lv, B.; Wang, L.; Shang, J.; Wang, Y.; Chang, C.; Ping, F.; Qian, J. Neurokinin-1 receptor is a novel positive regulator of Wnt/β-catenin signaling in melanogenesis. Oncotarget, 2016, 7(49), 81268-81280. doi: 10.18632/oncotarget.13222 PMID: 27835606Manning, B.D.; Toker, A. Toker, A. AKT/PKB signaling: Navigating the network. Cell, 2017, 169(3), 381-405. doi: 10.1016/j.cell.2017.04.001 PMID: 28431241Xie, Y.; Shi, X.; Sheng, K.; Han, G.; Li, W.; Zhao, Q.; Jiang, B.; Feng, J.; Li, J.; Gu, Y. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol. Med. Rep., 2018, 19(2), 783-791. doi: 10.3892/mmr.2018.9713 PMID: 30535469Akbarzadeh, M.; Mihanfar, A.; Akbarzadeh, S.; Yousefi, B.; Majidinia, M. Crosstalk between miRNA and PI3K/AKT/mTOR signaling pathway in cancer. Life Sci., 2021, 285, 119984. doi: 10.1016/j.lfs.2021.119984 PMID: 34592229Nussinov, R.; Zhang, M.; Tsai, C.J.; Jang, H. Phosphorylation and driver mutations in PI3Kα and PTEN autoinhibition. Mol. Cancer Res., 2021, 19(4), 543-548. doi: 10.1158/1541-7786.MCR-20-0818 PMID: 33288731Lien, E.C.; Dibble, C.C.; Toker, A. PI3K signaling in cancer: Beyond AKT. Curr. Opin. Cell Biol., 2017, 45, 62-71. doi: 10.1016/j.ceb.2017.02.007 PMID: 28343126Carnero, A. The PKB/AKT pathway in cancer. Curr. Pharm. Des., 2010, 16(1), 34-44. doi: 10.2174/138161210789941865 PMID: 20214616Peng, Y.; Wang, Y.; Zhou, C.; Mei, W.; Zeng, C. PI3K/Akt/mTOR pathway and its role in cancer therapeutics: Are we making headway? Front. Oncol., 2022, 12, 819128. doi: 10.3389/fonc.2022.819128 PMID: 35402264Huang, R.; Dai, Q.; Yang, R.; Duan, Y.; Zhao, Q.; Haybaeck, J.; Yang, Z. Review: PI3K/AKT/mTOR signaling pathway and its regulated eukaryotic translation initiation factors may be a potential therapeutic target in esophageal squamous cell carcinoma. Front. Oncol., 2022, 12, 817916. doi: 10.3389/fonc.2022.817916 PMID: 35574327McKenna, M.; Balasuriya, N.; Zhong, S.; Li, S.S.C.; O’Donoghue, P. Phospho-form specific substrates of protein kinase B (AKT1). Front. Bioeng. Biotechnol., 2021, 8, 619252. doi: 10.3389/fbioe.2020.619252 PMID: 33614606Ediriweera, M.K.; Tennekoon, K.H.; Samarakoon, S.R. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: Biological and therapeutic significance. Semin. Cancer Biol., 2019, 59, 147-160. doi: 10.1016/j.semcancer.2019.05.012 PMID: 31128298Fattahi, S.; Amjadi-Moheb, F.; Tabaripour, R.; Ashrafi, G.H.; Akhavan-Niaki, H. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci., 2020, 262, 118513. doi: 10.1016/j.lfs.2020.118513 PMID: 33011222Nepstad, I.; Hatfield, K.J.; Grønningsæter, I.S.; Reikvam, H. The PI3K-Akt-mTOR signaling pathway in human acute myeloid leukemia (AML) cells. Int. J. Mol. Sci., 2020, 21(8), 2907. doi: 10.3390/ijms21082907 PMID: 32326335Zou, Z.; Tao, T.; Li, H.; Zhu, X. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell Biosci., 2020, 10(1), 31. doi: 10.1186/s13578-020-00396-1 PMID: 32175074Iksen; Pothongsrisit, S.; Pongrakhananon, V. Targeting the PI3K/AKT/mTOR signaling pathway in lung cancer: An update regarding potential drugs and natural products. Molecules, 2021, 26(13), 4100. doi: 10.3390/molecules26134100 PMID: 34279440Stefani, C.; Miricescu, D.; Stanescu-Spinu, I.I.; Nica, R.I.; Greabu, M.; Totan, A.R.; Jinga, M. Growth factors, PI3K/AKT/mTOR and MAPK signaling pathways in colorectal cancer pathogenesis: Where are we now? Int. J. Mol. Sci., 2021, 22(19), 10260. doi: 10.3390/ijms221910260 PMID: 34638601Miricescu, D.; Totan, A.; Stanescu-Spinu, I.I.; Badoiu, S.C.; Stefani, C.; Greabu, M. PI3K/AKT/mTOR signaling pathway in breast cancer: From molecular landscape to clinical aspects. Int. J. Mol. Sci., 2020, 22(1), 173. doi: 10.3390/ijms22010173 PMID: 33375317Sun, K.; Luo, J.; Guo, J.; Yao, X.; Jing, X.; Guo, F. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: A narrative review. Osteoarthritis Cartilage, 2020, 28(4), 400-409. doi: 10.1016/j.joca.2020.02.027 PMID: 32081707Yang, L.; Zhang, Z.; Wang, D.; Jiang, Y.; Liu, Y. Targeting mTOR signaling in type 2 diabetes mellitus and diabetes complications. Curr. Drug Targets, 2022, 23(7), 692-710. doi: 10.2174/1389450123666220111115528 PMID: 35021971Ramasubbu, K. Devi Rajeswari, V. Impairment of insulin signaling pathway PI3K/Akt/mTOR and insulin resistance induced AGEs on diabetes mellitus and neurodegenerative diseases: A perspective review. Mol. Cell Biochem., 2023, 478(6), 1307-1324. doi: 10.1007/s11010-022-04587-x PMID: 36308670Xu, Q.; Fitzsimmons, B.; Steinauer, J.; Neill, A.O.; Newton, A.C.; Hua, X.Y.; Yaksh, T.L. Spinal phosphinositide 3-kinase-Akt-mammalian target of rapamycin signaling cascades in inflammation-induced hyperalgesia. J. Neurosci., 2011, 31(6), 2113-2124. doi: 10.1523/JNEUROSCI.2139-10.2011 PMID: 21307248Lasagni Vitar, R.; Triani, F.; Barbariga, M.; Fonteyne, P.; Rama, P.; Ferrari, G. Substance P/neurokinin-1 receptor pathway blockade ameliorates limbal stem cell deficiency by modulating mTOR pathway and preventing cell senescence. Stem Cell Rep., 2022, 17(4), 849-863. doi: 10.1016/j.stemcr.2022.02.012 PMID: 35334220Lim, J.E.; Chung, E.; Son, Y. A neuropeptide, Substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K/Akt/mTOR pathway even in the presence of IFNγ. Sci. Rep., 2017, 7(1), 9417. doi: 10.1038/s41598-017-09639-7 PMID: 28842601Wang, J.G.; Yu, J.; Hu, J.L.; Yang, W.L.; Ren, H.; Ding, D.; Zhang, L.; Liu, X.P. Neurokinin-1 activation affects EGFR related signal transduction in triple negative breast cancer. Cell. Signal., 2015, 27(7), 1315-1324. doi: 10.1016/j.cellsig.2015.03.015 PMID: 25817575Akazawa, T.; Kwatra, S.G.; Goldsmith, L.E.; Richardson, M.D.; Cox, E.A.; Sampson, J.H.; Kwatra, M.M. A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas. J. Neurochem., 2009, 109(4), 1079-1086. doi: 10.1111/j.1471-4159.2009.06032.x PMID: 19519779Kolorz, J.; Demir, S.; Gottschlich, A.; Beirith, I.; Ilmer, M.; Lüthy, D.; Walz, C.; Dorostkar, M.M.; Magg, T.; Hauck, F.; von Schweinitz, D.; Kobold, S.; Kappler, R.; Berger, M. The neurokinin-1 receptor is a target in pediatric rhabdoid tumors. Curr. Oncol., 2021, 29(1), 94-110. doi: 10.3390/curroncol29010008 PMID: 35049682Fong, T.M.; Anderson, S.A.; Yu, H.; Huang, R.R.; Strader, C.D. Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor. Mol. Pharmacol., 1992, 41(1), 24-30. PMID: 1310144Baker, S.J.; Morris, J.L.; Gibbins, I.L. Cloning of a C-terminally truncated NK-1 receptor from guinea-pig nervous system. Brain Res. Mol. Brain Res., 2003, 111(1-2), 136-147. doi: 10.1016/S0169-328X(03)00002-0 PMID: 12654513Mantyh, P.W.; Rogers, S.D.; Ghilardi, J.R.; Maggio, J.E.; Mantyh, C.R.; Vigna, S.R. Differential expression of two isoforms of the neurokinin-1 (substance P) receptor in vivo. Brain Res., 1996, 719(1-2), 8-13. doi: 10.1016/0006-8993(96)00050-9 PMID: 8782857Page, N.M. Characterization of the gene structures, precursor processing and pharmacology of the endokinin peptides. Vascul. Pharmacol., 2006, 45(4), 200-208. doi: 10.1016/j.vph.2005.08.028 PMID: 16931167Satake, H.; Kawada, T. Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors. Curr. Drug Targets, 2006, 7(8), 963-974. doi: 10.2174/138945006778019273 PMID: 16918325Douglas, S.D.; Leeman, S.E. Neurokinin-1 receptor: Functional significance in the immune system in reference to selected infections and inflammation. Ann. N. Y. Acad. Sci., 2011, 1217(1), 83-95. doi: 10.1111/j.1749-6632.2010.05826.x PMID: 21091716Tuluc, F.; Meshki, J.; Spitsin, S.; Douglas, S.D. HIV infection of macrophages is enhanced in the presence of increased expression of CD163 induced by substance P. J. Leukoc. Biol., 2014, 96(1), 143-150. doi: 10.1189/jlb.4AB0813-434RR PMID: 24577568Li, H.; Leeman, S.E.; Slack, B.E.; Hauser, G.; Saltsman, W.S.; Krause, J.E.; Blusztajn, J.K.; Boyd, N.D. A substance P (neurokinin-1) receptor mutant carboxyl-terminally truncated to resemble a naturally occurring receptor isoform displays enhanced responsiveness and resistance to desensitization. Proc. Natl. Acad. Sci. USA, 1997, 94(17), 9475-9480. doi: 10.1073/pnas.94.17.9475 PMID: 9256507Richardson, M.D.; Balius, A.M.; Yamaguchi, K.; Freilich, E.R.; Barak, L.S.; Kwatra, M.M. Human substance P receptor lacking the C-terminal domain remains competent to desensitize and internalize. J. Neurochem., 2003, 84(4), 854-863. doi: 10.1046/j.1471-4159.2003.01577.x PMID: 12562528Déry, O.; Defea, K.A.; Bunnett, N.W. Protein kinase C-mediated desensitization of the neurokinin 1 receptor. Am. J. Physiol. Cell Physiol., 2001, 280(5), C1097-C1106. doi: 10.1152/ajpcell.2001.280.5.C1097 PMID: 11287322Gao, X.; Frakich, N.; Filippini, P.; Edwards, L.J.; Vinkemeier, U.; Gran, B.; Tanasescu, R.; Bayraktutan, U.; Colombo, S.; Constantinescu, C.S. Effects of substance P on human cerebral microvascular endothelial cell line hCMEC/D3 are mediated exclusively through a truncated NK-1 receptor and depend on cell confluence. Neuropeptides, 2022, 95, 102265. doi: 10.1016/j.npep.2022.102265 PMID: 35696961Lai, J.P.; Lai, S.; Tuluc, F.; Tansky, M.F.; Kilpatrick, L.E.; Leeman, S.E.; Douglas, S.D. Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor. Proc. Natl. Acad. Sci., 2008, 105(34), 12605-12610. doi: 10.1073/pnas.0806632105 PMID: 18713853Muñoz, M.F.; Argüelles, S.; Rosso, M.; Medina, R.; Coveñas, R.; Ayala, A.; Muñoz, M. The neurokinin-1 receptor is essential for the viability of human glioma cells: A possible target for treating glioblastoma. BioMed Res. Int., 2022, 2022, 1-13. doi: 10.1155/2022/6291504 PMID: 35434136Molinos-Quintana, A.; Trujillo-Hacha, P.; Piruat, J.I.; Bejarano-García, J.A.; García-Guerrero, E.; Pérez-Simón, J.A.; Muñoz, M. Human acute myeloid leukemia cells express Neurokinin-1 receptor, which is involved in the antileukemic effect of neurokinin-1 receptor antagonists. Invest. New Drugs, 2019, 37(1), 17-26. doi: 10.1007/s10637-018-0607-8 PMID: 29721755Mozafari, M.; Ebrahimi, S.; Darban, R.A.; Hashemy, S.I. Potential in vitro therapeutic effects of targeting SP/NK1R system in cervical cancer. Mol. Biol. Rep., 2022, 49(2), 1067-1076. doi: 10.1007/s11033-021-06928-3 PMID: 34766230Zhou, Y.; Wang, M.; Tong, Y.; Liu, X.; Zhang, L.; Dong, D.; Shao, J.; Zhou, Y. miR-206 promotes cancer progression by targeting full-length neurokinin-1 receptor in breast cancer. Technol. Cancer Res. Treat., 2019, 18 doi: 10.1177/1533033819875168 PMID: 31506061Liu, X.; Zhang, L.; Tong, Y.; Yu, M.; Wang, M.; Dong, D.; Shao, J.; Zhang, F.; Niu, R.; Zhou, Y. MicroRNA-22 inhibits proliferation, invasion and metastasis of breast cancer cells through targeting truncated neurokinin-1 receptor and ERα. Life Sci., 2019, 217, 57-69. doi: 10.1016/j.lfs.2018.11.057 PMID: 30502362Berger, M.; Neth, O.; Ilmer, M.; Garnier, A.; Salinas-Martín, M.V.; de Agustín Asencio, J.C.; von Schweinitz, D.; Kappler, R.; Muñoz, M. Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo. J. Hepatol., 2014, 60(5), 985-994. doi: 10.1016/j.jhep.2013.12.024 PMID: 24412605Pohl, A.; Kappler, R.; Mühling, J.; VON Schweinitz, D.; Berger, M. Expression of truncated neurokinin-1 receptor in childhood neuroblastoma is independent of tumor biology and stage. Anticancer Res., 2017, 37(11), 6079-6085. PMID: 29061788Gao, X.; Wang, Z. Difference in expression of two neurokinin-1 receptors in adenoma and carcinoma from patients that underwent radical surgery for colorectal carcinoma. Oncol. Lett., 2017, 14(3), 3729-3733. doi: 10.3892/ol.2017.6588 PMID: 28927139Gillespie, E.; Leeman, S.E.; Watts, L.A.; Coukos, J.A.; O’Brien, M.J.; Cerda, S.R.; Farraye, F.A.; Stucchi, A.F.; Becker, J.M. Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer. Proc. Natl. Acad. Sci. USA, 2011, 108(42), 17420-17425. doi: 10.1073/pnas.1114275108 PMID: 21969570Patel, H.J.; Ramkissoon, S.H.; Patel, P.S.; Rameshwar, P. Transformation of breast cells by truncated neurokinin-1 receptor is secondary to activation by preprotachykinin-A peptides. Proc. Natl. Acad. Sci. USA, 2005, 102(48), 17436-17441. doi: 10.1073/pnas.0506351102 PMID: 16291810Nahas, G.R.; Murthy, R.G.; Patel, S.A.; Ganta, T.; Greco, S.J.; Rameshwar, P. The RNA-binding protein Musashi 1 stabilizes the oncotachykinin 1 mRNA in breast cancer cells to promote cell growth. FASEB J., 2016, 30(1), 149-159. doi: 10.1096/fj.15-278770 PMID: 26373800Navarro, P.; Ramkissoon, S.H.; Shah, S.; Park, J.M.; Murthy, R.G.; Patel, S.A.; Greco, S.J.; Rameshwar, P. An indirect