Functional consequences of alteration of N-linked glycosylation sites on the neurokinin 1 receptor

Tansky, Morris F.; Pothoulakis, Charalabos; Leeman, Susan E.

doi:10.1073/pnas.0703394104

Cited by 54 publications

(60 citation statements)

References 50 publications

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“…One of these may laterally interact with FcεRI through carbohydrate moieties attached to the FcεRIα extracellular domain, thus driving FcεRI to endocytic pathways. Glycosylation of G protein-coupled receptors has been shown to influence the kinetics or routing of endocytosis (43,44). Notably, FcεRI in BDCA1 + DCs appears to be glycosylated distinctly from FcεRI in basophils, as the hFcεRI immunoprecipitated from these DC lysates mobilized, according to SDS-PAGE, at a slightly faster rate.…”

Section: Discussionmentioning

confidence: 99%

Serum IgE clearance is facilitated by human FcεRI internalization

Greer¹,

Wu²,

Putnam³

et al. 2014

J. Clin. Invest.

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The high-affinity IgE receptor FcεRI is constitutively expressed in mast cells and basophils and is required for transmitting stimulatory signals upon engagement of IgE-bound allergens. FcεRI is also constitutively expressed in dendritic cells (DCs) and monocytes in humans; however, the specific functions of the FcεRI expressed by these cells are not completely understood. Here, we found that FcεRI expressed by human blood DC antigen 1-positive (BDCA1 + ) DCs and monocytes, but not basophils, traffics to endolysosomal compartments under steady-state conditions. Furthermore, IgE bound to FcεRI on BDCA1 + DCs was rapidly endocytosed, transported to the lysosomes, and degraded in vitro. IgE injected into mice expressing human FcεRIα (FCER1A-Tg mice) was endocytosed by conventional DCs and monocytes, and endocytosis was associated with rapid clearance of circulating IgE from these mice. Importantly, this rapid IgE clearance was dependent on monocytes or DCs but not basophils. These findings strongly suggest that constitutive internalization of human FcεRI by DCs and monocytes distinctively contributes to serum IgE clearance.

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Section: Discussionmentioning

confidence: 99%

Serum IgE clearance is facilitated by human FcεRI internalization

Greer¹,

Wu²,

Putnam³

et al. 2014

J. Clin. Invest.

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“…SP-NK1R interaction stimulates PKC␦ and activates NF-B, resulting in up-regulation of IL-8 expression (10,11,(13)(14)(15)(16)(17). SP induces IL-8 expression via NK1R in different cell systems, including mast cells (18), NCM 460 cells, a nontransformed human colonic epithelial cell line (13,14,19), human mesenteric preadipocytes (15), human corneal epithelial cells (20), human astrocytoma cell lines (10, 21, 22), but not in human blood mononuclear cells (22), which express only the truncated NK1R (6). The SP activation of NF-B requires mobilization of calcium (G␣ q signal) (10,11).…”

Section: Discussionmentioning

confidence: 99%

“…Full-length NK1R plasmid was a gift from Norma Gerard, Harvard University, Boston, MA; the truncated NK1R (⌬311) cDNA3.1Hygro(ϩ) plasmids were constructed from Lenti6/V5-D-Topo NK1R plasmids (19), which contain full-length wild-type NK1R. Using the lentiviral plasmids as templates, we introduced a premature stop codon at position 312 of the full-length NK1R by using site-directed mutagenesis [forward primer, 5-GCCTCAATGACAGGT-GACGTCTGGGCTTCAAGC-3Ј; reverse primer, 5Ј-GCTTGAAGCCCAGACGTCAC-CTGTCATTGAGGC-3Ј (QuikChange site-directed mutagenesis kit, Stratagene)].…”

