Receptor Trafficking via the Perinuclear Recycling Compartment Accompanied by Cell Division Is Necessary for Permanent Neurotensin Cell Sensitization and Leads to Chronic Mitogen-activated Protein Kinase Activation

Most G protein-coupled receptors are internalized after interaction with their respective ligand, a process that subsequently contributes to cell desensitization, receptor endocytosis, trafficking, and finally cell resensitization. Although cellular mechanisms leading to cell desensitization have been widely studied, those responsible for cell resensitization are still poorly understood. We examined here the traffic of the high affinity neurotensin receptor (NT1 receptor) following prolonged exposure to high agonist concentration. Fluorescence and confocal microscopy of Chinese hamster ovary, human neuroblastoma (CHP 212), and murine neuroblastoma (N1E-115) cells expressing green fluorescent protein-tagged NT1 receptor revealed that under prolonged treatment with saturating concentrations of neurotensin (NT) agonist, NT1 receptor and NT transiently accumulated in the perinuclear recycling compartment (PNRC). During this cellular event, cell surface receptors remained markedly depleted as detected by both confocal microscopy and 125I-NT binding assays. In dividing cells, we observed that following prolonged NT agonist stimulation, NT1 receptors were removed from the PNRC, accumulated in dispersed vesicles inside the cytoplasm, and subsequently reappeared at the cell surface. This NT binding recovery allowed for constant cell sensitization and led to a chronic activation of mitogen-activated protein kinases p42 and p44. Under these conditions, the constant activation of NT1 receptor generates an oncogenic regulation. These observations support the potent role for neuropeptides, such as NT, in cancer progression. Most G protein-coupled receptors are internalized after interaction with their respective ligand, a process that subsequently contributes to cell desensitization, receptor endocytosis, trafficking, and finally cell resensitization. Although cellular mechanisms leading to cell desensitization have been widely studied, those responsible for cell resensitization are still poorly understood. We examined here the traffic of the high affinity neurotensin receptor (NT1 receptor) following prolonged exposure to high agonist concentration. Fluorescence and confocal microscopy of Chinese hamster ovary, human neuroblastoma (CHP 212), and murine neuroblastoma (N1E-115) cells expressing green fluorescent protein-tagged NT1 receptor revealed that under prolonged treatment with saturating concentrations of neurotensin (NT) agonist, NT1 receptor and NT transiently accumulated in the perinuclear recycling compartment (PNRC). During this cellular event, cell surface receptors remained markedly depleted as detected by both confocal microscopy and 125I-NT binding assays. In dividing cells, we observed that following prolonged NT agonist stimulation, NT1 receptors were removed from the PNRC, accumulated in dispersed vesicles inside the cytoplasm, and subsequently reappeared at the cell surface. This NT binding recovery allowed for constant cell sensitization and led to a chronic activation of mitogen-activated protein kinases p42 and p44. Under these conditions, the constant activation of NT1 receptor generates an oncogenic regulation. These observations support the potent role for neuropeptides, such as NT, in cancer progression. G protein-coupled receptors (GPCRs) 1The abbreviations used are: GPCRs, G protein-coupled receptors; NT, neurotensin; NT1 receptor, high affinity neurotensin receptor 1; HT-29, human colon cancer cell line; CHP 212, human neuroblastoma cell line; CHO, Chinese hamster ovary cell line; N1E-115, murine neuroblastoma cell line; GFP, green fluorescence protein; EGFP, enhanced green fluorescence protein; NT1-EGFP receptor, fusion protein of NT1 receptor with EGFP; MAP, mitogen-activated protein; CHO-NT1-EGFP, CHO cells transfected with NT1 receptor/EGFP; CHP 212-NT1-EGFP, CHP 212 cells transfected with NT1 receptor/EGFP; N1E-115-NT1-EGFP, N1E-115 cells transfected with NT1 receptor/EGFP; JMV 449, H-LysΨ(CH2NH)Lys-Pro-Tyr-Ile-Leu-OH; FCS, fetal calf serum; PBS, phosphate-buffered saline; NRS, normal rabbit serum; PNRC, perinuclear recycling compartment; SR 48692, 