role for the oncomir-519b in the expression of truncated neurokinin-1 in breast cancer cells. Exp. Cell Res., 2012, 318(20), 2604-2615. doi: 10.1016/j.yexcr.2012.09.002 PMID: 22981979Ramkissoon, S.H.; Patel, P.S.; Taborga, M.; Rameshwar, P. Nuclear factor-kappaB is central to the expression of truncated neurokinin-1 receptor in breast cancer: implication for breast cancer cell quiescence within bone marrow stroma. Cancer Res., 2007, 67(4), 1653-1659. doi: 10.1158/0008-5472.CAN-06-3813 PMID: 17308106Muñoz, M.; Crespo, J.C.; Crespo, J.P.; Coveñas, R. Neurokinin-1 receptor antagonist aprepitant and radiotherapy, a successful combination therapy in a patient with lung cancer: A case report. Mol. Clin. Oncol., 2019, 11(1), 50-54. doi: 10.3892/mco.2019.1857 PMID: 31289677Muñoz, M.; Coveñas, R. Neurokinin receptor antagonism: a patent review (2014-present). Expert Opin. Ther. Pat., 2020, 30(7), 527-539. doi: 10.1080/13543776.2020.1769599 PMID: 32401556Avet, C.; Mancini, A.; Breton, B.; Le Gouill, C.; Hauser, A.S.; Normand, C.; Kobayashi, H.; Gross, F.; Hogue, M.; Lukasheva, V.; St-Onge, S.; Carrier, M.; Héroux, M.; Morissette, S.; Fauman, E.B.; Fortin, J.P.; Schann, S.; Leroy, X.; Gloriam, D.E.; Bouvier, M. Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 therapeutically relevant GPCRs. eLife, 2022, 11, e74101. doi: 10.7554/eLife.74101 PMID: 35302493Wang, F.I.; Ding, G.; Ng, G.S.; Dixon, S.J.; Chidiac, P. Luciferase-based GloSensor™ cAMP assay: Temperature optimization and application to cell-based kinetic studies. Methods, 2022, 203, 249-258. doi: 10.1016/j.ymeth.2021.10.009 PMID: 34737032Tei, R.; Baskin, J.M. Click chemistry and optogenetic approaches to visualize and manipulate phosphatidic acid signaling. J. Biol. Chem., 2022, 298(4), 101810. doi: 10.1016/j.jbc.2022.101810 PMID: 35276134Leo, K.T.; Chou, C.L.; Yang, C.R.; Park, E.; Raghuram, V.; Knepper, M.A. Bayesian analysis of dynamic phosphoproteomic data identifies protein kinases mediating GPCR responses. Cell Commun. Signal., 2022, 20(1), 80-86. doi: 10.1186/s12964-022-00892-6 PMID: 35659261Hijazi, M.; Smith, R.; Rajeeve, V.; Bessant, C.; Cutillas, P.R. Reconstructing kinase network topologies from phosphoproteomics data reveals cancer-associated rewiring. Nat. Biotechnol., 2020, 38(4), 493-502. doi: 10.1038/s41587-019-0391-9 PMID: 31959955Michel, M.C.; Charlton, S.J. Biased agonism in drug discovery-is it too soon to choose a path? Mol. Pharmacol., 2018, 93(4), 259-265. doi: 10.1124/mol.117.110890 PMID: 29326242Recio, R.; Lerena, P.; Pozo, E.; Calderón-Montaño, J.M.; Burgos-Morón, E.; López-Lázaro, M.; Valdivia, V.; Pernia Leal, M.; Mouillac, B.; Organero, J.