Neurotensin receptor-1 inducible palmitoylation is required for efficient receptor-mediated mitogenic-signaling within structured membrane microdomains

Heakal, Yasser; Woll, Matthew; Fox, Todd E.; Seaton, Kelly E.; Levenson, Robert; Kester, Mark

doi:10.4161/cbt.12.5.15984

Cited by 34 publications

(31 citation statements)

References 31 publications

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“…Interestingly, the Erk pathway was sensitive to 2BrP but not to Drd3 mutations, indicating that cellular palmitoylation rather than Drd3 palmitoylation is involved in this process, as previously suggested in cancer cells (75). On the contrary, dopamine signaling via the Akt pathway required GIPC1 regardless of 2BrP treatment, given that Drd3⌬C failed to inhibit Akt phosphorylation by dopamine.…”

Section: Discussionmentioning

confidence: 50%

A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling

Arango-Lievano

Şensoy

Borie

et al. 2016

Molecular and Cellular Biology

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f Palmitoylation is involved in several neuropsychiatric and movement disorders for which a dysfunctional signaling of the dopamine D3 receptor (Drd3) is hypothesized. Computational modeling of Drd3's homologue, Drd2, has shed some light on the putative role of palmitoylation as a reversible switch for dopaminergic receptor signaling. Drd3 is presumed to be palmitoylated, based on sequence homology with Drd2, but the functional attributes afforded by Drd3 palmitoylation have not been studied. Since these receptors are major targets of antipsychotic and anti-Parkinsonian drugs, a better characterization of Drd3 signaling and posttranslational modifications, like palmitoylation, may improve the prospects for drug development. Using molecular dynamics simulations, we evaluated in silico how Drd3 palmitoylation could elicit significant remodeling of the C-terminal cytoplasmic domain to expose docking sites for signaling proteins. We tested this model in cellulo by using the interaction of Drd3 with the G-alpha interacting protein (GAIP) C terminus 1 (GIPC1) as a template. From a series of biochemical studies, live imaging, and analyses of mutant proteins, we propose that Drd3 palmitoylation acts as a molecular switch for Drd3-biased signaling via a GIPC1-dependent route, which is likely to affect the mode of action of antipsychotic drugs.

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Section: Discussionmentioning

confidence: 50%

A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling

Arango-Lievano

Şensoy

Borie

et al. 2016

Molecular and Cellular Biology

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“…These findings are in accordance with a recent study that demonstrated the occurrence of a posttranscriptional maturation of the receptor, depending on glycosylation, after serum starvation. This mature NTSR1 is able to recruit small G proteins in membranous microdomains, especially under serum starvation (48). These data suggested that stress-culture conditions of B cell lines induced the maturation of NTSR1 as detected by higher molecular form of this receptor (48).…”

Section: Discussionmentioning

confidence: 68%

“…This mature NTSR1 is able to recruit small G proteins in membranous microdomains, especially under serum starvation (48). These data suggested that stress-culture conditions of B cell lines induced the maturation of NTSR1 as detected by higher molecular form of this receptor (48).…”

Section: Discussionmentioning

confidence: 68%

Differential Expression of Neurotensin and Specific Receptors, NTSR1 and NTSR2, in Normal and Malignant Human B Lymphocytes

Saada

Marget

Fauchais

et al. 2012

The Journal of Immunology

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Neurotensin, a neuropeptide growth factor, and its two specific neurotensin receptors, NTSR1 and NTSR2, were shown to be expressed by human B cell lines. Another NTSR, sortilin, which is common to neurotensin and neurotrophins, was also detected as we have previously described. Neurotensin was functional in B cell lines; it induced their proliferation and inhibited apoptosis induced by serum deprivation or Fas activation. Quantitative study of gene expression in two malignant B cell diseases showed that NTSR2 was overexpressed, NTSR1 decreased, and neurotensin was unexpressed in B cell leukemia patient’s cells, as compared with healthy B cells. However, these expressions did not significantly change in large diffuse B cell lymphoma lymph nodes compared with benign ones. This study points out that neurotensin and its two specific receptors are expressed in human B lymphocytes. Such expressions were not described, and their relationship in B cell diseases, especially in chronic B cell leukemia, needs to be considered further in regard to these findings.

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“…This lipidation allows its localization within cell membrane microdomains and enhances the interaction with Gαq /11 which mainly reside within structured microdomains. This NTSR-1-mediated MAPK signaling and cellular proliferation was demonstrated in breast cancer cells (Heakal et al, 2011). Endocytosis: After activation by neurotensin, NTSR1 is desensitized through its internalization in endosomal vesicles in association with β-arrestin.…”

Section: Localisationmentioning

confidence: 99%

“…Indeed, neurotensin induces Erk phosphorylation colonic HT29 cells through PLC activation leading to Inositol phosphate formation (Massa et al, 2011). The recruitment of G protein was described through NTSR1 activation in microdomains (Heakal et al, 2011). In other cell types, cell proliferation, migration and invasion are depending on a transactivation of EGFR by NTSR1 (Amorino et al, 2007;Moody et al, 2014 ) or act through the increase of expression and activation of EGFR, HER2, HER3 (Younes et al, 2014;Dupouy et al, 2014).…”

Section: Functionmentioning

confidence: 99%

NTSR1 (neurotensin receptor 1 (high affinity))

Saada¹,

Marget²,

Abacci³

et al. 2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Neurotensin receptor-1 inducible palmitoylation is required for efficient receptor-mediated mitogenic-signaling within structured membrane microdomains

Cited by 34 publications

References 31 publications

A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling

A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling

Differential Expression of Neurotensin and Specific Receptors, NTSR1 and NTSR2, in Normal and Malignant Human B Lymphocytes

NTSR1 (neurotensin receptor 1 (high affinity))

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