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazol-3-yl)carbonylamino]-tricyclo(3.3.1.1.3.7)decan-2-carboxylic acid; TRITC, tetramethylrhodamine isothiocyanate; Bodipy-NT, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene. and their agonists participate in numerous aspects of cellular and tissue regulation (1Pierce K.L. Premont R.T. Lefkowitz R.J. Nat. Rev. Mol. Cell Biol. 2002; 3: 639-650Crossref PubMed Scopus (2162) Google Scholar). Agonist interaction instantly leads to GPCR activation, phosphorylation, sequestration, and cell desensitization. Upon receptor endocytosis, the GPCRs may return to the cell surface directly from sorting endosomes (short cycle) (2Innamorati G. Le Gouill C. Balamotis M. Birnbaumer M. J. Biol. Chem. 2001; 276: 13096-13103Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). However, a long cycle involving the passage through the perinuclear recycling compartment (PNRC), before reaching the plasma membrane, has been suggested recently (2Innamorati G. Le Gouill C. Balamotis M. Birnbaumer M. J. Biol. Chem. 2001; 276: 13096-13103Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 3Signoret N. Pelchen-Matthews A. Mack M. Proudfoot A.E. Marsh M. J. Cell Biol. 2000; 151: 1281-1294Crossref PubMed Scopus (165) Google Scholar, 4Bremnes T. Paasche J.D. Mehlum A. Sandberg C. Bremnes B. Attramadal H. J. Biol. Chem. 2000; 275: 17596-17604Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). In the present study, by examining the effect of prolonged agonist exposure on neurotensin receptor (NT1 receptor) intracellular trafficking, we determined the conditions leading to cell agonist re-sensitization, along with the physiological consequences of this recovery on intracellular signalization. Neurotensin (NT) is a brain and gastrointestinal peptide that fulfils many central and peripheral functions through its interaction with specific receptors (5Carraway R. Leeman S.E. J. Biol. Chem. 1976; 251: 7045-7052Abstract Full Text PDF PubMed Google Scholar, 6Vincent J.P. Cell. Mol. Neurobiol. 1995; 15: 501-512Crossref PubMed Scopus (120) Google Scholar). Three subtypes of NT receptors have been cloned: NT1, NT2, and NT3 (7Tanaka K. Masu M. Nakanishi S. Neuron. 1990; 4: 847-854Abstract Full Text PDF PubMed Scopus (488) Google Scholar, 8Chalon P. Vita N. Kaghad M. Guillemot M. Bonnin J. Delpech B. Le Fur G. Ferrara P. Caput D. FEBS Lett. 1996; 386: 91-94Crossref PubMed Scopus (242) Google Scholar, 9Mazella J. Zsurger N. Navarro V. Chabry J. Kaghad M. Caput D. Ferrara P. Vita N. Gully D. Maffrand J.P. Vincent J.P. J. Biol. Chem. 1998; 273: 26273-26276Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar). NT1 and NT2 exhibit high (sub-nanomolar) and low (nanomolar) affinity for NT, respectively, and belong to the family of G protein-coupled receptors. NT3 is a single transmembrane domain receptor with 100% homology to gp95/sortilin (9Mazella J. Zsurger N. Navarro V. Chabry J. Kaghad M. Caput D. Ferrara P. Vita N. Gully D. Maffrand J.P. Vincent J.P. J. Biol. Chem. 1998; 273: 26273-26276Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar). All three receptors are internalized after interaction with NT (10Chabry J. Botto J.M. Nouel D. Beaudet A. Vincent J.P. Mazella J. J. Biol. Chem. 1995; 270: 2439-2442Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 11Botto J.M. Chabry J. Sarret P. Vincent J.P. Mazella J. Biochem. Biophys. Res. Commun. 1998; 243: 585-590Crossref PubMed Scopus (58) Google Scholar, 12Navarro V. Martin S. Sarret P. Nielsen M.S. Petersen C.M. Vincent J. Mazella J. FEBS Lett. 2001; 495: 100-105Crossref PubMed Scopus (50) Google Scholar). In the periphery, the bulk of NT is released into the circulation by endocrine cells, called N-cells, localized along the luminal epithelium of the gastrointestinal tract (13Helmstaedter V. Taugner C. Feurle G.E. Forssmann W.G. Histochemistry. 1977; 53: 35-41Crossref PubMed Scopus (132) Google Scholar). In the central nervous system, NT is released by neurons distributed throughout the neuraxis (14Jennes L. Stumpf W.E. Kalivas P.W. J. Comp. Neurol. 