Section: Methodsmentioning

confidence: 99%

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

Lai

Tuluc

et al. 2008

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

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The neurokinin-1 receptor (NK1R) has two naturally occurring forms that differ in the length of the carboxyl terminus: a fulllength receptor consisting of 407 aa and a truncated receptor consisting of 311 aa. We examined whether there are differential signaling properties attributable to the carboxyl terminus of this receptor by using stably transfected human embryonic kidney (HEK293) cell lines that express either full-length or truncated NK1R. Substance P (SP) specifically triggered intracellular calcium increase in HEK293 cells expressing full-length NK1R but had no effect in the cells expressing the truncated NK1R. In addition, in cells expressing full-length NK1R, SP activated NF-B and IL-8 mRNA expression, but in cells expressing the truncated NK1R, SP did not activate NF-B, and it decreased IL-8 mRNA expression. In cells expressing full-length NK1R, SP stimulated phosphorylation of PKC␦ but inhibited phosphorylation of PKC␦ in cells expressing truncated NK1R. There are also differences in the timing of SPinduced ERK activation in cells expressing the two different forms of the receptor. Full-length NK1R activation of ERK was rapid (peak within 1-2 min), whereas truncated NK1R-mediated activation was slower (peak at 20 -30 min). Thus, the carboxyl terminus of NK1R is the structural basis for differences in the functional properties of the full-length and truncated NK1R. These differences may provide important information toward the design of new NK1R receptor antagonists.G protein-coupled receptor ͉ cell signaling ͉ Substance P ͉ truncated neurokinin-1 ͉ calcium mobilization

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“…SP binds with varying affinities to 3 G protein-coupled, 7-transmembrane receptors: neurokinin (NK)1, NK2, and NK3 (6,10). NK1 and NK2 have been reported on BCCs.…”

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confidence: 99%

RE-1–silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells

Reddy¹,

Greco²,

Patel

et al. 2009

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

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Breast cancer remains the most prevalent cancer among women in the United States. Substance P, a peptide derived from the TAC1 gene, mediates oncogenic properties in breast and other cancers. TAC1 expression facilitates the entry of breast cancer cells into bone marrow. The transcriptional repressor element 1-silencing transcription factor (REST) has been implicated in both oncogenic and tumor-suppressor functions. REST binds to the 5 untranslated region of the TAC1 promoter and suppresses its expression. This study investigated a role for REST in TAC1 induction in breast cancer. Western blots and real-time PCR indicated that REST expression in breast cancer cells was inversely proportional to the cells' aggressiveness, for both cell lines and primary breast cancer cells. REST knockdown in low-metastatic T47D cells and nontumorigenic MCF12A cells resulted in increases in TAC1 induction, proliferation, and migration. These parameters were negatively affected by ectopic expression of REST in highly aggressive MDA-MB-231 cells. Together, these findings show a central role for REST in the oncogenic function of TAC1 and suggest a tumor-suppressor role for REST in breast cancer.REST ͉ substance P ͉ tachykinin D espite advances in diagnostic technologies and treatments, breast cancer (BC) continues to be among the leading causes of cancer-related deaths among women (1). The TAC1 gene has been implicated in the development of breast and other cancers (2-4). TAC1 (preprotachykinin-A) is a single-copy gene with 7 exons (5). Through alternative splicing and posttranslational modification, TAC1 produces peptides belonging to the tachykinin family (5-7). Substance P (SP) is the predominant peptide produced from TAC1 (8, 9).BC cells (BCCs) produce high levels of SP (6). SP binds with varying affinities to 3 G protein-coupled, 7-transmembrane receptors: neurokinin (NK)1, NK2, and NK3 (6, 10). NK1 and NK2 have been reported on BCCs. SP mediates BCC proliferation, imparts radiation resistance, protects from apoptosis, induces growth-and angiogenic-promoting factors, and facilitates BC metastasis to bone marrow (2,4,11,12). The truncated NK1 has also been linked to oncogenesis, partly through the induction of TAC1 (2).Stromal-derived factor-1␣, which is implicated in BC biology, regulates TAC1 expression (4, 13). Other cytokines also induce TAC1 expression in BCCs via autocrine stimulation (2, 14). RE-1 silencer of transcription (REST) represses TAC1 expression in mesenchymal stem cells (15). The link between REST and TAC1 could be relevant to disorders such as tumorigenesis and hippocampal seizure (16).REST, also known as neural restrictive silencing factor, is a zinc finger transcriptional repressor of neuronal genes in nonneuronal and immature neuronal cells (17). REST facilitates chromatin remodeling and inhibits gene expression by assembling a repressor complex (18), Sin3A/histone deacetylase, and co-REST at the N and C termini, respectively (18). REST has been implicated in both oncogenic and tumor-suppressor roles (19,20)....

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Functional consequences of alteration of N-linked glycosylation sites on the neurokinin 1 receptor

Cited by 54 publications

References 50 publications

Serum IgE clearance is facilitated by human FcεRI internalization

Serum IgE clearance is facilitated by human FcεRI internalization

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

RE-1–silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells

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