Á.; Khiar, N.; Fernández, I. Carbohydrate-based NK1R antagonists with broad-spectrum anticancer activity. J. Med. Chem., 2021, 64(14), 10350-10370. doi: 10.1021/acs.jmedchem.1c00793 PMID: 34236855Paradis, J.S.; Feng, X.; Murat, B.; Jefferson, R.E.; Sokrat, B.; Szpakowska, M.; Hogue, M.; Bergkamp, N.D.; Heydenreich, F.M.; Smit, M.J.; Chevigné, A.; Bouvier, M.; Barth, P. Computationally designed GPCR quaternary structures bias signaling pathway activation. Nat. Commun., 2022, 13(1), 6826. doi: 10.1038/s41467-022-34382-7 PMID: 36369272Morales-Pastor, A.; Nerín-Fonz, F.; Aranda-García, D.; Dieguez-Eceolaza, M.; Medel-Lacruz, B.; Torrens-Fontanals, M.; Peralta-García, A.; Selent, J. In silico study of allosteric communication networks in GPCR signaling bias. Int. J. Mol. Sci., 2022, 23(14), 7809. doi: 10.3390/ijms23147809 PMID: 35887157Ebrahimi, S.; Mirzavi, F.; Hashemy, S.I.; Khaleghi Ghadiri, M.; Stummer, W.; Gorji, A. The in vitro anti-cancer synergy of neurokinin-1 receptor antagonist, aprepitant, and 5-aminolevulinic acid in glioblastoma. Biofactors, 2023, 49(4), 900-911. doi: 10.1002/biof.1953 PMID: 37092793Ebrahimi, S.; Erfani, B.; Alalikhan, A.; Ghorbani, H.; Farzadnia, M.; Afshari, A.R.; Mashkani, B.; Hashemy, S.I. The in vitro pro-inflammatory functions of the SP/NK1R system in prostate cancer: A focus on nuclear factor-kappa B (NF-κB) and its pro-inflammatory target genes. Appl. Biochem. Biotechnol., 2023. doi: 10.1007/s12010-023-04495-w PMID: 37093533Królicki, L.; Kunikowska, J.; Bruchertseifer, F.; Kuliński, R.; Pawlak, D.; Koziara, H.; Rola, R.; Morgenstern, A.; Merlo, A. Locoregional treatment of glioblastoma with targeted α therapy: 213 BiBi-DOTA-substance P versus 225 AcAc-DOTA-substance P-analysis of influence parameters. Clin. Nucl. Med., 2023, 48(5), 387-392. doi: 10.1097/RLU.0000000000004608 PMID: 36854309Robinson, P.; Rosso, M.; Muñoz, M. Neurokinin-1 Receptor antagonists as a potential novel therapeutic option for osteosarcoma patients. J. Clin. Med., 2023, 12(6), 2135. doi: 10.3390/jcm12062135 PMID: 36983138Suthiram, J.; Pieters, A.; Mohamed Moosa, Z.; Zeevaart, J.R.; Sathekge, M.M.; Ebenhan, T.; Anderson, R.C.; Newton, C.L. Tachykinin receptor-selectivity of the potential glioblastoma-targeted therapy, DOTA-Thi8,Met(O2)11-substance P. Int. J. Mol. Sci., 2023, 24(3), 2134. doi: 10.3390/ijms24032134 PMID: 36768456Guan, L.; Yuan, S.; Ma, J.; Liu, H.; Huang, L.; Zhang, F. Neurokinin-1 receptor is highly expressed in cervical cancer and its antagonist induces cervical cancer cell apoptosis. Eur. J. Histochem., 2023, 67(1), 3570. doi: 10.4081/ejh.2023.3570 PMID: 36629320Kant, V.; Mahapatra, P.S.; Gupta, V.; Bag, S.; Gopalakrishnan, A.; Kumar, D.; Kumar, D. Substance P, a neuropeptide, promotes wound healing via neurokinin-1 receptor. Int. J. Low. Extrem. Wounds, 2023, 22(2), 291-297. doi: 10.1177/15347346211004060 PMID: 33856252Choi, J.G.; Choi, S.R.; Kang, D.W.; Shin, H.J.; Lee, M.; Hwang, J.; Kim, H.W. Inhibition of angiotensin converting enzyme increases PKCβI isoform expression via activation of substance P and bradykinin receptors in cultured astrocytes of mice. J. Vet. Sci., 2023, 24(2), e26. doi: 10.4142/jvs.22275 PMID: 37012034Al-Keilani, M.S.; Bdeir, R.; Elstaty, R.I.; Alqudah, M.A. Expression of substance P, neurokinin 1 receptor, Ki-67 and pyruvate kinase M2 in hormone receptor negative breast cancer and evaluation of impact on overall survival. BMC Cancer, 2023, 23(1), 158. doi: 10.1186/s12885-023-10633-8 PMID: 36797689