1982; 210: 211-224Crossref PubMed Scopus (489) Google Scholar). Most studies on the intracellular trafficking of GPCRs, including NT1 receptor, have been performed on cells and to agonists for from a to a of this GPCRs are to the plasma following a GPCRs are and to agonist Rev. 2001; 53: Google Scholar). However, studies these may NT1 receptor trafficking under normal physiological conditions, in the as long as to a in the of regulation. the of a a and prolonged in plasma of NT, for at L. R. P. R. Biol. 1998; Google Scholar). In cancer cells, of is in cancer and cell from J. C.M. PubMed Scopus Google D. J. 53: PubMed Scopus Google G.E. V. K. R. Forssmann W.G. D. PubMed Scopus Google and S. B. G. M. S. A. PubMed Scopus (132) Google Scholar). NT1 receptor to in human such as B. H. M. J. 1998; PubMed Scopus Google S. B. G. M. S. A. PubMed Scopus (132) Google and cell T. S. J. Res. Google an NT receptor studies that human colon cells, HT-29, human neuroblastoma cells, CHP 212, for with high concentrations of a NT agonist and NT sensitization P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. T. P. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In these a an NT1 receptor in the of cell stimulation, and the activation of NT1 receptor by NT agonist and cell resensitization. fluorescent NT that in neurons expressing NT1 receptor, the internalized with its receptor and in the perinuclear A. Nouel D. G. M. Vincent J.P. Beaudet A. J. 1995; 15: PubMed Google Scholar, Nouel D. Beaudet A. 1995; PubMed Scopus Google Scholar, D. R. R. Beaudet A. J. PubMed Google Scholar). to intracellular trafficking and of NT1 receptors after a prolonged agonist exposure in with cell resensitization. cellular we CHO, CHP 212, and N1E-115 cells, a fusion protein the NT1 receptor and the enhanced green fluorescent protein the of NT1 fusion and fluorescent NT, we were to intracellular trafficking of NT1 receptor and its We that cells were to high of NT agonist, NT1 receptors in the perinuclear recycling compartment and subsequently to the cell surface. the cells leading to the chronic activation of Cell and Cell cells were in and (CHP and murine (N1E-115) neuroblastoma cells were in All were with fetal calf and were at in a N1E-115 with and for B. T. J. PubMed Scopus Google Scholar). of N1E-115 and CHP 212 cell with a expressing NT1 receptor at the with the performed the for at Beaudet A. N. N. T. B. H. C. J. 2000; PubMed Scopus Google Scholar, J. T. Scholar). the were and for were with and were for a fluorescence at a and by 125I-NT binding assays. were performed as in with of and of for at cells were with a of JMV for and for cells were with in the in the of JMV In both transfected and cells were with JMV S. M. D. P. A. J. Res. Google for three in phosphate-buffered and with in PBS, for at cells were with PBS, in the and normal rabbit for and with cells were at with receptor at a of for transfected cells and for cells at the at a of in and three with PBS, cells were for at with a rabbit at a of for transfected cells and for CHP 212 cells and for N1E-115 cells, in were on with and examined by confocal of of the by of and NT1 were with JMV for before the of the to the fetal calf at a of for of the perinuclear recycling compartment S. J. Cell Biol. PubMed Scopus Google Scholar). were three with and with for were on with and examined by confocal in were on and were for and and with in the at with SR a NT1 receptor for were directly for confocal were from and cells the of H. A. P. M. Beaudet A. D. Biochem. J. 1995; PubMed Scopus Google Scholar). were three with in to agonist used for Under these conditions, the binding recovery of cells with JMV as with cells P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). binding studies were performed as of protein were with in a of of and for at binding in the of were by the of by through in three with of the on the in a a with a for for and cell and for the cell confocal here to the from a fluorescence a to for and to for of to green and with to the in to were to a single a with and cells and cells were with JMV for at cells were with were by and at for Cell were in of PBS, into an and at for Cell were in with and were for in for and at at for were protein for protein concentration. of protein were on a for at and at in of determined by the of p42 and an detected of its by a the in for at and with to in at three for with and with in for at three the were revealed with the enhanced with for at and with to in for at by with as Upon to a of NT1 and NT in a intracellular trafficking of NT1 receptor in CHO cells transfected with a expressing