Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor

Lai, Jian‐Ping; Lai, Saien; Tuluc, Florin; Tansky, Morris F.; Kilpatrick, Laurie E.; Leeman, Susan E.; Douglas, Steven D.

doi:10.1073/pnas.0806632105

Cited by 93 publications

(94 citation statements)

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“…Treatment with an NK-1R antagonist reduced cyclooxygenase-2 expression as well as expression of the proliferation marker ki67 (21), showing a potential functional role for NK-1R (although not necessarily tr-NK-1R) in CAC. In addition, Lai et al (26) showed that upon ligand binding, tr-NK-1R, which lacks a C-terminal tail that binds and activates G q , cannot initiate calcium influx or activate PKC and NF-κB; however, the truncated receptor can activate ERK in a delayed manner. The tr-NK-1R has also been reported to be resistant to desensitization (27,28).…”

Section: Discussionmentioning

confidence: 99%

“…tr-NK-1R is present in breast cancer tissue (24), and transfection of truncated but not full-length NK-1R into nontumorigenic breast epithelial cell lines creates a transformed phenotype with greatly increased growth capability (25). Signaling studies have shown that unlike fl-NK-1R, tr-NK-1R can neither initiate calcium influx via G q , nor activate PKC or NF-κB; however, ERK activation still occurs but at a slower rate (26). In light of these findings, we were particularly interested in examining the expression of tr-NK-1R in the transition from colonic inflammation to CAC.…”

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confidence: 99%

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Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Gillespie¹,

Leeman²,

Watts³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P = 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P = 0.02) in HGD and 80% (P = 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitisassociated cancer.colon cancer | receptor splice variants | substance P | IBD C hronic inflammation is associated with a higher rate of cancer development in various organs (1). More specifically, patients with ulcerative colitis (UC) are at high risk for developing colorectal cancer (2); both extent and duration of intestinal inflammation further increase risk (3, 4). These associations suggest that chronic intestinal inflammation is a causative factor in carcinogenesis in patients with UC, and that there is a causal link between chronic inflammation and increased risk of cancer. These observations raise the question of the signaling pathways by which long-standing inflammation might underlie the development of cancer.Substance P (SP) is a proinflammatory neuropeptide described by von Euler and Gaddum (5) and later isolated and characterized by Chang and Leeman (6). SP is synthesized by a variety of cells, most notably neurons and inflammatory cells such as macrophages (7). SP's primary receptor, the neurokinin-1 receptor (NK-1R), can mediate a variety of physiologic and pathophysiologic responses, including cell proliferation, migration, and inflammation (8). The NK-1R has been identified in epithelial cells in rodent models of colonic inflammation (9, 10) and in patients with UC as well as Crohn disease (11)(12)(13)(14). However, not all of these studies are in agreement regarding epithelial NK-1R e...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Gillespie¹,

Leeman²,

Watts³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…These isoforms have distinct signalling properties, with only the wild-type receptor being able to increase intracellular Ca 2+ concentration and activate the transcription factor NFκB, leading to increased expression of F o r R e v i e w O n l y mRNA for interleukin-8 [59]. In addition, compared to the wild-type receptor, the truncated NK 1 receptor variant may have an increased ability to interact with different G proteins, other GPCRs, or G protein-independent signalling pathways [59,63]. This could be of considerable importance in cells and tissues that have distinct expressions of the NK 1 receptor isoforms.…”

Section: Alternative Splicing Of Gpcr In Other Pathophysiological Conmentioning

confidence: 99%

“…[59][60][61][62][63][64] Neurokinin receptor 2 Exon exclusion Impaired ligand binding and signalling [65,66] Neuropeptide S receptor (GPRA) Alternative C-terminal exons, trancation Intracellular localization of truncated isoform [67] Opioid receptors Several Various Reviewed in [68] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Overview of GPCRs encoded by more than one exon. In the "pre-human genome era" it was assumed that more than 90% of human GPCRs were intronless [15].…”

Section: Closing Remarksmentioning

confidence: 99%

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

Markovic

Challiss

2009

Cell. Mol. Life Sci.