the NT1 receptor at the with the Beaudet A. N. N. T. B. H. C. J. 2000; PubMed Scopus Google Scholar). were on the a of and a of of binding affinity of NT1 is to the NT1 receptor from cells expressing the NT1 receptor revealed a of H. A. P. M. Beaudet A. D. Biochem. J. 1995; PubMed Scopus Google Scholar). to in cells, with the as in cell expressing the Beaudet A. N. N. T. B. H. C. J. 2000; PubMed Scopus Google Scholar, S. P. Vincent J.P. J. PubMed Scopus Google Scholar). In the of agonist, NT1 receptors were localized at the cell surface In to receptor trafficking, cells were for at with of a NT agonist, JMV S. M. D. P. A. J. Res. Google to saturating and binding conditions, of cells revealed that exposure to JMV 449, accumulated in a compartment This the at of at and at In cells were with JMV 449, the perinuclear observed at and of JMV of NT agonist the of fluorescence at the cell surface to that observed in cells this cellular after of JMV in saturating concentrations of JMV and and 100% binding respectively, in the perinuclear with NT, and of the NT observed in the perinuclear under agonist concentrations of and for and of NT1 receptor trafficking that the of the NT1 receptor in the compartment the were in CHP 212 cells, a human neuroblastoma cell that NT1 receptor M. M. T. P. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google and in N1E-115 cells, a murine neuroblastoma cell B. T. J. PubMed Scopus Google Scholar). cell were transfected with the Beaudet A. N. N. T. B. H. C. J. 2000; PubMed Scopus Google Scholar). In and cells, the green fluorescence at the cell surface as in cells, detected in the perinuclear of both cell following a treatment with JMV We by that the NT1 receptor still to the trafficking an the of NT1 in a and NT1 receptor we that the the human NT1 receptor in CHP 212 cells that in cells, murine NT1 receptor is in cells, the cells used in this are the NT1 receptor observed to the the green fluorescence to NT1 receptor In to the of NT1 receptor is responsible for NT1 receptor the NT1 receptor performed on CHP 212 cells and N1E-115 CHP 212 cells present a low of NT1 receptor with a of of N1E-115 cells NT1 receptor in the with a of of protein in the receptor is localized at the in cells, after of JMV NT1 receptor is accumulated in a compartment in both cell NT trafficking in cells by the as a fluorescent were with at the saturating of and examined by confocal and of NT1 receptors were internalized and distributed throughout the in in vesicles from those the cells were for with Bodipy-NT, both and NT1 receptor were in the perinuclear and green were still present in the of the in the compartment of the trafficking by performed at and with JMV under these conditions, as in NT1 receptor detected cells were to the NT1 receptor SR NT1 in the is an by the and the B. Cell. Full Text PDF PubMed Scopus Google as a compartment for the recycling of in the is the in the trafficking of internalized S. J. Cell Biol. PubMed Scopus Google Scholar). as a for PNRC, studies have that internalized G protein-coupled receptors may in the intracellular of NT1 receptors with in both and cells, following with of JMV for by the of before the of the in the bulk of NT1 receptor in the compartment in has a has been to with the S. S. M. J. Cell Biol. 1996; PubMed Scopus Google Scholar). in performed on cells, for with JMV 449, an of and NT1 NT1 in the have that NT1 receptor in the of saturating NT agonist for P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In to the the of NT1 receptors accumulated in PNRC, we cells with JMV for in the of a a we the 125I-NT binding of in with the NT1 receptor cells were with saturating NT agonist after of treatment of JMV treatment the binding of the cells with JMV with effect on the binding we the traffic of NT1 receptor following of agonist exposure in the of Under this NT1 receptor internalized throughout the in the of and JMV for NT1 receptor internalized and accumulated in the of effect on receptor trafficking In we that NT agonist effect on the the NT1 in the used to the cell in a with transiently transfected in cells and with concentrations of JMV from to a of observed on NT1 receptor cells were for and with JMV NT1 receptor activation by NT agonist is for NT1 receptor in PNRC, that NT1 receptor accumulated in the is internalized NT1 from the to the Cell a P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. T. P. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google we that under prolonged and saturating agonist neuroblastoma CHP 212 and colon cells a NT1 receptor after In N1E-115 cells, in NT1 receptor by were M. M. T. P. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In to the receptor in the we examined NT1 receptor traffic in N1E-115-NT1-EGFP, under and of NT1 receptor after of agonist treatment that in cells, NT1 receptor to the cell in cells, NT1 receptors remained in the performed on of with JMV for that as observed in cells, cells are in both prolonged agonist exposure 125I-NT binding to of in cells remained of in cells in NT1 receptor expressing in cells were with JMV for NT1 receptors remained in the PNRC, in CHP 212 cells NT1 receptors to the cell surface. We the of NT1 receptor from the to its its to the plasma In to this cells were with JMV 449, and performed S. Cell Res. 2002; 275: PubMed Scopus Google Scholar). a NT1 receptor is accumulated in the the to vesicles are dispersed in the of JMV the NT1 receptor is removed from the with of agonist NT1 receptor localized and at the plasma membrane, with detected In N1E-115-NT1-EGFP, for with JMV 449, NT1 receptor remained in PNRC, with of These that NT1 receptor is with In to the of NT1 receptor at the cell we the following cells were for with JMV in to NT1 receptor in the PNRC, and the treatment in the the of the protein cells were examined by confocal the from a is in NT1 receptor is localized at the in NT1 receptor is accumulated in PNRC, cells were with JMV cells were with an of JMV in the in the of NT1 receptor removed from the PNRC, and many of dispersed vesicles were detected in the NT1 receptor removed from the and dispersed in to the cell following an treatment and of the of for Cell NT1 of in by low is the to cell We the of NT1 cell surface receptor recovery in cells from from cell this we NT1 receptor trafficking in cells in is the in CHO cells after in and cells were to JMV NT for NT1 receptors were removed from cells were in FCS, and remained in the cells were in 125I-NT binding to of in cells in remained of in cells in binding observed cells were with the agonist of the for a prolonged of with the the cell cycle at A. 2000; PubMed Scopus Google Scholar, S. Cell Res. 2002; 275: PubMed Scopus Google Scholar). cells were for with NT agonist and NT1 receptor remained in the of the cells were with NT1 receptor remained at the cell surface cells, in the of the an of NT1 receptor in to that of in low concentrations to and the binding of cells with and JMV observations were in cells in and with and JMV NT1 receptors remained in the of a and JMV 449, for to cells with in a receptor as in cells with and were performed a potent of the as an by cells in the of the cell cycle S. M. K. 1998; PubMed Scopus Google Scholar, K. L. V. Res. Google Scholar). In CHO-NT1-EGFP, this the receptor in the PNRC, the still after of treatment with JMV and In to cell cycle is for NT1 receptor recovery at the plasma membrane, the cell cycle in by with M. M. M. J. T. J. Cell 2001; PubMed Google Scholar). we of the the of NT1 receptor in the and cells were with JMV for to the of NT1 receptor in the PNRC, and with JMV and for NT1 receptor at the plasma after of agonist in the of that the receptor recycling present in NT1 in a of has been that NT p42 and in CHO and in cells transfected with NT1 receptor C. M. M. Vita N. Gully D. Maffrand J.P. Le Fur G. P. Biochem. J. 1996; PubMed Scopus Google Scholar, D. S. C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). We the of p42 and in and and cells after and long agonist in and activation of p42 and detected cells were to JMV for In cells, the of and to with prolonged NT agonist exposure In in cells, a activation of p42 and detected after a JMV exposure for cell In cells in FCS, the activation detected after of JMV treatment This the conditions to the activation by NT the for at of from the C. M. M. Vita N. Gully D. Maffrand J.P. Le Fur G. P. Biochem. J. 1996; PubMed Scopus Google Scholar). In cells, in and with JMV of a activation observed In we observed that under and high of NT agonist dividing cells binding to cells led to a activation of p42 and p44. We here on cells in the of agonist following the intracellular of internalized NT1 we were to the cellular this process and to that in dividing cells, constant cell sensitization is with a chronic activation of prolonged with saturating of agonist, NT1 receptors are internalized and transiently in the the and This recycling compartment an in the recycling of receptors to the cell surface S. J. Cell Biol. PubMed Scopus Google Scholar). in the is to NT1 GPCRs, such as receptor, N. Pelchen-Matthews A. Mack M. Proudfoot A.E. Marsh M. J. Cell Biol. 2000; 151: 1281-1294Crossref PubMed Scopus (165) Google the receptor T. Paasche J.D. Mehlum A. Sandberg C. Bremnes B. Attramadal H. J. Biol. Chem. 2000; 275: 17596-17604Abstract Full Text Full Text PDF PubMed Scopus (216) Google and the receptor (2Innamorati G. Le Gouill C. Balamotis M. Birnbaumer M. J. Biol. Chem. 2001; 276: 13096-13103Abstract Full Text Full Text PDF PubMed Scopus (136) Google are to this cellular compartment after agonist However, NT1 receptor from is the for NT1 receptor of agonist to the as with for and receptors and for the role of the receptor traffic and the receptor in cells, we used NT1 receptor cells transfected with NT1 receptor with subsequently to its in the PNRC, we observed that the NT1 receptor removed and in the and at the cell surface In a study, we have that in the human colon cells, HT-29, as as in human neuroblastoma cells, CHP 212, NT1 receptors to the cell surface. We this with a of NT1 receptor and NT1 receptor activation by NT agonist P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. T. P. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). present to under saturating conditions the receptor is by the of cell to we NT1 receptor activation by NT agonist is for cell we observed here that NT agonist effect on the the in cells the NT1 receptor activation is as in CHP 212 M. M. T. P. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google is that both NT1 receptors and NT1 receptors from the activation participate in cell to this that NT1 receptors were to the plasma were to and were by performed with cells to agonist to recycling observed after agonist and cell S. Vincent J.P. Mazella J. J. Cell 2002; Google Scholar, Nouel D. Vincent J. Mazella J. Beaudet A. J. Cell 2000; PubMed Google Scholar, J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). that the agonist exposure is prolonged cellular mechanisms and the cell are to the receptor to the cell surface. mechanisms are to in on the physiological In the released NT is the receptor the as suggested by the with neurons M. J.M. PubMed Scopus Google Scholar). In cancer cells NT is and NT1 receptor receptor recycling and cell sensitization the cellular has on neuropeptides, for are as 2001; PubMed Scopus Google Scholar). receptors for these are of the studies that the the of the family 2001; PubMed Scopus Google Scholar). the of these in to to GPCR in a chronic activation of as here that these may in cancer progression. In in cells with of regulation NT, an of this for a in cancer J. R. Res. 2000; Google from the a for NT1 NT1 receptor and NT1 receptor revealed the NT1 receptor in human of ovary, and and B. H. M. J. 1998; PubMed Scopus Google Scholar, J. R. Res. 2000; Google Scholar, L. H. H. A. M. Res. 2000; Google Scholar, B. J. PubMed Scopus Google Scholar). that is in cancer and cell from and J. C.M. PubMed Scopus Google Scholar, D. J. 53: PubMed Scopus Google Scholar, G.E. V. K. R. Forssmann W.G. D. PubMed Scopus Google Scholar, S. B. G. M. S. A. PubMed Scopus (132) Google Scholar). In has been that the of the of human colon cancer cell cell cancer is by NT and by a NT1 SR J. M. D. 2001; PubMed Scopus Google Scholar, C. Gully D. M. J. PubMed Scopus Google Scholar). of NT1 receptor and NT in the of the of an oncogenic neurotensin regulation. In this we observed that cell resensitization is in dividing This on the by with the cell cycle are used for a Cell Res. 2002; 273: PubMed Scopus Google Scholar). In cancer cells the is to the cell and the of NT1 receptor cell resensitization here In this study, we under specific cells the of agonist leading to the of such as neuropeptides, as under these to the of receptor the of GPCR an in cancer We to for in the of the and for We for the of for the of their for and for We for on binding studies and Gully for SR

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