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Abstract. The G protein-coupled receptors (GPCRs) are a superfamily of transmembrane receptors that have a broad distribution and can collectively recognize a diverse array of ligands. Activation or inhibition of GPCR signalling can affect many (patho)physiological processes and consequently they are a major target for existing and emerging drug therapies.A common observation has been that the pharmacological, signalling and regulatory properties of GPCRs can vary in a cell-and tissue-specific manner. Such "phenotypic" diversity might be attributable to post-translational modifications and/or association of GPCRs with accessory proteins, however, post-transcriptional mechanisms are also likely to contribute. Although, approximately 50% of GPCR genes are intronless, those that possess introns can undergo alternative splicing, generating GPCR subtype isoforms that may differ in their pharmacological, signalling and regulatory properties. In this Review we shall highlight recent research into GPCR splice-variation, and discuss the potential consequences this might have for GPCR function in health and disease.

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“…Other mechanisms can regulate the duration of MAPK signals transmitted by the angiotensin AT1A receptor, including the dual specificity phosphatase MKP7, which interacts with ␤-arrestins and dephosphorylates JNK3 bound to ␤-arrestin2 (46). NK 1 R⌬325-407 interacts with ␤-arrestins only transiently (6,32). In contrast to the fulllength NK 1 R, ECE-1 inhibition did not cause retention of NK 1 R⌬325-407 with ␤-arrestins in endosomes and failed to cause sustained NK 1 R⌬325-407-mediated ERK2 activation.…”

Section: Ece-1 Degrades Sp In Endosomes Andmentioning

confidence: 99%

Endosomal Endothelin-converting Enzyme-1

Cottrell

Padilla

Amadesi

et al. 2009

Journal of Biological Chemistry

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Neuropeptide signaling at the cell surface is regulated by metalloendopeptidases, which degrade peptides in the extracellular fluid, and ␤-arrestins, which interact with G protein-coupled receptors (GPCRs) to mediate desensitization. ␤-Arrestins also recruit GPCRs and mitogen-activated protein kinases to endosomes to allow internalized receptors to continue signaling, but the mechanisms regulating endosomal signaling are unknown. We report that endothelin-converting enzyme-1 (ECE-1) degrades substance P (SP) in early endosomes of epithelial cells and neurons to destabilize the endosomal mitogen-activated protein kinase signalosome and terminate signaling. ECE-1 inhibition caused endosomal retention of the SP neurokinin 1 receptor, ␤-arrestins, and Src, resulting in markedly sustained ERK2 activation in the cytosol and nucleus, whereas ECE-1 overexpression attenuated ERK2 activation. ECE-1 inhibition also enhanced SP-induced expression and phosphorylation of the nuclear death receptor Nur77, resulting in cell death. Thus, endosomal ECE-1 attenuates ERK2-mediated SP signaling in the nucleus to prevent cell death. We propose that agonist availability in endosomes, here regulated by ECE-1, controls ␤-arrestin-dependent signaling of endocytosed GPCRs.Signal transduction at the plasma membrane is tightly regulated by well characterized mechanisms. For the large family of G protein-coupled receptors (GPCRs), 2 regulation of extracellular agonist concentration and receptor coupling to heterotrimeric G proteins control signal transduction. Cell-surface metalloendopeptidases, exemplified by neprilysin, degrade neuropeptides in the extracellular fluid to regulate receptor activation (1, 2). G protein receptor kinases phosphorylate activated GPCRs to promote their interaction with ␤-arrestins, which uncouple receptors from G proteins and mediate desensitization (3). However, activated GPCRs internalize, and endocytosed receptors continue to signal by G protein-independent mechanisms. ␤-Arrestins mediate endocytosis and intracellular signaling of GPCRs. ␤-Arrestins couple GPCRs to clathrin and AP2 to mediate endocytosis (4, 5) and are scaffolds that recruit Src, Raf-1, and mitogen-activated protein kinases (MAPKs) to GPCRs in endosomes forming a MAPK signalosome, which determines the location and function of activated extracellular signal-regulated kinases (ERKs) (6 -9). Compared with our understanding of receptor regulation at the plasma membrane, little is known about the mechanisms that regulate GPCR signaling and trafficking at the endosomal membrane. Specifically, it is not known whether agonist interaction with GPCRs or GPCR interaction with ␤-arrestins is necessary for receptor signaling in endosomes. Regulation of these interactions could determine the duration of ␤-arrestin-mediated ERK activation, with important functional implications (10, 11). We hypothesized that mechanisms that regulate GPCRs at the plasma membrane also control receptor signaling and trafficking at the endosomal membrane. We recently reported t...

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Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor

Cited by 93 publications

References 38 publications

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

Endosomal Endothelin-converting Enzyme-1

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